97 results on '"Lyle R. McKinnon"'
Search Results
2. Non-Lactobacillus-Dominant and Polymicrobial Vaginal Microbiomes Are More Common in Younger South African Women and Predictive of Increased Risk of Human Immunodeficiency Virus Acquisition
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Yiran Wang, Laura Noël-Romas, Michelle Perner, Samantha Knodel, Refilwe Molatlhegi, Sarah Hoger, Kenzie Birse, Christina Farr Zuend, Lyle R McKinnon, and Adam D Burgener
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Microbiology (medical) ,Infectious Diseases - Abstract
Background Adolescent girls and young women aged 15‒24 years in sub-Saharan Africa are at disproportionate risk of human immunodeficiency virus (HIV) infection. Given the known association between vaginal microbial dysbiosis and HIV susceptibility, we performed an age-stratified analysis of the vaginal microbiome in South African women and compared this to their risk of HIV acquisition. Methods Vaginal microbiome data were generated by mass spectrometry–based proteomic analysis of cervicovaginal lavages collected from participants (n = 688) in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial. Participants were grouped by age (18–19 years, n = 93; 20–24 years, n = 326; 25–41 years, n = 269). Results Four microbiome types were identified based on predominant taxa, including Lactobacillus crispatus (CST-LC, 12.2%), Lactobacillus iners (CST-LI, 43.6%), Gardnerella vaginalis (CST-GV, 26.6%), or polymicrobial (CST-PM, 15.1%). Women aged 18–19 and 20–24 years had increased CST-PM and a non-Lactobacillus-dominant microbiome compared to those 25–41 years (odds ratio [OR], 3.14 [95% confidence interval {CI}, 1.12–7.87], P = .017; OR, 2.81 [95% CI, 1.07–7.09], P = .038, respectively; and OR, 1.65 [95% CI, 1.02–2.65], P = .028; OR, 1.40 [95% CI, 1.01–1.95], P = .030, respectively). The HIV incidence rate of women with CST-PM microbiome was 7.19-fold higher compared to women with CST-LC (hazard ratio [HR], 7.19 [95% CI, 2.11–24.5], P = .00162), which was also consistent in women aged 20–24 years (HR, 4.90 [95% CI, 1.10–21.9], P = .0375). Conclusions Younger women were more likely to have a higher-risk polymicrobial microbiome suggesting that vaginal microbiota are contributing to increased HIV-1 susceptibility in this group. Clinical Trials Registration NCT00441298.
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- 2022
3. Geographical associations of HIV prevalence in female sex workers from Nairobi, Kenya (2014-2017)
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Souradet Y. Shaw, Neil Reed, Tabitha Dipl Wanjiru, Festus Muriuki, Julius Dipl Munyao, Maureen Akolo, Achieng Tago, Lawrence Gelmon, Joshua Kimani, and Lyle R. McKinnon
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Infectious Diseases ,Pharmacology (medical) - Published
- 2023
4. High prevalence of vaccine‐preventable anal human papillomavirus infections is associated with <scp>HIV</scp> infection among gay, bisexual, and men who have sex with men in Nairobi, Kenya
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Myo Minn Oo, Samantha Moore, Suzanne Gibbons, Wendy Adhiambo, Peter Muthoga, Naomi Siele, Maureen Akolo, Henok Gebrebrhan, Aida Sivro, Blake T. Ball, Robert R. Lorway, Alberto Severini, Joshua Kimani, and Lyle R. McKinnon
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Cancer Research ,Oncology ,Radiology, Nuclear Medicine and imaging - Published
- 2023
5. Nonoptimal bacteria species induce neutrophil-driven inflammation and barrier disruption in the female genital tract
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Marina Costa-Fujishima, Atta Yazdanpanah, Samantha Horne, Alana Lamont, Paul Lopez, Christina Farr Zuend, Kenzie Birse, Morgan Taverner, Riley Greenslade, Max Abou, Laura Noel-Romas, Bernard Abrenica, Oluwaseun Ajibola, Nnamdi Ikeogu, Ruey-Chyi Su, Lyle R. McKinnon, Helen Pymar, Vanessa Poliquin, Alicia R. Berard, Adam D. Burgener, and Thomas T. Murooka
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Immunology ,Immunology and Allergy - Published
- 2023
6. TEMPORAL TRENDS AND TRANSMISSION DYNAMICS OF PRE-TREATMENT HIV-1 DRUG RESISTANCE WITHIN AND BETWEEN RISK GROUPS IN KENYA, 1986-2020
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George M. Nduva, Frederick Otieno, Joshua Kimani, Yiakon Sein, Dawit A. Arimide, Lyle R. McKinnon, Francois Cholette, Morris K. Lawrence, Maxwell Majiwa, Moses Masika, Gaudensia Mutua, Omu Anzala, Susan M. Graham, Larry Gelmon, Matt A. Price, Adrian D. Smith, Robert C. Bailey, Patrik Medstrand, Eduard J. Sanders, Joakim Esbjörnsson, and Amin S. Hassan
- Abstract
BackgroundEvidence on the distribution of pre-treatment HIV-1 drug resistance (HIVDR) by risk groups is limited in Africa. We assessed prevalence, trends, and transmission dynamics of pre-treatment HIVDR within-and-between men who have sex with men (MSM), people who inject drugs (PWID), female sex workers (FSW), heterosexuals (HET), and children infected perinatally in Kenya.MethodsHIV-1 partialpolsequences from antiretroviral-naïve samples collected between 1986-2020 were used. Pre-treatment RTI, PI and INSTI mutations were assessed using the Stanford HIVDR database. Phylogenetics methods were used to determine and date transmission clusters.ResultsOf 3567 sequences analysed, 550 (15.4%, 95% CI: 14.2-16.6) had at least one pre-treatment HIVDR mutation, which was most prevalent amongst children (41.3%), followed by PWID (31.0%), MSM (19.9%), FSW (15.1%) and HET (13.9%). No INSTI resistance mutations were detected. Among HET, pre-treatment HIVDR increased from 6.6% in 1986-2005 to 20.2% in 2011-2015 but dropped to 6.5% in 2016-2020. Overall, 22 clusters with shared pre-treatment HIVDR mutations were identified. The largest was a K103N mutation cluster involving 16 MSM sequences sampled between 2010-2017, with an estimated tMRCA of 2005 (HPD, 2000-2008). This lineage had a growth rate=0.1/year and R0=1.1, indicating propagation over 12 years among ART-naïve MSM in Kenya.ConclusionsCompared to HET, children and key populations had higher levels of pre-treatment HIVDR. Introduction of INSTIs after 2016 may have reversed the increase in pre-treatment RTI mutations in Kenya. Continued surveillance of HIVDR, with a particular focus on children and key populations, is warranted to inform treatment strategies in Kenya.SummaryCompared to the heterosexual population, key populations had higher levels of pre-treatment HIV-1 drug resistance (HIVDR). Propagation of HIVDR was risk-group exclusive. Introduction of integrase inhibitors abrogated propagation of reverse transcriptase inhibitors mutations among the heterosexual, but not key populations.
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- 2023
7. Socioeconomic Burdens of the COVID-19 Pandemic on LMIC Populations with Increased HIV Vulnerabilities
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Sushena Reza-Paul, Marissa Becker, Joshua Kimani, Robert Lorway, Olga Balakireva, Daria Pavlova, Lyle R. McKinnon, Leigh M McClarty, Tetiana Tarasova, and Lisa Lazarus
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medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,HIV Infections ,Context (language use) ,Violence ,Virology ,Environmental health ,Pandemic ,medicine ,Humans ,Developing Countries ,Pandemics ,Socioeconomic status ,Sex work ,Sex Workers ,SARS-CoV-2 ,Public health ,COVID-19 ,HIV ,Key populations ,Implementation Science (E Geng, Section Editor) ,Livelihood ,Mental health ,Infectious Diseases ,Geography ,Socioeconomic Factors ,Communicable Disease Control ,Community responses - Abstract
Purpose of Review To review the impact of the COVID-19 pandemic and its public health response on key populations at risk of HIV infection, with a focus on sex workers. Recent Findings Since last year several groups have documented how the COVID-19 pandemic has impacted the livelihoods and health of sex workers. We focus on case studies from Kenya, Ukraine, and India and place these in the broader global context of sex worker communities, drawing on common themes that span geographies. Summary COVID-19-associated lockdowns have significantly disrupted sex work, leading to economic and health challenges for sex workers, ranging from HIV-related services to mental health and exposure to violence. Several adaptations have been undertaken by sex workers and frontline workers, including migration, a move to mobile services, and struggling to find economic supports. Strengthening community-based responses for future pandemics and other shocks is critical to safeguard the health of marginalized populations.
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- 2021
8. Non-Lactobacillus dominant and polymicrobial vaginal microbiomes are more common in younger South African women and predictive of increased risk of HIV acquisition
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Yiran, Wang, Laura, Noël-Romas, Michelle, Perner, Samantha, Knodel, Refilwe, Molatlhegi, Sarah, Hoger, Kenzie, Birse, Christina Farr, Zuend, Lyle R, McKinnon, and Adam D, Burgener
- Abstract
Adolescent girls and young women aged 15-24 in sub-Saharan Africa are at disproportionate risk of HIV infection. Given the known association between vaginal microbial dysbiosis and HIV susceptibility, we performed an age-stratified analysis of the vaginal microbiome in South African women and compared this to their risk of HIV acquisition.Vaginal microbiome data were generated by mass spectrometry-based proteomic analysis of cervicovaginal lavages collected from participants (n = 688) in the CAPRISA 004 trial. Participants were grouped by age (18-19 years old (y), n = 93; 20-24y, n = 326; 25-41y, n = 269).Four microbiome types were identified based on predominant taxa including: L. crispatus (CST-LC, 12.2%), L. iners (CST-LI, 43.6%), G. vaginalis (CST-GV, 26.6%) or polymicrobial (CST-PM, 15.1%). Compared to the 25-41y group, 18-19y and 20-24y women increased CST-PM and a non-Lactobacillus-dominant (nLD) microbiome (OR = 3.14, 95% CI: 1.12-7.87, P = 0.017; OR = 2.81, 95% CI: 1.07-7.09, P = 0.038, respectively; and OR = 1.65, 95% CI: 1.02-2.65, P = 0.028; OR = 1.40, 95% CI: 1.01-1.95, P = 0.030, respectively). Compared to 25-41y women, 18-19y women were more likely to have increased abundance of Megasphaera (L2FD = 1.72, P = 0.0023, adj. P = 0.0498). HIV incidence rate of women with CST-PM microbiome was 7.19-fold higher compared to women with CST-LC in all study participants (HR = 7.19, 95% CI: 2.11-24.5, P = 0.00162), which was also consistent in 20-24y women (HR = 4.90, 95% CI: 1.10-21.9, P = 0.0375).Younger women were more likely to have a higher risk polymicrobial microbiome that associated with substantial increased risk of HIV acquisition. These data suggest that the vaginal microbiota is a contributing factor to increased HIV-1 susceptibility in younger women.
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- 2022
9. Expansion of cytotoxic tissue-resident CD8+ T cells and CCR6+CD161+ CD4+ T cells in the nasal mucosa following mRNA COVID-19 vaccination
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Aloysious Ssemaganda, Huong Mai Nguyen, Faisal Nuhu, Naima Jahan, Catherine M. Card, Sandra Kiazyk, Giulia Severini, Yoav Keynan, Ruey-Chyi Su, Hezhao Ji, Bernard Abrenica, Paul J. McLaren, T. Blake Ball, Jared Bullard, Paul Van Caeseele, Derek Stein, and Lyle R. McKinnon
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Vaccines against SARS-CoV-2 have shown high efficacy in clinical trials, yet a full immunologic characterization of these vaccines, particularly within the human upper respiratory tract, is less well known. Here, we enumerate and phenotype T cells in nasal mucosa and blood using flow cytometry before and after vaccination with the Pfizer-BioNTech COVID-19 vaccine (n = 21). Tissue-resident memory (Trm) CD8+ T cells expressing CD69+CD103+ increase in number ~12 days following the first and second doses, by 0.31 and 0.43 log10 cells per swab respectively (p = 0.058 and p = 0.009 in adjusted linear mixed models). CD69+CD103+CD8+ T cells in the blood decrease post-vaccination. Similar increases in nasal CD8+CD69+CD103− T cells are observed, particularly following the second dose. CD4+ cells co-expressing CCR6 and CD161 are also increased in abundance following both doses. Stimulation of nasal CD8+ T cells with SARS-CoV-2 spike peptides elevates expression of CD107a at 2- and 6-months (p = 0.0096) post second vaccine dose, with a subset of donors also expressing increased cytokines. These data suggest that nasal T cells may be induced and contribute to the protective immunity afforded by this vaccine.
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- 2022
10. An urgent call to include men who have sex with men in the HPV immunisation programme in Kenya
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Robert R Lorway, Pascal Macharia, John Maina, John Mathenge, Samuel Anyula Gorigo, Lyle R McKinnon, Parinita Bhattacharjee, Peter Arimi, Souradet Shaw, Yoav Keynan, Stephen Moses, Joshua Kimani, Marissa L Becker, Sharmistha Mishra, Lisa Lazarus, and Matthew Thomann
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Male ,Sexual and Gender Minorities ,Immunization Programs ,Health Policy ,Papillomavirus Infections ,Public Health, Environmental and Occupational Health ,Humans ,Homosexuality, Male ,Kenya - Published
- 2022
11. Viral suppression among pregnant adolescents and women living with HIV in rural KwaZulu-Natal, South Africa: a cross sectional study to assess progress towards UNAIDS indicators and Implications for HIV Epidemic Control
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Nonzwakazi P. Ntombela, Ayesha B. M. Kharsany, Adenike Soogun, Nonhlanhla Yende-Zuma, Cheryl Baxter, Hans-Peter Kohler, Lyle R. McKinnon, and University of Manitoba
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Adult ,Acquired Immunodeficiency Syndrome ,Adolescent ,Anti-HIV Agents ,Obstetrics and Gynecology ,HIV Infections ,Viral Load ,Infectious Disease Transmission, Vertical ,South Africa ,Young Adult ,Cross-Sectional Studies ,Reproductive Medicine ,Pregnancy ,Humans ,Female ,Pregnant Women ,Aged - Abstract
Background South Africa has made significant progress in scaling up antiretroviral therapy (ART) to achieve the aspirational goal of HIV epidemic control. The aim of this study was to determine the prevalence of HIV, assess progress towards each of the Joint United Nations Programme on HIV/AIDS (UNAIDS) indicators and determine factors associated with achieving viral suppression among pregnant adolescents and women living with HIV in rural KwaZulu-Natal, South Africa. Methods Pregnant adolescents and women, 12 years and older seeking antenatal care at six primary health care clinics were enrolled in a cross-sectional study. Following written informed consent, structured questionnaires were administered, and finger-prick blood samples were collected for HIV antibody testing and viral load measurement. Viral suppression was defined as HIV viral load of Results Between Dec 2016 and March 2017, among the 546 enrolled participants, data for 545 were analysed. The overall HIV prevalence was 40.2% [95% Confidence Interval (CI) 36.1–44.3]. Age-stratified prevalence increased from 22.1% (95% CI, 15.9–30.0) in the 14–19 year age group to 63.9% (95% CI, 55.1–71.9) among women ≥ 30 years (Χ2 trend P P Conclusions The proportion of HIV positive pregnant women achieving viral suppression was encouraging though far short of the target towards achieving epidemic control. Importantly, adolescent pregnant women were less likely to know their HIV status and to achieve viral suppression, underscoring the public health implications of sustained risk of HIV transmission. Thus, greater effort and strong social support are essential to improve HIV knowledge of status and care continuum towards the goal to achieving HIV epidemic control. Plain language summary To “fast-track” the response to achieve HIV epidemic control and end the AIDS epidemic, the Joint United Nations Programme on HIV/AIDS (UNAIDS) set ambitious HIV testing and treatment targets for people living with HIV. Meeting these targets through scaling up testing for HIV, initiating and sustaining antiretroviral therapy (ART) to maintain viral suppression provides both therapeutic and preventive benefits with the potential to reduce HIV transmission. Viral suppression among pregnant adolescents and women living with HIV is crucial for the prevention of mother-to-child transmission of HIV including onward transmission to sexual partners. As a public health approach, in South Africa all pregnant women are offered routine HIV testing and immediate initiation of lifelong ART irrespective of CD4 cell count. It is, therefore, important to ascertain progress towards reaching the targets. The proportion of HIV positive pregnant adolescents and women achieving viral suppression was encouraging though far short of the target towards achieving epidemic control. Importantly, pregnant adolescents were less likely to know their HIV status and to achieve viral suppression, underscoring the public health implications of sustained risk of HIV transmission. Thus, greater effort and strong social support are essential to improve HIV knowledge of status and care continuum towards the goal to achieving HIV epidemic control.
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- 2022
12. Impact of point-of-care testing and treatment of sexually transmitted infections and bacterial vaginosis on genital tract inflammatory cytokines in a cohort of young South African women
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Jo-Ann S. Passmore, Anne Rompalo, Nigel Garrett, Ayesha B. M. Kharsany, Lindi Masson, Andile Mtshali, Ravesh Singh, Lenine J. P. Liebenberg, Salim S. Abdool Karim, Koleka Mlisana, Lyle R. McKinnon, Farzana Osman, Nireshni Mitchev, Hope Ngobese, and Adrian Mindel
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Adult ,Chemokine ,Adolescent ,medicine.medical_treatment ,Sexually Transmitted Diseases ,Dermatology ,medicine.disease_cause ,Reproductive Tract Infections ,Proinflammatory cytokine ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Prospective Studies ,030212 general & internal medicine ,Macrophage inflammatory protein ,030304 developmental biology ,Inflammation ,0303 health sciences ,biology ,business.industry ,Vaginosis, Bacterial ,medicine.disease ,Anti-Bacterial Agents ,Infectious Diseases ,Cytokine ,Point-of-Care Testing ,Vagina ,Immunology ,biology.protein ,Cytokines ,Female ,Trichomonas vaginalis ,Nugent score ,Bacterial vaginosis ,business ,Chlamydia trachomatis - Abstract
ObjectivesSTIs cause inflammation that is detrimental for both HIV risk and reproductive health. We assessed the impact of point-of-care (POC) STI testing, immediate treatment and expedited partner therapy (EPT) on genital tract cytokines among a cohort of young South African women.MethodsHIV-negative women underwent POC testing for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) by Xpert CT/NG and OSOM TV, and for bacterial vaginosis (BV) by microscopy. Women with STIs and/or BV received immediate treatment, EPT for STIs and retested after 6 and 12 weeks. Concentrations of 48 cytokines were measured in cervicovaginal fluid at each visit using multiplex ELISA technology. The impact of STI treatment on cytokine concentrations was assessed by multivariable linear mixed models and principal component analysis.ResultsThe study enrolled 251 women with median age of 23 years (IQR 21–27). The prevalence of CT, NG and TV were 14.3%, 4.4% and 4.0%, and 34.3% had BV. Women with STIs or BV at baseline (n=94) had significantly higher concentrations of pro-inflammatory cytokines (interleukin (IL)-1α, IL-1β, IL-6, tumour necrosis factor (TNF)-α, TNF-β, IL-18 and macrophage inflammatory factor (MIF)) and chemokines (IL-8, IL-16, macrophage inflammatory protein (MIP)-1α, IFN-α2, monokine induced by gamma interferon (MIG), monocyte chemoattractant protein (MCP)-3, regulated on activation normal T cell expressed and secreted and eotaxin) compared with women without (n=157). STI treatment was strongly associated with reduced concentrations of pro-inflammatory cytokines IL-6 (p=0.004), IL-1β (p=0.013), TNF-α (p=0.018) and chemokines MIG (p=0.008) and growth-related oncogene (GRO)-α (p=0.025). A lower Nugent score was associated with a reduction in pro-inflammatory cytokines IL-1α (p=0.003), TNF-related apoptosis-inducing ligand (p=0.004), MIF (p=0.010) and IL-18 (pConclusionsA comprehensive STI intervention effectively reduced genital inflammation among young women, thereby improving vaginal health and potentially reducing HIV risk.
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- 2021
13. Prevalence and Risk Factors for HIV Infection Among Heterosexual Men Recruited from Socializing Venues in Rural KwaZulu-Natal, South Africa
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Hans-Peter Kohler, Nonhlanhla Yende-Zuma, Lyle R. McKinnon, Ayesha B. M. Kharsany, Nonzwakazi P Ntombela, and Adenike Soogun
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Adult ,Male ,Rural Population ,medicine.medical_specialty ,Social Psychology ,Population ,HIV Infections ,Article ,Gee ,South Africa ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Interquartile range ,Prevalence ,medicine ,Humans ,030212 general & internal medicine ,Heterosexuality ,education ,Generalized estimating equation ,education.field_of_study ,030505 public health ,business.industry ,Public health ,Public Health, Environmental and Occupational Health ,Odds ratio ,Confidence interval ,Infectious Diseases ,0305 other medical science ,business ,Serostatus ,Demography - Abstract
Young heterosexual men have low uptake of HIV prevention and treatment services and represent an important key population that may require novel strategies. We recruited 1271 heterosexual men, 12 years and older from socializing venues such as “shebeens”, transport hubs, “spaza” shops, and community centers in rural KwaZulu-Natal, South Africa. Participants completed a questionnaire and were tested for HIV serostatus. Generalized estimating equations (GEE) with exchangeable covariance structure estimated factors independently associated with prevalent HIV infection. Median age was 25 years [Interquartile range (IQR) 21–29]. HIV prevalence was 15.5% [95% confidence interval (CI) 11.0–21.9] and increased significantly by age. Factors associated with higher odds of HIV infection were being 25 years and older [adjusted odds ratio (aOR) 4.82, 95% CI 3.47–6.69; p
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- 2021
14. Declines in HIV prevalence in female sex workers accessing an HIV treatment and prevention programme in Nairobi, Kenya over a 10-year period
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Gloria Gakii, Souradet Y. Shaw, Achieng Tago, Julius Munyao, Lawrence Gelmon, Tabitha Wanjiru, Festus K. Muriuki, Anthony Kariri, Neil Reed, Lyle R. McKinnon, Maureen Akolo, and Joshua Kimani
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0301 basic medicine ,Vaginal discharge ,Immunology ,Population ,HIV Infections ,Hiv testing ,law.invention ,Condoms ,Continuous variable ,03 medical and health sciences ,0302 clinical medicine ,Condom ,law ,Prevalence ,Humans ,Immunology and Allergy ,Medicine ,030212 general & internal medicine ,Hiv treatment ,education ,education.field_of_study ,Sex Workers ,business.industry ,virus diseases ,Female sex ,Hiv prevalence ,Kenya ,Cross-Sectional Studies ,030104 developmental biology ,Infectious Diseases ,Female ,medicine.symptom ,business ,Demography - Abstract
OBJECTIVES Empirical time trends in HIV prevalence in female sex workers (FSWs) are helpful to understand the evolving HIV epidemic, and to monitor the scale-up, coverage, and impact of ongoing HIV prevention and treatment programmes. DESIGN Serial HIV prevalence study. METHODS We analyzed time trends in HIV prevalence in FSWs accessing services at seven Sex Worker Outreach Programme (SWOP) clinics in Nairobi from 2008 to 2017 (N = 33 560). The Mantel--Haenszel test for trend and independent samples Kruskal--Wallis test were used to analyze categorical and continuous variables, respectively. Multivariable binomial regression was used to estimate prevalence ratios/year, adjusting for several covariates. RESULTS HIV prevalence decreased over time in all age groups. This was particularly evident among FSWs less than 25 years of age; HIV was 17.5% in 2008-2009, decreasing to 12.2% in 2010-2011, 8.3% in 2012-2013, 7.3% in 2014-2015, and 4.8% in 2016-2017 (P
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- 2021
15. Quantifying rates of HIV-1 flow between risk groups and geographic locations in Kenya: A country-wide phylogenetic study
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George M Nduva, Frederick Otieno, Joshua Kimani, Elizabeth Wahome, Lyle R McKinnon, Francois Cholette, Maxwell Majiwa, Moses Masika, Gaudensia Mutua, Omu Anzala, Susan M Graham, Larry Gelmon, Matt A Price, Adrian D Smith, Robert C Bailey, Guy Baele, Philippe Lemey, Amin S Hassan, Eduard J Sanders, and Joakim Esbjörnsson
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DRUG-RESISTANCE ,Science & Technology ,POPULATION-DYNAMICS ,transmission ,virus diseases ,MEN ,HIGH-PREVALENCE ,molecular epidemiology ,PREVENTION ,Microbiology ,MOLECULAR EPIDEMIOLOGY REVEALS ,Virology ,HIV-1 ,key populations ,FEMALE SEX WORKERS ,TRANSMISSION NETWORKS ,SUB-SAHARAN AFRICA ,Life Sciences & Biomedicine ,TYPE-1 - Abstract
In Kenya, HIV-1 key populations including men having sex with men (MSM), people who inject drugs (PWID) and female sex workers (FSW) are thought to significantly contribute to HIV-1 transmission in the wider, mostly heterosexual (HET) HIV-1 transmission network. However, clear data on HIV-1 transmission dynamics within and between these groups are limited. We aimed to empirically quantify rates of HIV-1 flow between key populations and the HET population, as well as between different geographic regions to determine HIV-1 'hotspots' and their contribution to HIV-1 transmission in Kenya. We used maximum-likelihood phylogenetic and Bayesian inference to analyse 4058 HIV-1 pol sequences (representing 0.3 per cent of the epidemic in Kenya) sampled 1986-2019 from individuals of different risk groups and regions in Kenya. We found 89 per cent within-risk group transmission and 11 per cent mixing between risk groups, cyclic HIV-1 exchange between adjoining geographic provinces and strong evidence of HIV-1 dissemination from (i) West-to-East (i.e. higher-to-lower HIV-1 prevalence regions), and (ii) heterosexual-to-key populations. Low HIV-1 prevalence regions and key populations are sinks rather than major sources of HIV-1 transmission in Kenya. Targeting key populations in Kenya needs to occur concurrently with strengthening interventions in the general epidemic. ispartof: VIRUS EVOLUTION vol:8 issue:1 ispartof: location:England status: published
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- 2022
16. Sexual health among Kenyan male sex workers in a time of COVID-19
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Robert Lorway, John Mathenge, Lyle R. McKinnon, Erastus Ndunda, Samantha Moore, Pascal Macharia, and Lisa Lazarus
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Government ,Kenya ,030505 public health ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Public Health, Environmental and Occupational Health ,Human sexuality ,Mental health ,Men who have sex with men ,03 medical and health sciences ,0302 clinical medicine ,Environmental health ,Pandemic ,030212 general & internal medicine ,0305 other medical science ,business ,Psychology ,Reproductive health - Abstract
Objective: This report identifies the profound effects that the COVID-19 pandemic and the resultant government lockdown have had on sexual health services delivery to a community of marginalised male sex workers in Nairobi, Kenya. Methods: Based on the experiences shared during ongoing virtual conversations with peer health workers, a case study was developed to identify the challenges encountered by peer health workers. Findings: Peer health workers confronted the new health crisis surrounding COVID-19 while also persisting in their efforts to deliver HIV services to male sex workers. Unable to receive status as ‘essential workers’, their actions often fell short in efforts to maintain male sex workers’ access to vital HIV prevention, treatment and care resources. Conclusion: The struggles encountered, amid dwindling resources, underscore the vital work needed to meet the health needs of a marginalised group that remains largely excluded from the government health system.
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- 2020
17. Phylogeographic Assessment Reveals Geographic Sources of HIV-1 Dissemination Among Men Who Have Sex With Men in Kenya
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George M, Nduva, Frederick, Otieno, Joshua, Kimani, Lyle R, McKinnon, Francois, Cholette, Paul, Sandstrom, Susan M, Graham, Matt A, Price, Adrian D, Smith, Robert C, Bailey, Amin S, Hassan, Joakim, Esbjörnsson, and Eduard J, Sanders
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HIV-1 transmission dynamics involving men who have sex with men (MSM) in Africa are not well understood. We investigated the rates of HIV-1 transmission between MSM across three regions in Kenya: Coast, Nairobi, and Nyanza. We analyzed 372 HIV-1 partial
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- 2021
18. Endocervical Regulatory T Cells Are Associated With Decreased Genital Inflammation and Lower HIV Target Cell Abundance
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Amy Lee, François Cholette, Apollo Gitau, Joshua Kimani, Lyle R. McKinnon, Tabitha Wanjiru, Wendy Adhiambo, Henok Gebrebrhan, Faisal Nuhu, Tosin E. Omole, Naima Jahan, Ruth S. Mwatelah, Michelle Perner, Peter M. Wambugu, Aloysious Ssemaganda, and Cheli Kambaran
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Adult ,CD4-Positive T-Lymphocytes ,Eotaxin ,T cell ,Immunology ,Cell ,HIV Infections ,chemical and pharmacologic phenomena ,Context (language use) ,Inflammation ,Cervix Uteri ,Biology ,regulatory T cells ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Immunology and Allergy ,CTLA-4 Antigen ,030212 general & internal medicine ,IL-2 receptor ,Tissue homeostasis ,Original Research ,vaginal microbiota ,030304 developmental biology ,0303 health sciences ,Microbiota ,HIV ,FOXP3 ,Forkhead Transcription Factors ,hemic and immune systems ,RC581-607 ,medicine.anatomical_structure ,inflammation ,Vagina ,female genital tract ,Cytokines ,Female ,Immunologic diseases. Allergy ,medicine.symptom ,030215 immunology - Abstract
Regulatory T cells (Tregs) play important roles in tissue homeostasis, but few studies have investigated tissue Tregs in the context of genital inflammation, HIV target cell density, and vaginal microbiota in humans. In women from Nairobi (n=64), the proportion of CD4+ CD25+ CD127lowTregs in the endocervix correlated with those in blood (r=0.31, p=0.01), with a higher Treg frequency observed in the endocervix (median 3.8vs2.0%, pvs6.0%, pLactobacillusdominant vaginal microbiota, which was not associated with endocervical Tregs or CD4+ T cell abundance. In a multivariable linear regression, endocervical Treg proportions were inversely associated with the number of elevated pro-inflammatory cytokines (p=0.03). Inverse Treg associations were also observed for specific cytokines including IL-1β, G-CSF, Eotaxin, IL-1RA, IL-8, and MIP-1 β. Higher endocervical Treg proportions were associated with lower abundance of endocervical CD4+ T cells (0.30 log10CD4+ T cells per log10Treg, p=0.00028), with a similar trend for Th17 cells (p=0.09). Selectively increasing endocervical Tregs may represent a pathway to reduce genital tract inflammation in women.
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- 2021
19. Genital Immune Cell Activation and Tenofovir Gel Efficacy: A Case-Control Study
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Lenine J P Liebenberg, Jo Ann S Passmore, Farzana Osman, Janine Jewanraj, Andile Mtshali, J Gerardo Garcia-Lerma, Walid Heneine, Angela Holder, Derseree Archary, Sinaye Ngcapu, Aida Sivro, Leila E Mansoor, Quarraisha Abdool Karim, Salim S Abdool Karim, and Lyle R McKinnon
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Microbiology (medical) ,Infectious Diseases ,Deoxyadenosines ,Anti-HIV Agents ,Case-Control Studies ,Brief Report ,Emtricitabine ,Humans ,Female ,HIV Infections ,Pre-Exposure Prophylaxis ,Genitalia ,Tenofovir - Abstract
Genital inflammation (GI) undermines topical human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) efficacy through unknown mechanisms. Here, associations between activated endocervical CD4 + T-cell numbers and higher deoxyadenosine triphosphate (dATP) concentrations suggest that competition for intracellular metabolites within HIV target cells may reduce the efficacy of antiretroviral-based PrEP in women with GI.
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- 2021
20. Higher Mucosal Antibody Concentrations in Women with Genital Tract Inflammation
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Lyle R. McKinnon, Cheryl Baxter, Salim S. Abdool Karim, Thevani Pillay, Lenine J. P. Liebenberg, Derseree Archary, Parveen Sobia, Quarraisha Abdool Karim, Leila E. Mansoor, Farzana Osman, Aida Sivro, and Jo-Ann S. Passmore
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Adolescent ,Science ,Immunology ,Immunoglobulins ,Diseases ,Inflammation ,HIV Antibodies ,Article ,Antibodies ,Double-Blind Method ,Humans ,Medicine ,Tenofovir ,Retrospective Studies ,Mucous Membrane ,Multidisciplinary ,business.industry ,Genitalia, Female ,Case-Control Studies ,Genital tract ,Cytokines ,Female ,Mucosal antibodies ,medicine.symptom ,business - Abstract
Inflammatory cytokines augment humoral responses by stimulating antibody production and inducing class-switching. In women, genital inflammation (GI) significantly modifies HIV risk. However, the impact of GI on mucosal antibodies remains undefined. We investigated the impact of GI, pre-HIV infection, on antibody isotypes and IgG subclasses in the female genital tract. Immunoglobulin (Ig) isotypes, IgG subclasses and 48 cytokines were measured prior to HIV infection in cervicovaginal lavages (CVL) from 66 HIV seroconverters (cases) and 66 matched HIV-uninfected women (controls) enrolled in the CAPRISA 004 and 008 1% tenofovir gel trials. Pre-HIV infection, cases had significantly higher genital IgM (4.13; IQR, 4.04–4.19) compared to controls (4.06; IQR, 3.90–4.20;p = 0.042). More than one-quarter of cases (27%) had GI compared to just over one-tenth (12%) in controls. Significantly higher IgG1, IgG3, IgG4 and IgM (allp p
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- 2021
21. Endothelial Cells Promote Productive HIV Infection of Resting CD4
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Catherine M, Card, Bernard, Abrenica, Lyle R, McKinnon, Terry Blake, Ball, and Ruey-Chyi, Su
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CD4-Positive T-Lymphocytes ,T-Lymphocytes ,Cell Adhesion ,Endothelial Cells ,Humans ,Vascular Cell Adhesion Molecule-1 ,HIV Infections ,Intercellular Adhesion Molecule-1 ,Lymphocyte Function-Associated Antigen-1 - Abstract
Resting CD4
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- 2021
22. Pre-infection plasma cytokines and chemokines as predictors of HIV disease progression
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Samukelisiwe Ngcobo, Refilwe P. Molatlhegi, Farzana Osman, Sinaye Ngcapu, Natasha Samsunder, Nigel J. Garrett, Salim S. Abdool Karim, Quarraisha Abdool Karim, Lyle R. McKinnon, and Aida Sivro
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Adult ,Multidisciplinary ,Adolescent ,Anti-HIV Agents ,CD4-CD8 Ratio ,Immunity ,HIV Infections ,Viral Load ,Prognosis ,Cohort Studies ,South Africa ,Young Adult ,Treatment Outcome ,Double-Blind Method ,HIV Seropositivity ,Disease Progression ,HIV-1 ,Humans ,Female ,Chemokines ,Tenofovir ,Biomarkers - Abstract
Previous studies have highlighted the role of pre-infection systemic inflammation on HIV acquisition risk, but the extent to which it predicts disease progression outcomes is less studied. Here we examined the relationship between pre-infection plasma cytokine expression and the rate of HIV disease progression in South African women who seroconverted during the CAPRISA 004 tenofovir gel trial. Bio-Plex 200 system was used to measure the expression of 47 cytokines/chemokines in 69 seroconvertors from the CAPRISA 004 trial. Cox proportional hazards regression analyses were used to measure associations between cytokine expression and CD4 decline prior to antiretroviral therapy initiation. Linear regression models were used to assess whether pre-infection cytokine expression were predictors of disease progression outcomes including peak and set-point viral load and CD4:CD8 ratio at less and greater than180 days post infection. Several cytokines were associated with increased peak HIV viral load (including IL-16, SCGFβ, MCP-3, IL-12p40, SCF, IFNα2 and IL-2). The strongest association with peak viral load was observed for SCGFβ, which was also inversely associated with lowest CD4:CD8 ratio p = 0.008) in multivariable analysis adjusting for age, study site, contraception, baseline HSV-2 status and trial arm allocation. Our results show that pre-infection systemic immune responses could play a role in HIV disease progression, especially in the early stages of infection.
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- 2021
23. Immunological Correlates of the HIV-1 Replication-Competent Reservoir Size
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Alan S. Perelson, Quarraisha Abdool Karim, Sarah B. Joseph, Carolyn Williamson, Wendy A. Burgers, Melissa-Rose Abrahams, David M. Margolis, Lyle R. McKinnon, Nancie M. Archin, Matthew Moeser, Sherazaan D. Ismail, Salim S. Abdool Karim, Ronald Swanstrom, Nigel Garrett, Farzana Osman, Catherine Riou, and Tyler Cassidy
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CD4-Positive T-Lymphocytes ,Microbiology (medical) ,business.industry ,Human immunodeficiency virus (HIV) ,HIV Infections ,Viral Load ,Virus Replication ,medicine.disease_cause ,Antiretroviral therapy ,Virology ,Replication competent virus ,Virus Latency ,Chronic infection ,Infectious Diseases ,Anti-Retroviral Agents ,Replication (statistics) ,HIV-1 ,Humans ,Medicine ,Brief Reports ,business ,Nadir (topography) ,CD8 - Abstract
This is the accepted manuscript version of the work published in its final form as Ismail, S. D., Riou, C., Joseph, S. B., Archin, N. M., Margolis, D. M., Perelson, A. S., Cassidy, T., Abrahams, M., Moeser, M., Council, O. D., McKinnon, L. R., Osman, F., Karim, Q. A., Karim, S. S. A., Swanstrom, R., Williamson, C., Garrett, N. J., & Wendy A Burgers. (2021). Immunological Correlates of the HIV-1 Replication-Competent Reservoir Size.Clinical Infectious Diseases,73(8), 1528-1531. https://doi.org/10.1093/cid/ciab587 Deposited byshareyourpaper.organdopenaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailinghelp@openaccessbutton.org.
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- 2021
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24. An updated review on the effects of depot medroxyprogesterone acetate on the mucosal biology of the female genital tract
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Lyle R. McKinnon, Christina Farr Zuend, Adam Burgener, Hossaena Ayele, Michelle Perner, and Kenzie Birse
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0301 basic medicine ,Female circumcision ,medicine.drug_class ,Immunology ,Review: Clinical Reproductive Immunology ,Physiology ,chemokines ,Medroxyprogesterone Acetate ,Review Article ,Biology ,03 medical and health sciences ,immune cells ,0302 clinical medicine ,Immune system ,Contraceptive Agents, Female ,medicine ,Humans ,Immunology and Allergy ,Medroxyprogesterone acetate ,Sex organ ,Mucous Membrane ,030219 obstetrics & reproductive medicine ,Microbiota ,Mortality rate ,vaginal microbiome ,Obstetrics and Gynecology ,Genitalia, Female ,cytokines ,3. Good health ,depot medroxyprogesterone acetate ,DMPA ,030104 developmental biology ,Reproductive Medicine ,vaginal epithelium ,Delayed-Action Preparations ,Vagina ,Vaginal microbiome ,Female ,Observational study ,Progestin ,medicine.drug - Abstract
Background Access to safe, effective, and affordable contraception is important for women’s health and essential to mitigate maternal and fetal mortality rates. The progestin‐based contraceptive depot medroxyprogesterone acetate (DMPA) is a popular contraceptive choice with a low failure rate and convenient administration schedule. Aim In this review, we compiled observational data from human cohorts that examine how DMPA influences the mucosal biology of the female genital tract (FGT) that are essential in maintaining vaginal health, including resident immune cells, pro‐inflammatory cytokines, epithelial barrier function, and the vaginal microbiome Materials and Methods This review focused on the recent published literature published in 2019 and 2020. Results Recent longitudinal studies show that DMPA use associates with an immunosuppressive phenotype, increase in CD4+CCR5+ T cells, and alterations to growth factors. In agreement with previous meta‐analyses, DMPA use is associated with minimal effects of the composition of the vaginal microbiome. Cross‐sectional studies associate a more pro‐inflammatory relationship with DMPA, but these studies are confounded by inherent weaknesses of cross‐sectional studies, including differences in study group sizes, behaviors, and other variables that may affect genital inflammation. Discussion & Conclusion These recent results indicate that the interactions between DMPA and the vaginal mucosa are complex emphasizing the need for comprehensive longitudinal studies that take into consideration the measurement of multiple biological parameters.
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- 2021
25. Expansion of tissue-resident CD8+ T cells and CD4+ Th17 cells in the nasal mucosa following mRNA COVID-19 vaccination
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Hezhao Ji, Lyle R. McKinnon, Hai Nguyen, Severini G, Van Caeseele P, Aloysious Ssemaganda, Ruey-Chyi Su, Terry B. Ball, Catherine M. Card, Naima Jahan, Yoav Keynan, Derek R. Stein, Sandra Kiazyk, Faisal Nuhu, Bernard Abrenica, Jared Bullard, and Paul J. McLaren
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business.industry ,CD69 ,hemic and immune systems ,chemical and pharmacologic phenomena ,Mucous membrane of nose ,Stimulation ,Vaccination ,medicine.anatomical_structure ,Immunology ,medicine ,Cytotoxic T cell ,CD154 ,business ,CD8 ,Respiratory tract - Abstract
Vaccines against SARS-CoV-2 have shown high efficacy in clinical trials, yet a full immunologic characterization of these vaccines, particularly within the upper respiratory tract, remains lacking. We enumerated and phenotyped T cells in nasal mucosa and blood before and after vaccination with the Pfizer-BioNTech COVID-19 vaccine (n =21). Tissue-resident memory (Trm) CD8+ T cells expressing CD69+CD103+ expanded ∼12 days following the first and second doses, by 0.31 and 0.43 log10cells per swab respectively (p=0.058 and p=0.009 in adjusted linear mixed models). CD69+CD103+CD8+ T cells in the blood decreased post-vaccination. Similar increases in nasal CD8+CD69+CD103-T cells were observed, particularly following the second dose. CD4+ Th17 cells were also increased in abundance following both doses. Following stimulation with SARS-CoV-2 spike peptides, CD8+ T cells increased expression of CD107a and CD154. These data suggest that nasal T cells may be induced and contribute to the protective immunity afforded by this vaccine.
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- 2021
26. The Evolving Facets of Bacterial Vaginosis: Implications for HIV Transmission
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Nichole R. Klatt, Jacques Ravel, Catriona S. Bradshaw, Sharon L. Achilles, Gilda Tachedjian, Janneke van de Wijgert, Rupert Kaul, Adam Burgener, Lindi Masson, Jeanne M. Marrazzo, Lyle R. McKinnon, Charu Kaushic, David N. Fredricks, Tania Crucitti, Douglas S. Kwon, R. Scott McClelland, Lenka A. Vodstrcil, and Heather B. Jaspan
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Adult ,Risk ,0301 basic medicine ,medicine.medical_specialty ,Immunology ,Human immunodeficiency virus (HIV) ,HIV Infections ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Cytokines metabolism ,Clinical Perspective ,RNA, Ribosomal, 16S ,Terminology as Topic ,Virology ,Disease Transmission, Infectious ,Journal Article ,medicine ,Humans ,030212 general & internal medicine ,Intensive care medicine ,Hiv transmission ,vaginal microbiota ,Inflammation ,business.industry ,Microbiota ,female reproductive tract ,genital inflammation ,High-Throughput Nucleotide Sequencing ,HIV ,Vaginosis, Bacterial ,medicine.disease ,3. Good health ,HIV transmission ,Lactobacillus ,030104 developmental biology ,Infectious Diseases ,Vagina ,Cytokines ,Female ,Disease Susceptibility ,Bacterial vaginosis ,Female Reproductive Tract ,business ,bacterial vaginosis - Abstract
Bacterial vaginosis (BV) is a common yet poorly understood vaginal condition that has become a major focus of HIV transmission and immunology research. Varied terminologies are used by clinicians and researchers to describe microbial communities that reside in the female reproductive tract (FRT), which is driven, in part, by microbial genetic and metabolic complexity, evolving diagnostic and molecular techniques, and multidisciplinary perspectives of clinicians, epidemiologists, microbiologists, and immunologists who all appreciate the scientific importance of understanding mechanisms that underlie BV. This Perspectives article aims to clarify the varied terms used to describe the cervicovaginal microbiota and its “nonoptimal” state, under the overarching term of BV. The ultimate goal is to move toward language standardization in future literature that facilitates a better understanding of the impact of BV on FRT immunology and risk of sexually transmitted infections, including HIV.
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- 2019
27. Genital and systemic immune effects of the injectable, contraceptive norethisterone enanthate (NET‐EN), in South African women
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Samkelisiwe Ngcobo, Sinaye Ngcapu, Natasha Samsunder, Jo-Ann S. Passmore, John H. Adamson, Lyle R. McKinnon, Mthobisi M Zondi, Lenine J. P. Liebenberg, Alasdair Leslie, Amanda Mabhula, Salim S. Abdool Karim, Quarraisha Abdool Karim, Nobuhle Nokubonga Mchunu, Katya Govender, Aida Sivro, and Refilwe P Molatlhegi
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Adult ,0301 basic medicine ,Adolescent ,medicine.medical_treatment ,Immunology ,Physiology ,South Africa ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Tandem Mass Spectrometry ,Contraceptive Agents, Female ,Humans ,Immunology and Allergy ,Medicine ,Sex organ ,030219 obstetrics & reproductive medicine ,business.industry ,Growth factor ,Confounding ,Obstetrics and Gynecology ,030104 developmental biology ,Cytokine ,Reproductive Medicine ,chemistry ,Vagina ,Cytokines ,Immunohistochemistry ,Female ,Tumor necrosis factor alpha ,Norethisterone enanthate ,Norethindrone ,business ,Chromatography, Liquid ,Hormone - Abstract
PROBLEM Injectable hormonal contraceptives (IHC) have been associated with altered mucosal and systemic milieu which might increase HIV risk, but most studies have focused on DMPA and not NET-EN, despite the growing popularity and lower HIV risk associated with the latter in observational studies. METHOD OF STUDY We used high-performance liquid chromatography in combination with tandem triple quadrupole mass spectrometry (HPLC-LC-MS/MS) to measure steroid hormones in plasma samples of CAPRISA004 study participants. Concentrations of 48 cytokines were measured in the cervicovaginal lavage (CVL) and plasma, and their expression was compared between participants with detectable NET-EN (n = 201) versus non-detectable IHC (n = 90). Each log10 cytokine concentration was tested as an outcome in linear-mixed models, with NET-EN detection as the main explanatory variable. Multivariable models were adjusted for potential confounders. RESULTS In bivariate analysis, detectable NET-EN was associated with reduced cervicovaginal M-CSF (P = 0.008), GM-CSF (P = 0.025) and G-CSF (P = 0.039), and elevated levels MIF (P = 0.008), IL-18 (P = 0.011), RANTES (P = 0.005) and IL-1Rα (P
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- 2021
28. Rectal microbiota diversity in Kenyan MSM is inversely associated with frequency of receptive anal sex, independent of HIV status
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Naomi Siele, Henok Gebrebrhan, Ruth S. Mwatelah, Sandra Choi, Paul Sandstrom, N. Vincent Reyes, Joshua Kimani, Lyle R. McKinnon, Irene Martin, Maureen Akolo, John E. Kim, François Cholette, Jie Li, T. Blake Ball, John L. Ho, Hezhao Ji, Peter M. Njogu, Cheli Kambaran, Robert Lorway, Wendy Adhiambo, Michael G. Becker, Supriya D. Mehta, Aida Sivro, Paul J. McLaren, and Shelley W. Peterson
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Male ,Kenya ,media_common.quotation_subject ,Sexual Behavior ,Immunology ,HIV Infections ,Men who have sex with men ,Sexual and Gender Minorities ,RNA, Ribosomal, 16S ,Prevotella ,Prevalence ,Immunology and Allergy ,Humans ,Microbiome ,Homosexuality, Male ,media_common ,biology ,Microbiota ,virus diseases ,biology.organism_classification ,Europe ,Infectious Diseases ,Cross-Sectional Studies ,North America ,Alpha diversity ,Hiv status ,Roseburia ,Demography ,Diversity (politics) - Abstract
Objective Both HIV infection and identifying as MSM have been linked to altered rectal microbiota composition, but few studies have studied sexual behavioural associations with rectal microbiota within MSM. In addition, most rectal microbiota studies in MSM have been limited geographically to Europe and North America, and replication of findings in lower and middle-income countries is lacking. Design A cross-sectional study. Methods We enrolled MSM from Nairobi, Kenya, and determined their HIV/sexually transmitted infection status. Rectal specimens were obtained for 16s rRNA sequencing of the rectal microbiota, and sexual behaviour was characterized using a standardized questionnaire. Microbiome differences were modelled using nonparametric statistics, Bray-Curtis ecological distance metrics and analyses of differential taxa abundance. Multivariable linear regression was used to model HIV status and recent sexual activity as predictors of alpha diversity, controlling for a range of covariates. Results Alpha diversity was consistently lower in Kenyan HIV-infected MSM (n = 80), including those on antiretroviral therapy (ART) compared with HIV-uninfected MSM. A statistical trend was observed for clustering of HIV status by Prevotella or Bacteroides dominance (P = 0.13). Several taxa were enriched in HIV-positive men, including Roseburia, Lachnospira, Streptococcus and Granulicatella. Receptive anal sex with several types of sexual partners (paying, regular, casual) was associated with lower Chao1 and Simpson diversity, independent of HIV status, while HIV infection was associated lower Chao1 (P = 0.030) but not Simpson diversity (P = 0.049). Conclusion Both HIV infection and sexual behaviour were associated with rectal microflora alpha diversity, in particular richness, but not Prevotella spp. dominance, in Kenyan MSM. Associations were more robust for sexual behaviour.
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- 2021
29. Simian Immunodeficiency Virus Susceptibility, Immunology, and Microbiome in the Female Genital Tract of Adolescent Versus Adult Pigtail Macaques
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Alicia R, Berard, Charlene, Miller, Mariluz, Araínga, Courtney Ann, Broedlow, Laura, Noël-Romas, Luca, Schifanella, Tiffany, Hensley-McBain, Alex, Roederer, Connor B, Driscoll, Ernesto, Coronado, Jennifer, Manuzak, Lyle R, McKinnon, Francois, Villinger, Thomas J, Hope, Adam D, Burgener, and Nichole R, Klatt
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Adult ,Proteomics ,Adolescent ,Microbiota ,Simian Acquired Immunodeficiency Syndrome ,HIV Infections ,Genitalia, Female ,RNA, Ribosomal, 16S ,Animal Studies ,Animals ,Humans ,Female ,Simian Immunodeficiency Virus ,Macaca nemestrina - Abstract
In Sub-Saharan Africa, young women 15–24 years of age account for nearly 30% of all new HIV infections, however, biological and epidemiological factors underlying this disproportionate infection rate are unclear. In this study, we assessed biological contributors of SIV/HIV susceptibility in the female genital tract (FGT) using adolescent (n = 9) and adult (n = 10) pigtail macaques (PTMs) with weekly low-dose intravaginal challenges of SIV. Immunological variables were captured in vaginal tissue of PTMs by flow cytometry and cytokine assays. Vaginal biopsies were profiled by proteomic analysis. The vaginal microbiome was assessed by 16S rRNA sequencing. We were powered to detect a 2.2-fold increase in infection rates between age groups, however, we identified no significant differences in susceptibility. This model cannot capture epidemiological factors or may not best represent biological differences of HIV susceptibility. No immune cell subsets measured were significantly different between groups. Inflammatory marker MCP-1 was significantly higher (adj p = .02), and sCD40L trended higher (adj p = .06) in vaginal cytobrushes of adults. Proteomic analysis of vaginal biopsies showed no significant (adj p
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- 2021
30. SIV susceptibility, immunology and microbiome in the female genital tract of adolescent versus adult pigtail macaques
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Laura Noël-Romas, Francois Villinger, Connor B. Driscoll, Tiffany Hensley-McBain, Alex Roederer, Jennifer A. Manuzak, Adam Burgener, Luca Schifanella, Courtney Broedlow, Alicia R. Berard, Nichole R. Klatt, Ernesto Coronado, Mariluz Araínga, Lyle R. McKinnon, Thomas J. Hope, and Charlene Miller
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0301 basic medicine ,Female circumcision ,Non human primate ,biology ,Epidemiological Factors ,business.industry ,Immunology ,Human immunodeficiency virus (HIV) ,Pigtail macaque ,Simian immunodeficiency virus ,biology.organism_classification ,medicine.disease_cause ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Infectious Diseases ,Virology ,parasitic diseases ,Vaginal microbiome ,medicine ,030212 general & internal medicine ,Microbiome ,business - Abstract
In Sub-Saharan Africa, young women 15–24 years of age account for nearly 30% of all new HIV infections, however, biological and epidemiological factors underlying this disproportionate infection ra...
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- 2021
31. 'Heavy Drinking' and HIV Vulnerability Among African Male Sex Workers: Narratives from a Community-Based Participatory Study in Nairobi, Kenya
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John Mathenge, Helgar Musyoki, Robert Lorway, Lyle R. McKinnon, Matthew Thomann, Lisa Lazarus, Akram Pasha, Pascal Macharia, Parinita Bhattacharjee, Joshua Kimani, Sushena Reza-Paul, and Monika Doshi
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education.field_of_study ,medicine.medical_specialty ,business.industry ,Public health ,Population ,Vulnerability ,Psychological intervention ,Participatory action research ,Gender studies ,Men who have sex with men ,Global health ,medicine ,Sociology ,education ,business ,Reproductive health - Abstract
With growing attention to the vulnerability of men who have sex with men in African contexts to HIV, public health scientists and others have begun to draw connections between alcohol use in this population and the transmission of HIV and other sexually transmitted infections. In this chapter, we consider the role of the global health discourse in shaping the meanings, experiences, and subjectivities of male sex workers in Kenya with respect to heavy drinking, referred to locally in Kiswahili as kulewa (getting drunk). Employing a community-based participatory research approach, we conducted in-depth interviews with male sex workers (n = 41) in Nairobi, Kenya. Our findings illuminate how drinking narratives are influenced by regionally based HIV interventions. Global health discourse, we contend, (1) constructs the sexual health of male sex workers as continually ‘in jeopardy’ while it (2) compels male sex workers to reflect on and enact ways to improve ‘community health.’ We describe how male sex workers rework reigning global health discourses that reduce problem drinking to ‘poor’ individual decision making. Instead, their narratives depict heavy drinking as tied to multiple overlapping oppressions faced by a wider community of male sex workers.
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- 2021
32. Endothelial cells promote productive HIV infection of resting CD4+ T cells by an integrin-mediated cell adhesion-dependent mechanism
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Bernard Abrenica, Lyle R. McKinnon, Ruey-Chyi Su, T. Blake Ball, and Catherine M. Card
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medicine.diagnostic_test ,Cell adhesion molecule ,T cell ,Cell ,Integrin ,C-C chemokine receptor type 6 ,Biology ,Cell biology ,Flow cytometry ,medicine.anatomical_structure ,Immune system ,medicine ,biology.protein ,Cell adhesion - Abstract
Resting CD4+ T cells do not support HIV replication in vitro, yet are primary targets of early HIV infection events in vivo. There is an established role for factors in the tissue microenvironment, including endothelial cells, in enhancing the susceptibility of resting CD4+ T cells to productive infection, yet the mechanisms behind this are not well understood. Endothelial cells facilitate immune cell trafficking throughout the body. Cell adhesion molecules expressed by endothelial cells engage integrins on activated and memory T cells and mediate transmigration into inflamed tissues. These cell trafficking pathways have overlapping roles in facilitating HIV replication but their relevance to endothelial cell-mediated enhancement of HIV susceptibility in resting CD4+ T cells has not previously been examined. We used flow cytometry to characterize the phenotype resting CD4+ T cells that became productively infected when exposed to HIV in the presence of endothelial cells. Infected CD4+ T cells were primarily central memory cells enriched for high expression of the integrins LFA-1 and VLA-4 and had variable expression of α4β7, CCR6 and CD69. Blocking LFA-1 and VLA-4 on resting CD4+ T cells abrogated infection in the co-culture model, indicating that engagement of these integrins is essential for enhancement of resting CD4+ T cell HIV susceptibility by endothelial cells. Cellular activation of CD4+ T cells did not appear to be the primary mechanism enabling HIV replication since only a small proportion of resting CD4+ T cells became activated over the course of the co-culture and fewer than half of infected cells had an activated phenotype. The demonstration that endothelial cells enhance the cellular HIV susceptibility of resting memory CD4+ T cells through cell trafficking pathways engaged during the transmigration of memory T cells into inflamed tissues highlights the physiological relevance of these findings for HIV acquisition and opportunities for intervention.Author SummaryHIV acquisition risk per coital act is relatively low, but this risk is amplified by various behavioural and biological variables. Genital inflammation is a key biological variable associated with increased risk of HIV acquisition, but the mechanisms driving this are incompletely understood. Inflammation is a complex process, with direct effects on HIV target cells as well as the tissue in which those cells reside and encounter virus. The first HIV target cells in vivo are resting memory CD4+ T cells, yet these cells are do not support viral replication when purified and exposed to HIV in vitro. Rather, signals from tissue microenvironment are required to support viral replication within resting memory CD4+ T cells. Endothelial cells line tissue vasculature and guide immune cell trafficking to inflamed tissues through engagement of integrins by endothelial-expressed cell adhesion molecules. We show here that these same cell-trafficking pathways enable endothelial cells to promote HIV replication within resting memory CD4+ T cells in vitro. Blockade of integrins on resting memory CD4+ T cells prevented endothelial enhancement of HIV infection. These findings further our understanding of the determinants of cellular susceptibility to HIV infection and offer a potential mechanism by which inflammation promotes HIV acquisition.
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- 2020
33. The effects of COVID-19 on the health and socio-economic security of sex workers in Nairobi, Kenya: Emerging intersections with HIV
- Author
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Robert Lorway, Peninah Mwangi, Helgar Musyoki, Pascal Macharia, Joyce Adhiambo, Stephen Moses, François Cholette, Rosemary Kasiba, Marissa Becker, John Mathenge, Samantha Moore, Parinita Bhattacharjee, Keith R. Fowke, Lyle R. McKinnon, Souradet Y. Shaw, Joshua Kimani, and Veronica Were
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Adult ,Male ,Coronavirus disease 2019 (COVID-19) ,Pneumonia, Viral ,Human immunodeficiency virus (HIV) ,Stigma (botany) ,Sex workers ,HIV Infections ,medicine.disease_cause ,03 medical and health sciences ,Betacoronavirus ,0302 clinical medicine ,Political science ,Pandemic ,medicine ,Humans ,030212 general & internal medicine ,Socioeconomics ,Pandemics ,Sex work ,030505 public health ,Sex Workers ,SARS-CoV-2 ,Economic sector ,Public Health, Environmental and Occupational Health ,COVID-19 ,Kenya ,Scale (social sciences) ,Public Health Practice ,Female ,0305 other medical science ,Coronavirus Infections - Abstract
The COVID-19 pandemic, and its attendant responses, has led to massive health, social, and economic challenges on a global scale. While, so far, having a relatively low burden of COVID-19 infection, it is the response in lower- and middle- income countries that has had particularly dire consequences for impoverished populations such as sex workers, many of whom rely on regular income in the informal economic sector to survive. This commentary captures the challenges in Kenya posed by daily curfews and lost economic income, coupled with further changes to sex work that increase potential exposure to infection, stigmatisation, violence, and various health concerns. It also highlights the ways in which communities and programmes have demonstrated resourcefulness in responding to this unprecedented disruption in order to emerge healthy when COVID-19, and the measures to contain it, subside.
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- 2020
34. Sex Work Is Associated With Increased Vaginal Microbiome Diversity in Young Women From Mombasa, Kenya
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Sharmistha Mishra, Nzioki King’ola, Lyle R. McKinnon, Alexander S. Zevin, Peter Gichangi, Sammy Wambua, Michael G. Becker, Aida Sivro, Cheli Kambaran, Nichole R. Klatt, Paul J. McLaren, Marissa Becker, Eve Cheuk, Huiting Ma, Henok Gebrebrhan, and Ruth S. Mwatelah
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medicine.medical_specialty ,Kenya ,Adolescent ,Transactional sex ,030312 virology ,03 medical and health sciences ,Young Adult ,Interquartile range ,RNA, Ribosomal, 16S ,Epidemiology ,Lactobacillus iners ,Prevotella ,Medicine ,Humans ,Pharmacology (medical) ,Microbiome ,Sex work ,0303 health sciences ,biology ,Bacteria ,business.industry ,Microbiota ,biology.organism_classification ,Sex Work ,RNA, Bacterial ,Infectious Diseases ,Vagina ,Female ,business ,Demography - Abstract
BACKGROUND Although nonoptimal vaginal bacteria and inflammation have been associated with increased HIV risk, the upstream drivers of these phenotypes are poorly defined in young African women. SETTING Mombasa, Kenya. METHODS We characterized vaginal microbiome and cytokine profiles of sexually active young women aged 14-24 years (n = 168) in 3 study groups: those engaging in formal sex work, in transactional sex, and nonsex workers. Vaginal secretions were collected using self-inserted SoftCup, and assayed for cytokines and vaginal microbiome through multiplex ELISA and 16S rRNA sequencing, respectively. Epidemiological data were captured using a validated questionnaire. RESULTS The median age of participants was 20 years (interquartile range: 18-22 years). Approximately two-thirds of young women (105/168) had vaginal microbial communities characterized by Gardnerella and/or Prevotella spp. dominance; a further 29% (49/168) were predominantly Lactobacillus iners. Microbiome clustering explained a large proportion of cytokine variation (>50% by the first 2 principal components). Age was not associated with vaginal microbial profiles in bivariable or multivariable analyses. Women self-identifying as sex workers had increased alpha (intraindividual) diversity, independent of age, recent sexual activity, HIV, and other sexually transmitted infections (beta = 0.47, 95% confidence interval: 0.05 to 0.90, P = 0.03). Recent sex (number of partners or sex acts last week, time since last vaginal sex) correlated with increased alpha diversity, particularly in participants who were not involved in sex work. CONCLUSION Nonoptimal vaginal microbiomes were common in young Kenyan women and associated with sex work and recent sexual activity, but independent of age. Restoring optimal vaginal microflora may represent a useful HIV prevention strategy.
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- 2020
35. Beyond biomedical and comorbidity approaches: Exploring associations between affinity group membership, health and health seeking behaviour among MSM/MSW in Nairobi, Kenya
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Robert Lorway, Sushena Reza-Paul, Lyle R. McKinnon, Parinita Battacharjee, K. Rivet Amico, Pascal Macharia, Joshua Kimani, James F. Blanchard, Helgar Musyoki, Monika Doshi, and John Mathenge
- Subjects
Gerontology ,Male ,Health Status ,Sex workers ,Health Promotion ,Men who have sex with men ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,medicine ,Humans ,030212 general & internal medicine ,Homosexuality, Male ,030505 public health ,Group membership ,Sex Workers ,Health seeking ,Public Health, Environmental and Occupational Health ,virus diseases ,Patient Acceptance of Health Care ,medicine.disease ,Mental health ,Comorbidity ,Kenya ,female genital diseases and pregnancy complications ,Group Processes ,General health ,0305 other medical science ,Psychology ,Psychosocial - Abstract
We explored general health and psychosocial characteristics among male sex workers and other men who have sex with men in Nairobi, Kenya. A total of 595 MSM/MSW were recruited into the study. We assessed group differences among those who self-reported HIV positive (SR-HIVP) and those who self-reported HIV negative (SR-HIVN) and by affinity group membership. Quality of life among SR-HIVP participants was significantly worse compared to SR-HIVN participants. Independent of HIV status and affinity group membership, participants reported high levels of hazardous alcohol use, harmful substance use, recent trauma and childhood abuse. The overall sample exhibited higher prevalence of moderate to severe depressive symptoms compared to the general population. Quality of life among participants who did not report affinity group membership (AGN) was significantly worse compared to participants who reported affinity group membership (AGP). AGN participants also reported significantly lower levels of social support. Membership in affinity groups was found to influence health seeking behaviour. Our findings suggest that we need to expand the mainstay biomedical and comorbidity focused research currently associated with MSM/MSW. Moreover, there are benefits to being part of MSM/MSW organisations and these organisations can potentially play a vital role in the health and well-being of MSM/MSW.
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- 2020
36. Live Attenuated Zoster Vaccine Boosts Varicella Zoster Virus (VZV)–Specific Humoral Responses Systemically and at the Cervicovaginal Mucosa of Kenyan VZV-Seropositive Women
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Jemima Nyakio, Catia T. Perciani, Timothy Kotikot, Borna A. Nyaoke, Nelly Wanjiku, Kelly S. MacDonald, Rose Ndambuki, Marion Agwaya, Sabrina Hundal, Lyle R. McKinnon, Rose Mahira, Elizabeth Mutiska, Matrona Akiso, Emmanuel Museve, Catherine Kamau, Lewa Said, Julius Oyugi, H Ogutu, Hannah Nduta Gakure, A. Omu Anzala, James Wakonyo, Robert Langat, Judith Omungo, Jacquelyn Nyange, Mercy Musanga, Walter Jaoko, Mario A. Ostrowski, Lydia Atambo, Roselyne Malogo, Ruth Chirchir, Simon Ogola, Jason Ndalamia, Jackton Indangasi, Laura Lusik, Moses Muriuki, Bashir Farah, Catherine Ngeli, Naomi Mwakisha, Joshua Kimano, Manmeet Sekhon, Erastus Irungu, Brian Onsembe, Richard Alila, Irene Mwangi, Mary W Gichuho, Dorothy Essendi, and Gaudensia Mutua
- Subjects
0301 basic medicine ,Immunoglobulin A ,Herpesvirus 3, Human ,HIV/AIDS vaccine ,vaccine vector ,zoster vaccine ,viruses ,virus ,Antibodies, Viral ,Vaccines, Attenuated ,medicine.disease_cause ,Virus ,Major Articles and Brief Reports ,03 medical and health sciences ,Immunity ,Herpes Zoster Vaccine ,Humans ,Immunology and Allergy ,Medicine ,Mucous Membrane ,Reactogenicity ,integumentary system ,biology ,business.industry ,Immunogenicity ,Varicella zoster virus ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,Kenya ,eye diseases ,Immunity, Humoral ,3. Good health ,Vaccination ,030104 developmental biology ,Infectious Diseases ,Varicella Zoster Virus Infection ,varicella zoster ,Vagina ,Viruses ,Immunology ,biology.protein ,mucosal immunity ,Female ,Zoster vaccine ,business ,medicine.drug - Abstract
We show that VZV-seropositive women sustain VZV-specific humoral immunity at the gastrointestinal and genital mucosa and that this immunity can be boosted upon vaccination. Our findings encourage further investigation of VZV as a potential vector in vaccines including HIV., Background Attenuated varicella zoster virus (VZV) is a promising vector for recombinant vaccines. Because human immunodeficiencyvirus (HIV) vaccines are believed to require mucosal immunogenicity, we characterized mucosal VZV-specific humoral immunity following VZVOka vaccination. Methods Adult Kenyan VZV-seropositive women (n = 44) received a single dose of the live zoster VZVOka vaccine. The anamnestic responses to the virus were followed longitudinally in both plasma and mucosal secretions using an in-house glycoprotein enzyme-linked immunosorbent assay and safety and reactogenicity monitored. VZV seroprevalence and baseline responses to the virus were also characterized in our cohorts (n = 288). Results Besides boosting anti-VZV antibody responses systemically, vaccination also boosted anti-VZV immunity in the cervicovaginal mucosa with a 2.9-fold rise in immunoglobulin G (P < .0001) and 1.6-fold rise in immunoglobulin A (IgA) (P = .004) from the time before immunization and 4 weeks postvaccination. Baseline analysis demonstrated high avidity antibodies at the gastrointestinal and genital mucosa of VZV-seropositive women. Measurement of VZV-specific IgA in saliva is a sensitive tool for detecting prior VZV infection. Conclusions VZVOka vaccine was safe and immunogenic in VZV-seropositive adult Kenyan women. We provided compelling evidence of VZV ability to induce genital mucosa immunity. Clinical Trials Registration NCT02514018.
- Published
- 2018
37. Plasma Cytokine Predictors of Tuberculosis Recurrence in Antiretroviral-Treated Human Immunodeficiency Virus-infected Individuals from Durban, South Africa
- Author
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Kogieleum Naidoo, Nonhlanhla Yende-Zuma, Santhana Gengiah, Lyle R. McKinnon, Natasha Samsunder, Salim S. Abdool Karim, and Aida Sivro
- Subjects
Adult ,Male ,0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Tuberculosis ,HIV Infections ,Disease ,South Africa ,03 medical and health sciences ,Recurrence ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Interleukin 6 ,Articles and Commentaries ,biology ,business.industry ,Interleukin ,Odds ratio ,medicine.disease ,Clinical trial ,030104 developmental biology ,Infectious Diseases ,Anti-Retroviral Agents ,Cohort ,Immunology ,biology.protein ,Cytokines ,Female ,business - Abstract
Background Immune correlates of tuberculosis (TB) risk in populations infected with human immunodeficiency virus (HIV) remain understudied, despite HIV being associated with a high burden of TB disease. Here we describe plasma cytokine correlates of TB recurrence in a well-characterized cohort of HIV-infected individuals on antiretroviral therapy (ART) with a history of prior TB cure. Methods Study participants were drawn from a prospective cohort study initiated at the conclusion of a randomized clinical trial in which individuals presented with untreated HIV infection and active pulmonary TB. At baseline, ART was initiated, and TB successfully cured. Participants were screened for TB recurrence quarterly for up to 4 years. TB recurrent cases (n = 63) were matched to controls (n = 123) on sex, study arm assignment in the original trial, and month of enrollment with a subset of cases sampled longitudinally at several time-points. Results Three cytokines were associated with increased rates of TB recurrence in univariate models: interleukin 6 (IL6) (odds ratio [OR] 2.66, 95% confidence interval [CI] 1.34-5.28, P = .005), IP10 (OR 4.62, 95% CI 1.69-12.65, P = .003), monokine induced by IFN-γ (MIG) (OR 3.11, 95% CI 1.10-8.82, P = .034). Conversely, interferon β (IFNβ) was associated with decreased TB risk (OR 0.34, 95% CI 0.13-0.87, P = .025). Following multivariate analyses adjusting for covariates IL6, interleukin 1β (IL1β), and interleukin 1Rα (IL1Rα) were associated with increased risk and IFNβ with decreased TB risk. Longitudinal analysis showed that levels of many TB-associated markers, including IL6, IP10, sCD14, and interferon γ (IFNγ) are reduced following TB treatment. Conclusion These data show that TB recurrence, in HIV-infected individuals on ART is predicted by biomarkers of systemic inflammation, many of which are implicated in more rapid HIV disease progression. Clinical trials registration NCT 01539005.
- Published
- 2017
38. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women
- Author
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Adam Burgener, Irene Y. Xie, Quarraisha Abdool Karim, Salim S. Abdool Karim, Alexander S. Zevin, Nichole R. Klatt, Michelle Perner, Laura Noël-Romas, Jennifer. Butler, Lyle R. McKinnon, Leila E. Mansoor, Anna Christina. Grobler, Kenzie Birse, Jo-Ann S. Passmore, Garrett Westmacott, and Ryan Cheu
- Subjects
Adult ,0301 basic medicine ,Drug ,Gardnerella ,Proteome ,Tenofovir ,media_common.quotation_subject ,HIV Infections ,medicine.disease_cause ,Antiviral Agents ,Mass Spectrometry ,Article ,Microbiology ,South Africa ,03 medical and health sciences ,Acquired immunodeficiency syndrome (AIDS) ,RNA, Ribosomal, 16S ,Lactobacillus ,Microbicide ,medicine ,Humans ,Gardnerella vaginalis ,media_common ,Multidisciplinary ,Bacteria ,biology ,Microbiota ,virus diseases ,Biodiversity ,biology.organism_classification ,medicine.disease ,Virology ,3. Good health ,030104 developmental biology ,Vagina ,Female ,Anaerobic bacteria ,medicine.drug - Abstract
Antiretroviral-based strategies for HIV prevention have shown inconsistent results in women. We investigated whether vaginal microbiota modulated tenofovir gel microbicide efficacy in the CAPRISA (Centre for the AIDS Program of Research in South Africa) 004 trial. Two major vaginal bacterial community types—one dominated by Lactobacillus (59.2%) and the other where Gardnerella vaginalis predominated with other anaerobic bacteria (40.8%)—were identified in 688 women profiled. Tenofovir reduced HIV incidence by 61% ( P = 0.013) in Lactobacillus- dominant women but only 18% ( P = 0.644) in women with non- Lactobacillus bacteria, a threefold difference in efficacy. Detectible mucosal tenofovir was lower in non- Lactobacillus women, negatively correlating with G. vaginalis and other anaerobic bacteria, which depleted tenofovir by metabolism more rapidly than target cells convert to pharmacologically active drug. This study provides evidence linking vaginal bacteria to microbicide efficacy through tenofovir depletion via bacterial metabolism.
- Published
- 2017
39. Mechanisms of sexually transmitted infection‐induced inflammation in women: implications for<scp>HIV</scp>risk
- Author
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Quarraisha Abdool Karim, Salim S. Abdool Karim, Lyle R. McKinnon, Cheryl Baxter, and Ruth S. Mwatelah
- Subjects
adaptive immune responses ,Sexually Transmitted Diseases ,Human immunodeficiency virus (HIV) ,HIV Infections ,Inflammation ,medicine.disease_cause ,Asymptomatic ,immunology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Humans ,030212 general & internal medicine ,Vaginitis ,sexually transmitted infections ,Reproductive health ,030505 public health ,Infection induced ,business.industry ,Public Health, Environmental and Occupational Health ,HIV ,virus diseases ,Vaginosis, Bacterial ,medicine.disease ,Acquired immune system ,3. Good health ,mucosal immune responses ,Infectious Diseases ,Immunology ,Commentary ,Female ,women ,medicine.symptom ,Bacterial vaginosis ,0305 other medical science ,business ,bacterial vaginosis - Abstract
Introduction Globally, sexually transmitted infections (STI) affect >300 million people annually, and are a major cause of sexual and reproductive health complications in women. In this commentary, we describe how STIs interact with the immune and non‐immune cells, both within and below the cervicovaginal mucosal barrier, to cause inflammation, which in turn has been associated with increased HIV acquisition risk. Discussion STIs have a major impact on the female genital mucosa, which is an important biological and physical barrier that forms the first line of defence against invading microorganisms such as HIV. Pattern recognition of STI pathogens, by receptors expressed either on the cell surface or inside the cell, typically triggers inflammation at the mucosal barrier. The types of mucosal responses vary by STI, and can be asymptomatic or culminate in the formation of discharge, ulcers and/or warts. While the aim of this response is to clear the invading microbes, in many cases these responses are either evaded or cause pathology that impairs barrier integrity and increases HIV access to target cells in the sub‐mucosa. In addition, innate responses to STIs can result in an increased number of immune cells, including those that are the primary targets of HIV, and may contribute to the association between STIs and increased susceptibility to HIV acquisition. Many of these cells are mediators of adaptive immunity, including tissue‐resident cells that may also display innate‐like functions. Bacterial vaginosis (BV) is another common cause of inflammation, and evidence for multiple interactions between BV, STIs and HIV suggest that susceptibility to these conditions should be considered in concert. Conclusions STIs and other microbes can induce inflammation in the genital tract, perturbing the normal robust function of the mucosal barrier against HIV. While the impact of STIs on the mucosal immune system and HIV acquisition is often under‐appreciated, understanding their interactions of the infections with the immune responses play an important role in improving treatment and reducing the risk of HIV acquisition. The frequent sub‐clinical inflammation associated with STIs underscores the need for better STI diagnostics to reverse the immunological consequences of infection.
- Published
- 2019
40. P338 Prevalence and mucosal impact of STIs in young women from mombasa, kenya with varying exposure to sex work
- Author
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Shelley W. Peterson, Christine Bonner, Eve Cheuk, Irene Martin, Sharmistha Mishra, Grant McClarty, Peter Gichangi, Sammy Wambua, Faisal Nuhu, Marissa Becker, Tosin E. Omole, Nzioki King'ola, Lyle R. McKinnon, Naima Jahan, and Ruth S. Mwatelah
- Subjects
medicine.medical_specialty ,biology ,business.industry ,Obstetrics ,Gonorrhea ,Mycoplasma hominis ,urologic and male genital diseases ,medicine.disease_cause ,biology.organism_classification ,medicine.disease ,Asymptomatic ,female genital diseases and pregnancy complications ,Medicine ,Trichomonas vaginalis ,medicine.symptom ,business ,Chlamydia trachomatis ,Mycoplasma genitalium ,Sex work ,Ureaplasma urealyticum - Abstract
Background Bacterial STIs increase mucosal inflammation and HIV acquisition risk. However, most data are limited to symptomatic STIs, and more data are required regarding the prevalence and correlates of asymptomatic bacterial STIs among high-risk young women, and how these vary by exposure to sex work. Methods We estimated the prevalence of 6 STIs in urine collected during a cross-sectional study of women aged 14–24 years in Mombasa, Kenya (n=870). Participants were recruited from sex work hotspots, and self-identified as engaged or not engaged in formal sex work. STIs including Ureaplasma urealyticum (UU), Chlamydia trachomatis (CT), Mycoplasma hominis (MH), Trichomonas vaginalis (TV), Mycoplasma genitalium (MG) and Neisseria gonorrhea (NG) were detected using the Seegene Anyplex qPCR panel. The cervicovaginal microbiome and cytokines were also characterized in a subset of 168 participants. Results The prevalence of any STI was 25.1% (95% CI, 22.3–28.0%). The most common STIs were UU (13.2%) and MH (11.3%), followed by CT (6.6%), TV (3.2%), NG (0.3%), and MG (0.5%). U. urealyticum was more prevalent among sex workers compared to non-sex workers (19.7 vs 10.4%, p=0.001). Number of partners positively correlated with UU (P=0.004), while duration of sexual activity was positively correlated with MH (P Conclusion U. urealyticum and M. hominis were the most prevalent STIs among young women from Mombasa, Kenya, and these organisms were associated with sexual exposure and an inflammatory mucosal milieu that has been linked to increased HIV acquisition. Disclosure No significant relationships.
- Published
- 2019
41. Plasma concentration of injectable contraceptive correlates with reduced cervicovaginal growth factor expression in South African women
- Author
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Nobuhle Mchunu, Amanda Mabhula, Adam Burgener, Refilwe P Molatlhegi, Jo-Ann S. Passmore, Michelle Perner, Salim S. Abdool Karim, Sinaye Ngcapu, Alasdair Leslie, Lenine J. P. Liebenberg, Laura Noël-Romas, Natasha Samsunder, Kenzie Birse, Lyle R. McKinnon, Katya Govender, Nigel Garrett, John H. Adamson, and Quarraisha Abdool Karim
- Subjects
0301 basic medicine ,Adult ,medicine.medical_treatment ,Immunology ,Physiology ,Cervix Uteri ,03 medical and health sciences ,South Africa ,Young Adult ,0302 clinical medicine ,Immune system ,Tandem Mass Spectrometry ,Contraceptive Agents, Female ,Immunology and Allergy ,Medicine ,Humans ,Sex organ ,Hiv acquisition ,Young adult ,Host protein ,Mucous Membrane ,business.industry ,Growth factor ,Microbiota ,030104 developmental biology ,Gene Expression Regulation ,Plasma concentration ,Vagina ,Vaginal microbiome ,Cytokines ,Intercellular Signaling Peptides and Proteins ,Female ,Drug Monitoring ,business ,Biomarkers ,030215 immunology ,Chromatography, Liquid - Abstract
Long-acting injectable contraceptives have been associated with mucosal immune changes and increased HIV acquisition, but studies have often been hampered by the inaccuracy of self-reported data, unknown timing of injection, and interactions with mucosal transmission co-factors. We used mass spectrometry to quantify the plasma concentrations of injectable contraceptives in women from the CAPRISA004 study (n = 664), with parallel quantification of 48 cytokines and >500 host proteins in cervicovaginal lavage. Higher DMPA levels were associated with reduced CVL concentrations of GCSF, MCSF, IL-16, CTACK, LIF, IL-1α, and SCGF-β in adjusted linear mixed models. Dose-dependent relationships between DMPA concentration and genital cytokines were frequently observed. Unsupervised clustering of host proteins by DMPA concentration suggest that women with low DMPA had increases in proteins associated with mucosal fluid function, growth factors, and keratinization. Although DMPA was not broadly pro-inflammatory, DMPA was associated with increased IP-10 in HSV-2 seropositive and older women. DMPA–cytokine associations frequently differed by vaginal microbiome; in non-Lactobacillus-dominant women, DMPA was associated with elevated IL-8, MCP-1, and IP-10 concentrations. These data confirm a direct, concentration-dependant effect of DMPA on functionally important immune factors within the vaginal compartment. The biological effects of DMPA may vary depending on age, HSV-2 status, and vaginal microbiome composition.
- Published
- 2019
42. Diminished HIV Infection of Target CD4+ T Cells in a Toll-Like Receptor 4 Stimulated
- Author
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Ross, Cromarty, Alex, Sigal, Lenine J P, Liebenberg, Lyle R, McKinnon, Salim S, Abdool Karim, Jo-Ann S, Passmore, and Derseree, Archary
- Subjects
CD4-Positive T-Lymphocytes ,Immunology ,innate antiviral immunity ,HIV ,HIV Infections ,Lymphocyte Activation ,immune activation ,cytokines ,Toll-like receptors ,Toll-Like Receptor 4 ,inflammation ,Humans ,Cells, Cultured ,Original Research - Abstract
Genital inflammation is associated with increased HIV acquisition risk. Induction of an inflammatory response can occur through the recognition of pathogenic or commensal microbes by Toll-like receptors (TLRs) on various immune cells. We used a in vitro peripheral blood mononuclear cell (PBMC) system to understand the contribution of TLR stimulation in inducing inflammation and the activation of target T cells, and its effect on HIV susceptibility. PBMCs were stimulated with TLR agonists LPS (TLR4), R848 (TLR7/8), and Pam3CSK4 (TLR1/2), and then infected with HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines in cell culture supernatants. Flow cytometry was used to measure the activation state (CD38 and HLA-DR), and CCR5 expression on CD4+ and CD8+ T cells. Although TLR agonists induced higher cytokine and chemokine secretion, they did not significantly activate CD4+ and CD8+ T cells and showed decreased CCR5 expression relative to the unstimulated control. Despite several classes of inflammatory cytokines and chemokines being upregulated by TLR agonists, CD4+ T cells were significantly less infectable by HIV after TLR4-stimulation than the unstimulated control. These data demonstrate that the inflammatory effects that occur in the presence TLR agonist stimulations do not necessarily translate to the activation of T cells. Most importantly, the finding that TLR4-stimulation reduces rather than increases susceptibility of CD4+ T cells to HIV infection in this in vitro system strongly suggests that the increased chemokine and possible antiviral factor expression induced by these TLR agonists play a powerful although complex role in determining HIV infection risk.
- Published
- 2019
43. Burden of Sexually Transmitted Infections (STI) in Rural and Peri-Urban KwaZulu-Natal, South Africa: Findings from a Population-Based Household Survey
- Author
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Kaymarlin Govender, Gavin George, Lyle R. McKinnon, Sean Beckett, Cherie Cawood, Domiciled Venessa Maseko, Kassahun Ayalew, Carlos Toledo, Ayesha B. M. Kharsany, David Khanyile, Lara Lewis, and Tawni C. Goodman
- Subjects
medicine.medical_specialty ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Public health ,Population ,medicine.disease ,medicine.disease_cause ,Rapid plasma reagin ,Syndemic ,Acquired immunodeficiency syndrome (AIDS) ,medicine ,Syphilis ,Chlamydia trachomatis ,business ,education ,Reproductive health ,Demography - Abstract
Background: Sexually transmitted infections (STI) contribute to enhancing HIV transmission and acquisition; however, population level prevalence of STI from high HIV burden settings are limited Methods: A population-based household survey undertaken between June 2014 and June 2015 enrolled 15–49 year old males and females in the Vulindlela and Greater Edendale areas of KwaZulu-Natal, South Africa. Data collected includedself-reported sociodemographic, behavioral, and clinical variables. For curable STIs, first-pass urine (males) or self-collected vulvo-vaginal swabs (females) were tested for Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Mycoplasma genitalium using multiplex real-time polymerase chain reaction (PCR) and for syphilis serum sample was tested using a non-treponemal rapid plasma reagin (RPR) assay. Herpes simplex virus type 2 (HSV-2) and HIV antibodies were assessed by enzyme-linked immunosorbent assays. Prevalence of all STIs was measured and the association between participant characteristics and curable STIs was estimated using Poisson regression. Findings: Among the 9812 enrolled participants, 38·9% were under the age of 25 years and 63·9% were females. Among males and females, the prevalence of HIV was 28·0% and 44·1%, p
- Published
- 2019
44. Sex Work and Sexual Behaviour: Associations with Vaginal Microbiome and Cytokine Profiles in Young Women from Mombasa, Kenya
- Author
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Nichole R. Klatt, Sammy Wambua, Huiting Ma, Paul J. McLaren, Marissa Becker, Peter Gichangi, Nzioki King’ola, Eve Cheuk, Ruth S. Mwatelah, Aida Sivro, Lyle R. McKinnon, Sharmistha Mishra, Cheli Kambaran, Alexander S. Zevin, and Henok Gebrebrhan
- Subjects
Multivariate analysis ,biology ,business.industry ,medicine.medical_treatment ,Developing country ,Disease cluster ,biology.organism_classification ,Clinical trial ,Cytokine ,medicine ,Prevotella ,Microbiome ,business ,Sex work ,Demography - Abstract
Background: Certain cervicovaginal microbiota and inflammatory cytokines are strongly associated with each other and with HIV acquisition, but the upstream drivers of this "risk milieu" remain partially defined. Methods: We characterized the vaginal microbiome and cytokine profiles of sexually active young women aged 14-24 years from Mombasa, Kenya (n=168) who were recruited from venues or "hotspots" associated with sex work. Vaginal secretions were collected via self-inserted SoftCupTM, and assayed for cytokines and vaginal microbiome via multiplex ELISA and 16S rRNA sequencing, respectively. Findings: The median age of participants was 20 (IQR: 18-22). In 63% of women (105/168) the vaginal microbial communities were characterized by Gardnerella and/or Prevotella spp.-dominance; a further 29% (49/168) were predominantly Lactobaccillus iners. Microbiome cluster explained a large proportion of cytokine variation (>50% by the first 2 principle components). Age was not associated with vaginal microbial profiles in univariate or multivariate analyses. Women self-identifying as sex workers had increased alpha (intra-individual) diversity, independent of age, recent sexual activity, HIV and other STIs (beta = 0.55, 95% CI: 0.13-0.97, p = 0.01). Recent sex (number of partners or vaginal sex acts last week, time since last vaginal sex) correlated with increased alpha diversity, even in participants who were not involved in sex work. Interpretation: HIV risk-associated vaginal microbial profiles and inflammation were highly associated with each other and both highly prevalent in young women from Mombasa, Kenya. These risk profiles did not differ by age, but were increased in those engaging in formal sex work, and in all participants engaging in recent and/or more frequent sexual activity. Funding Statement: The Transitions study was funded by an operating grant (MOP-13044) from the Canadian Institutes of Health Research (CIHR). Biological aspects of the study were funded by the Canadian Institute of Health Research (CIHR), grant numbers TMI 138658 and PJT-148796. AS is funded by the European & Developing Countries Clinical Trials Partnership (EDCTP) Career Development Fellowship; SM is supported by a CIHROHTN New Investigator Award; MB and LRM are supported by CIHR New Investigator Awards. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The study was approved by the ethical review boards of the University of Manitoba and Kenyatta National Hospital.
- Published
- 2019
45. Mucosal HIV Shedding During ART
- Author
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Lyle R. McKinnon and Aida Sivro
- Subjects
0301 basic medicine ,business.industry ,Human immunodeficiency virus (HIV) ,HIV Infections ,Viral Load ,medicine.disease_cause ,030112 virology ,Virology ,Antiretroviral therapy ,Major Articles and Brief Reports ,03 medical and health sciences ,0302 clinical medicine ,Infectious Diseases ,HIV-1 ,Prevalence ,medicine ,Humans ,Immunology and Allergy ,Female ,Genitalia ,030212 general & internal medicine ,Viral shedding ,business ,Viral load - Abstract
Genital HIV shedding was infrequent among women on antiretroviral therapy (ART) with undetectable plasma viral load, and was associated with advanced disease, time on ART, and genital ulcers. Treating genital tract infections may further decrease HIV-1 shedding and potential transmission.
- Published
- 2017
46. Vaginal microbiome-hormonal contraceptive interactions associate with the mucosal proteome and HIV acquisition
- Author
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Adam Burgener, Lyle R. McKinnon, Sarah Hoger, Alana Lamont, Alicia R. Berard, Vanessa Poliquin, Kenzie Birse, Michelle Perner, Christina Farr Zuend, Renee Heffron, Stuart McCorrister, Garett Westmacott, Laura Noël-Romas, Al Leslie, Amanda Mabhula, and Refilwe P Molatlhegi
- Subjects
RNA viruses ,Proteome ,Proteomes ,Epidemiology ,Physiology ,HIV Infections ,Pathology and Laboratory Medicine ,Biochemistry ,chemistry.chemical_compound ,0302 clinical medicine ,Immunodeficiency Viruses ,Contraceptive Agents, Female ,Medicine and Health Sciences ,Medroxyprogesterone acetate ,Biology (General) ,Immune Response ,0303 health sciences ,030219 obstetrics & reproductive medicine ,Microbiota ,Obstetrics and Gynecology ,Genomics ,Middle Aged ,3. Good health ,Contraception ,Contraceptive Agents, Hormonal ,Medical Microbiology ,Viral Pathogens ,Vagina ,Viruses ,Cohort ,Female ,Pathogens ,Research Article ,medicine.drug ,Adult ,QH301-705.5 ,Immunology ,Context (language use) ,Microbial Genomics ,Microbiology ,03 medical and health sciences ,Signs and Symptoms ,Virology ,Retroviruses ,Genetics ,medicine ,Humans ,Female Contraception ,Sex organ ,Microbiome ,Microbial Pathogens ,Molecular Biology ,030304 developmental biology ,Inflammation ,Mucous Membrane ,Bacteria ,business.industry ,Lentivirus ,Gut Bacteria ,Organisms ,Biology and Life Sciences ,HIV ,Proteins ,RC581-607 ,Lactobacillus ,chemistry ,Medical Risk Factors ,Relative risk ,Women's Health ,Parasitology ,Norethisterone enanthate ,Clinical Medicine ,Immunologic diseases. Allergy ,business ,Hormone - Abstract
Alterations to the mucosal environment of the female genital tract, such as genital inflammation, have been associated with increased HIV acquisition in women. As the microbiome and hormonal contraceptives can affect vaginal mucosal immunity, we hypothesized these components may interact in the context of HIV susceptibility. Using previously published microbiome data from 685 women in the CAPRISA-004 trial, we compared relative risk of HIV acquisition in this cohort who were using injectable depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), and combined oral contraceptives (COC). In women who were Lactobacillus-dominant, HIV acquisition was 3-fold higher in women using DMPA relative to women using NET-EN or COC (OR: 3.27; 95% CI: 1.24–11.24, P = 0.0305). This was not observed in non-Lactobacillus-dominant women (OR: 0.95, 95% CI: 0.44–2.15, P = 0.895) (interaction P = 0.0686). Higher serum MPA levels associated with increased molecular pathways of inflammation in the vaginal mucosal fluid of Lactobacillus-dominant women, but no differences were seen in non-Lactobacillus dominant women. This study provides data suggesting an interaction between the microbiome, hormonal contraceptives, and HIV susceptibility., Author summary Alterations to the mucosal environment of the female genital tract have been associated with increased HIV acquisition in women. As both the vaginal microbiome and hormonal contraceptives affect mucosal immunity, we investigated their interaction with HIV susceptibility. We characterized the vaginal microbiomes in 685 women from the CAPRISA-004 trial, who utilized three major types of hormonal contraceptives including injectable depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), and combined oral contraceptives (COC). In the 40% of women with Lactobacillus-depleted microbiomes, HIV acquisition was not different between contraceptive groups. However, in the 60% of women with Lactobacillus as the dominant bacterial taxa, HIV acquisition risk was 3-fold higher (in women using DMPA relative to women using NET-EN and COC). Higher serum medroxyprogesterone acetate levels in Lactobacillus dominant women associated with increased cervicovaginal inflammation pathways in the mucosal proteome, biomarkers of which associated with HIV susceptibility. This study provides data suggesting an interaction between the microbiome, hormonal contraceptives, and HIV susceptibility.
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- 2020
47. Descriptive Epidemiology of Factors Associated with HIV Infections Among Men and Transgender Women Who Have Sex with Men in South India
- Author
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Shajy Isac, Lyle R. McKinnon, Sushena Reza-Paul, Reynold Washington, Souradet Y. Shaw, James F. Blanchard, Elsabé du Plessis, Robert Lorway, Laura H. Thompson, Parinita Bhattacharjee, Stephen Moses, and Banadakoppa M Ramesh
- Subjects
Male ,HIV risk ,Human immunodeficiency virus (HIV) ,men who have sex with men ,HIV Infections ,Logistic regression ,medicine.disease_cause ,Transgender women ,law.invention ,Men who have sex with men ,Condoms ,0302 clinical medicine ,law ,Odds Ratio ,Prevalence ,030212 general & internal medicine ,education.field_of_study ,Obstetrics and Gynecology ,Regression analysis ,Psychiatry and Mental health ,Female ,0305 other medical science ,Adult ,medicine.medical_specialty ,Adolescent ,Alcohol Drinking ,Urology ,Population ,India ,Dermatology ,Transgender Persons ,Young Adult ,03 medical and health sciences ,Condom ,medicine ,Humans ,Homosexuality, Male ,education ,Sex work ,Gynecology ,030505 public health ,business.industry ,Public Health, Environmental and Occupational Health ,Original Articles ,alcohol use ,Sex Work ,Cross-Sectional Studies ,Logistic Models ,Socioeconomic Factors ,Multivariate Analysis ,business ,Demography - Abstract
Purpose: Men and transgender women who have sex with men (MTWSM) continue to be an at-risk population for human immunodeficiency virus (HIV) infection in India. Identification of risk factors and determinants of HIV infection is urgently needed to inform prevention and intervention programming. Methods: Data were collected from cross-sectional biological and behavioral surveys from four districts in Karnataka, India. Multivariable logistic regression models were constructed to examine factors related to HIV infection. Sociodemographic, sexual history, sex work history, condom practices, and substance use covariates were included in regression models. Results: A total of 456 participants were included; HIV prevalence was 12.4%, with the highest prevalence (26%) among MTWSM from Bellary District. In bivariate analyses, district (P = 0.002), lack of a current regular female partner (P = 0.022), and reported consumption of an alcoholic drink in the last month (P = 0.004) were associated with HIV infection. In multivariable models, only alcohol use remained statistically significant (adjusted odds ratios: 2.6, 95% confidence intervals: 1.2–5.8; P = 0.02). Conclusion: The prevalence of HIV continues to be high among MTWSM, with the highest prevalence found in Bellary district.
- Published
- 2016
48. Factors Driving the HIV Epidemic in Southern Africa
- Author
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Lyle R. McKinnon and Quarraisha Abdool Karim
- Subjects
0301 basic medicine ,Health Knowledge, Attitudes, Practice ,Sexual Behavior ,Hiv epidemic ,Population ,Human immunodeficiency virus (HIV) ,HIV Infections ,Context (language use) ,Biology ,medicine.disease_cause ,Africa, Southern ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Virology ,Environmental health ,Pandemic ,Prevalence ,medicine ,Humans ,030212 general & internal medicine ,Social Behavior ,education ,Health Education ,Africa South of the Sahara ,education.field_of_study ,Transmission (medicine) ,030104 developmental biology ,Infectious Diseases ,Socioeconomic Factors ,Sexual behavior ,Immunology ,Women's Health ,Health education - Abstract
The HIV pandemic has disproportionately impacted sub-Saharan Africa and Southern Africa in particular. The concurrent presence of overlapping epidemic drivers likely underpins how and why the HIV epidemic is so explosive in this region, with implications for understanding approaches to reduce transmission. In this review, we discuss the relative contribution and interaction between epidemic drivers in the Southern African context, including factors both distally and proximally associated with the likelihood and degree of exposure to HIV and factors that increase the probability of transmission when exposure occurs. In particular, we focus on young women as a key population in need of HIV prevention and highlight factors that increase their risk on several levels.
- Published
- 2016
49. Identification of preferential CD4+ T-cell targets for HIV infection in the cervix
- Author
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J O Obila, Lyle R. McKinnon, J Liu, Sanja Huibner, S Kimwaki, Omu Anzala, Rupert Kaul, Joshua Kimani, Billy Nyanga, S T Kidane, K E Besel, James Arthos, Vineet Joag, Julius Oyugi, Mario A. Ostrowski, and Mark H. Yudin
- Subjects
Adult ,Antigens, Differentiation, T-Lymphocyte ,CD4-Positive T-Lymphocytes ,0301 basic medicine ,Integrins ,Virus genetics ,Receptors, CCR5 ,Primary Cell Culture ,Immunology ,Integrin ,Cervix Uteri ,Integrin alpha4beta1 ,Biology ,03 medical and health sciences ,Interleukin 21 ,Antigen ,Antigens, CD ,Viral entry ,Humans ,Immunology and Allergy ,Lectins, C-Type ,Receptor ,Immunity, Mucosal ,CD69 ,env Gene Products, Human Immunodeficiency Virus ,virus diseases ,Middle Aged ,Virus Internalization ,Virology ,Molecular biology ,030104 developmental biology ,Gene Expression Regulation ,Organ Specificity ,Cell culture ,Host-Pathogen Interactions ,HIV-1 ,biology.protein ,Receptors, Virus ,Female ,Signal Transduction - Abstract
A better understanding of the cellular targets of HIV infection in the female genital tract may inform HIV prevention efforts. Proposed correlates of cellular susceptibility include the HIV co-receptor CCR5, peripheral homing integrins, and immune activation. We used a CCR5-tropic pseudovirus to quantify HIV entry into unstimulated endocervical CD4(+) T cells collected by cytobrush. Virus entry was threefold higher into cervix-derived CD4(+) T cells than blood, but was strongly correlated between these two compartments. Cervix-derived CD4(+) T cells expressing CD69, α(4)β(7), or α(4)β(1) were preferential HIV targets; this enhanced susceptibility was strongly correlated with increased CCR5 expression in α(4)β(7)(+) and CD69(+) CD4(+) T cells, and to a lesser extent in α(4)β(1)(+) CD4(+) T cells. Direct binding of gp140 to integrins was not observed, integrin inhibitors had no effect on virus entry, and pseudotypes with an env that preferentially binds α(4)β(7) still demonstrated enhanced entry into α(4)β(1)(+) cells. In summary, a rapid and sensitive HIV entry assay demonstrated enhanced susceptibility of activated endocervical CD4(+) T cells, and those expressing α(4)β(7) or α(4)β(1). This may relate to increased CCR5 expression by these cell subsets, but did not appear to be due to direct interaction of α(4)β(7) or α(4)β(1) with HIV envelope.
- Published
- 2016
50. Integrin α 4 β 7 expression on peripheral blood CD4 + T cells predicts HIV acquisition and disease progression outcomes
- Author
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Rupert Kaul, James Arthos, Aida Sivro, Lyle R. McKinnon, Lenine J. P. Liebenberg, Salim S. Abdool Karim, Natasha Samsunder, Anthony S. Fauci, Vineet Joag, Nigel Garrett, Aftab A. Ansari, Jintanat Ananworanich, Anisha Balgobin, AO Anzala, Alexandra Schuetz, Jo-Ann S. Passmore, Nittaya Phanuphak, Ruth S. Mwatelah, Quarraisha Abdool Karim, Nonhlanhla Yende-Zuma, Bernard S. Bagaya, Daniel J. Sheward, Rv study groups, Noah Kiwanuka, Joshua Kimani, Claudia Cicala, Sergey Yegorov, Andrew T. Stalker, Fatima Nawaz, Carolyn Williamson, and Philippe Selhorst
- Subjects
0301 basic medicine ,biology ,business.industry ,medicine.drug_class ,T cell ,Inflammation ,General Medicine ,Simian immunodeficiency virus ,medicine.disease_cause ,Monoclonal antibody ,Pathogenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,Immunology ,medicine ,biology.protein ,030212 general & internal medicine ,medicine.symptom ,business ,Viral load ,Lipopolysaccharide binding protein - Abstract
The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α4β7 promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that α4β7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α4β7+ peripheral blood CD4+ T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for α4β7 binding. In addition, pre-HIV α4β7+ CD4+ T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4+ T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV α4β7+ CD4+ T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4+ T cells expressing α4β7 were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between α4β7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α4β7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α4β7 integrin as a clinical intervention during HIV infection.
- Published
- 2018
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