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Understanding variables that influence antibody responses to COVID-19 vaccination within a population can provide valuable information on future vaccination strategies. In this population-based study, we examined the antibody responses to COVID-19 vaccination in Manitoba using residual serum specimens collected between January 2021 and March 2022 (n = 20,365). Samples were tested for spike and nucleocapsid IgG against SARS-CoV-2 using clinically validated assays. We assessed the impacts of multiple factors on post-vaccination antibody titres including type of vaccine, age, sex, geographic location, number of doses received, and timing of vaccination. Our investigation demonstrated that vaccination with one dose of Moderna mRNA-1273 elicited higher anti-spike IgG titres overall compared to Pfizer BNT162b2 vaccination, while one dose of Pfizer BNT162b2 followed by a second dose of Moderna mRNA-1273 exhibited higher titres than two doses of Pfizer BNT162b2 or Moderna mRNA-1273, irrespective of age. Age and time post-vaccination had considerable effects on antibody responses, with older age groups exhibiting lower anti-spike IgG titres than younger ages, and titres of those vaccinated with Pfizer BNT162b2 waning faster than those vaccinated with Moderna mRNA-1273 or a combination of Pfizer BNT162b2 and Moderna mRNA-1273. Antibody titres did not appear to be affected by sex or geographic location. Our results identify how factors such as age and type of vaccine can influence antibody responses to vaccination, and how antibody titres wane over time. This information highlights the importance of tailoring vaccine regimens to specific populations, especially those at increased risk of severe COVID-19 and can be used to inform future vaccination strategies, scheduling of booster doses, and public health measures.

Background: Evidence on the distribution of pre-treatment HIV-1 drug resistance (HIVDR) among risk groups is limited in Africa. We assessed the prevalence, trends and transmission dynamics of pre-treatment HIVDR within and between MSM, people who inject drugs (PWID), female sex workers (FSWs), heterosexuals (HETs) and perinatally infected children in Kenya., Methods: HIV-1 partial pol sequences from antiretroviral-naive individuals collected from multiple sources between 1986 and 2020 were used. Pre-treatment reverse transcriptase inhibitor (RTI), PI and integrase inhibitor (INSTI) mutations were assessed using the Stanford HIVDR database. Phylogenetic methods were used to determine and date transmission clusters., Results: Of 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%), FSWs (15.1%) and HETs (13.9%). Overall, pre-treatment HIVDR increased consistently, from 6.9% (before 2005) to 24.2% (2016-20). Among HETs, pre-treatment HIVDR increased from 6.6% (before 2005) to 20.2% (2011-15), but dropped to 6.5% (2016-20). Additionally, 32 clusters with shared pre-treatment HIVDR mutations were identified. The majority of clusters had R0 ≥ 1.0, indicating ongoing transmissions. The largest was a K103N cluster involving 16 MSM sequences sampled between 2010 and 2017, with an estimated time to the most recent common ancestor (tMRCA) of 2005 [95% higher posterior density (HPD), 2000-08], indicating propagation over 12 years., Conclusions: Compared to HETs, children and key populations had higher levels of pre-treatment HIVDR. Introduction of INSTIs after 2017 may have abrogated the increase in pre-treatment RTI mutations, albeit in the HET population only. Taken together, our findings underscore the need for targeted efforts towards equitable access to ART for children and key populations in Kenya., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

We aimed to illuminate the challenges of treating anal diseases among gay, bisexual and other men who have sex with men (GBMSM) in a homophobic climate amid resource constraints. Building on a long-term Kenyan-Canadian collaboration, an anal healthcare intervention study, known as the WEMAH Project, was initiated in January 2022. The initial collaborative work strengthened existing anal health services provided at a community-based clinic serving GBMSM in Nairobi. The illness and treatment journey for one patient is highlighted. Prior to attending the community clinical programme, reluctance to disclose symptoms to other healthcare workers, misdiagnoses and incorrect treatment, absence of physical exam conducted, lack of access to effective medications, and self-treatment attempts not only led to late disease detection but also exacerbated the illness itself, culminating in advanced disease progression accompanied by severe pain and suffering. However, once connected to the community clinic with the enhanced anal healthcare programme, the disease was effectively managed by the clinical team. Although specialised clinics have been established throughout Kenya to meet the STI-related needs of GBMSM, the constellation of factors highlighted in one patient's journey, from illness to recovery, reveals important gaps in Kenya's existing sexual health programme for GBMSM.

Importance: It has been previously shown that genetic variants near CHD1L on chromosome 1 are associated with reduced HIV VL in African populations. However, the impact of these variants on viral diversity and how they restrict viral replication are unknown. We report on a regional association analysis in a South African population and show evidence of selective pressure by variants near CHD1L on HIV RT and gag. Our findings provide further insight into how genetic variability at this locus contributes to host control of HIV in a South African population., Competing Interests: The authors declare no conflict of interest.

Background: HIV programming in Ukraine largely targets "key population" groups. Men who purchase sex are not directly reached. The aim of our study was to explore the prevalence of sexually transmitted and blood-borne infections (STBBIs) among men who purchase sex from female sex workers., Methods: Following geographic mapping and population size estimation at each "hotspot", we conducted a cross-sectional bio-behavioural survey with men who purchase sex between September 2017 and March 2018 in Dnipro, Ukraine. Eligibility criteria included purchasing sex services at a "hotspot" and being ≥ 18 years. Participants completed a structured questionnaire, followed by HIV/HCV rapid testing and a dried blood spot (DBS) sample collection for confirmatory serology., Results: The study enrolled 370 participants. The median age was 32 (interquartile range [IQR] = 27-38) and the median age of first purchase of sexual services was 22 (IQR = 19-27). Over half (56%) of participants reported ever testing for HIV; four participants (2%, N = 206) reported having tested positive for HIV, with three out of the four reporting being on ART. Forty percent of participants had ever tested for HCV, with three (2%, N = 142) having ever tested positive for HCV. In DBS testing, nine participants (2.4%) tested positive for HIV and 24 (6.5%) tested positive for ever having an HCV infection., Conclusion: Prevalence of HIV and HCV in this population was high. Given high rates of study enrolment and testing, efforts should be made to reach men who purchase sex with expanded STBBI programming., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Kenya's HIV epidemic is heterogeneously distributed. Although HIV incidence in Kenya has shown signs of recent decline, focused interventions are still needed for female sex workers (FSWs). Geospatially informed approaches have been advocated for targeted HIV prevention. We quantified heterogeneity in HIV burden in Nairobi-based FSWs by place of origin within Kenya and hotspots and residence within Nairobi., Methods: Data were collected as part of enrolment in the Sex Workers Outreach Program in Nairobi between 2014 and 2017. Prevalence ratios were used to quantify the risk of HIV by high-prevalence counties using modified Poisson regression analyses. Crude and fully adjusted models were fitted to the data. In heterogeneity analyses, hotspots and residences were aggregated to the Nairobi constituency level (n = 17). Inequality in the geographic distribution of HIV prevalence was measured using the Gini coefficient., Results: A total of 11,899 FSWs were included. Overall HIV prevalence was 16%. FSWs originating from a high-prevalence country were at 2-fold increased risk of living with HIV in adjusted analysis (prevalence ratio 1.95; 95% CI: 1.76 to 2.17). HIV prevalence was also highly heterogeneous by hotspot, ranging from 7% to 52% by hotspot (Gini coefficient: 0.37; 95% CI: 0.23 to 0.50). By contrast, the constituency of residence had a Gini coefficient of 0.08 (95% CI: 0.06 to 0.10), suggesting minimal heterogeneity by residence., Conclusion: HIV prevalence in FSWs is heterogeneous by place of work within Nairobi and by county of birth within Kenya. As HIV incidence declines and financial commitments flatline, tailoring interventions to FSWs at highest HIV risk becomes increasingly important., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Understanding the complex interactions of the immune response mediated by Mycobacterium tuberculosis and HIV co-infection is fundamental to disease biomarker discovery, vaccine, and drug development. Using flow cytometry, we characterized the frequencies and phenotypic differences in monocytes and dendritic cell populations using peripheral blood mononuclear cells from individuals with recurrent, active pulmonary tuberculosis with and without coexisting HIV infection (CAPRISA 011, Clinicaltrials.gov, NCT02114684, 29/01/2014) and compared them to samples from HIV positive individuals and healthy controls. Additionally, we assessed the associations between the frequency of monocyte and dendritic cell subsets and time to culture conversion and cavitary disease in patients with active TB using a cox proportional hazards and logistic regression models., Results: Compared to healthy controls, the frequency of total monocytes (HLA-DR + CD14 +) was significantly higher in the TB/HIV and TB groups and the frequency of dendritic cells (HLA-DR + CD14-) was significantly higher in TB/HIV and HIV groups. We observed significant variation in the expression of CCR2, CD40, CD11b, CD86, CD163, CX3CR1 across different cell subsets in the four study groups. Increase in CCR2, CD11b and CD40 was associated with active TB infection, while decrease in CX3CR1 and increase in CD163 was associated with HIV infection. Expression of CX3CR1 (aHR 0.98, 95% CI 0.963 - 0.997, p = 0.019) on non-classical monocytes associated with longer time to TB culture conversion in the multivariable model correcting for randomization arm, age, sex, HIV status, lung cavitation, alcohol use, smoking and BMI. Higher surface expression of CD86 (aOR 1.017, 95% CI 1.001 - 1.032, p = 0.033) on intermediate monocytes associated with the presence of lung cavitation, while higher expression of transitional monocytes (aOR 0.944, 95% CI 0.892 - 0.999, p = 0.047) associated with the absence of lung cavitation in the multivariable model., Conclusion: These data provide valuable insight into the heterogenous role of monocyte and dendritic cells in TB and HIV infections., (© 2023. The Author(s).)

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8 +  and CD4 +  T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Neutrophil recruitment and activation within the female genital tract are often associated with tissue inflammation, loss of vaginal epithelial barrier integrity, and increased risk for sexually transmitted infections, such as HIV-1. However, the direct role of neutrophils on vaginal epithelial barrier function during genital inflammation in vivo remains unclear. Using complementary proteome and immunological analyses, we show high neutrophil influx into the lower female genital tract in response to physiological surges in progesterone, stimulating distinct stromal, immunological, and metabolic signaling pathways. However, despite the release of extracellular matrix-modifying proteases and inflammatory mediators, neutrophils contributed little to physiological mucosal remodeling events such as epithelial shedding or re-epithelialization during transition from diestrus to estrus phase. In contrast, the presence of bacterial vaginosis-associated bacteria resulted in a rapid and sustained neutrophil recruitment, resulting in vaginal epithelial barrier leakage and decreased cell-cell junction protein expression in vivo. Thus, neutrophils are important mucosal sentinels that rapidly respond to various biological cues within the female genital tract, dictating the magnitude and duration of the ensuing inflammatory response at steady state and during disease processes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Human papillomavirus (HPV) infection is associated with anal cancers and is more prevalent in gay, bisexual, and men who have sex with men (gbMSM), partly due to their vulnerability to HIV infection. Baseline HPV genotype distributions and risk factors can inform the design of next-generation HPV vaccines to prevent anal cancer., Methods: A cross-sectional study was conducted among gbMSM receiving care at a HIV/STI clinic in Nairobi, Kenya. Anal swabs were genotyped using a Luminex microsphere array. Multiple logistic regression methods were used to identify risk factors for four HPV outcomes (any HPV, any HR-HPV, and 4- and 9-valent vaccine-preventable HPVs)., Results: Among 115 gbMSM, 51 (44.3%) were HIV-infected. Overall HPV prevalence was 51.3%; 84.3% among gbMSM living with HIV and 24.6% among gbMSM without HIV (p < 0.001). One-third (32.2%) had HR-HPV and the most prevalent vaccine-preventable HR-HPV genotypes were 16, 35, 45, and 58. HPV-18 was uncommon (n = 2). The 9-valent Gardasil vaccine would have prevented 61.0% of HPV types observed in this population. In multivariate analyses, HIV status was the only significant risk factor for any HPV (adjusted odds ratio [aOR]:23.0, 95% confidence interval [95% CI]: 7.3-86.0, p < 0.001) and for HR-HPV (aOR: 8.9, 95% CI: 2.8-36.0, p < 0.001). Similar findings were obtained for vaccine-preventable HPVs. Being married to a woman significantly increased the odds of having HR-HPV infections (aOR: 8.1, 95% CI: 1.6-52.0, p = 0.016)., Conclusions: GbMSM living with HIV in Kenya are at higher risk of anal HPV infections including genotypes that are preventable with available vaccines. Our findings support the need for a targeted HPV vaccination campaign in this population., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To infer the timing of HIV acquisition in relation to self-reported events in the sexual life course of adolescent girls and young women (AGYW) who self-identify as female sex workers (FSW) in Mombasa, Kenya., Design: Next-generation viral sequencing of samples of AGYW living with HIV in the Transitions study, a cross-sectional bio-behavioural survey of AGYW aged 14-24 years in Mombasa, Kenya., Method: Dried blood spot specimens were collected from study participants ( n  = 37, all FSW). A portion of the HIV pol gene was sequenced using an in-house next-generation sequencing assay for HIV drug resistance mutation genotyping. Estimated time since infection (ETI) was inferred using the HIV EVO web-based tool ( https://hiv.biozentrum.unibas.ch/ETI/ ), and data on self-reported events were obtained from the survey., Results: The median ETI among FSW was 3.4 (interquartile range = 1.7, 6.3) years, with a median ETI of 1.5 years prior to entry into formal sex work. We estimated that 74.1% (95% confidence interval = 53.7-88.9%) of participants living with HIV and who self-identified as FSW likely acquired HIV prior to self-identification as a sex worker., Conclusions: Findings suggest a large fraction of prevalent HIV infection among AGYW engaged in sex work stems from acquisition prior to entry into formal sex work. Current HIV prevention programs tailored for sex workers may miss key opportunities for HIV prevention as they are designed to reach women after entry into formal sex work, signaling a need for tailored programs to reach high-risk AGYW earlier on in their sexual life course., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: Potential conflicts of interest. M. P. reports participation as an editorial advisory board member for Global Graduate and Postgraduate Research Publishing (unpaid, started October 2022); and a leadership role as a board member of the not-for-profit charity Bridging Villages Inc (unpaid). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Most cervicovaginal microbiome-immunology studies to date have relied on 16S rDNA microbial profiling which does not resolve the molecular subgroups of Gardnerella , believed to be central to the pathogenesis of bacterial vaginosis (BV) and subsequent risk of HIV acquisition. Here we used the cpn 60 universal target which in addition to other microbial taxa, resolves four Gardnerella subgroups, for cervicovaginal microbial profiling in a longitudinal cohort of Kenyan women to examine associations with cellular and soluble markers of inflammation and HIV susceptibility. Participants (N = 41) were sampled, contributing 362 samples for microbiome analysis. All non- Lactobacillus dominant microbial communities were associated with high pro-inflammatory cytokine levels. Divergent associations were observed among different Gardnerella subgroup dominated communities with respect to the chemokine IP-10. Specifically, Gardnerella subgroup A dominant and polymicrobial communities were associated with reduced concentrations of IP-10 in adjusted linear mixed models (p<0.0001), compared to microbial communities dominated by Lactobacillus (non-iners) species. However, these associations did not translate to significant differences in the proportion or absolute number of CCR5, HLA-DR and CD38 expressed on cervical CD4 + T- cells. These findings suggest that some associations between Gardnerella subgroup dominant microbiomes and mucosal immunity differ and are relevant for the study of BV-pathogenesis and understanding the mechanisms of BV-associated HIV risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shvartsman, Perciani, Richmond, Russell, Tough, Vancuren, Hill, KAVI-ICR, Jaoko, McKinnon, Sandstrom and MacDonald.)

Background: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence., Methods: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples., Results: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1β, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here., Conclusions: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies., (© 2022. The Author(s).)

Background: The identification of baseline host determinants that associate with robust HIV-1 vaccine-induced immune responses could aid HIV-1 vaccine development. We aimed to assess both the collective and relative performance of baseline characteristics in classifying individual participants in nine different Phase 1-2 HIV-1 vaccine clinical trials (26 vaccine regimens, conducted in Africa and in the Americas) as High HIV-1 vaccine responders., Methods: This was a meta-analysis of individual participant data, with studies chosen based on participant-level (vs. study-level summary) data availability within the HIV-1 Vaccine Trials Network. We assessed the performance of 25 baseline characteristics (demographics, safety haematological measurements, vital signs, assay background measurements) and estimated the relative importance of each characteristic in classifying 831 participants as High (defined as within the top 25th percentile among positive responders or above the assay upper limit of quantification) versus Non-High responders. Immune response outcomes included HIV-1-specific serum IgG binding antibodies and Env-specific CD4+ T-cell responses assessed two weeks post-last dose, all measured at central HVTN laboratories. Three variable importance approaches based on SuperLearner ensemble machine learning were considered., Findings: Overall, 30.1%, 50.5%, 36.2%, and 13.9% of participants were categorized as High responders for gp120 IgG, gp140 IgG, gp41 IgG, and Env-specific CD4+ T-cell vaccine-induced responses, respectively. When including all baseline characteristics, moderate performance was achieved for the classification of High responder status for the binding antibody responses, with cross-validated areas under the ROC curve (CV-AUC) of 0.72 (95% CI: 0.68, 0.76) for gp120 IgG, 0.73 (0.69, 0.76) for gp140 IgG, and 0.67 (95% CI: 0.63, 0.72) for gp41 IgG. In contrast, the collection of all baseline characteristics yielded little improvement over chance for predicting High Env-specific CD4+ T-cell responses [CV-AUC: 0.53 (0.48, 0.58)]. While estimated variable importance patterns differed across the three approaches, female sex assigned at birth, lower height, and higher total white blood cell count emerged as significant predictors of High responder status across multiple immune response outcomes using Approach 1. Of these three baseline variables, total white blood cell count ranked highly across all three approaches for predicting vaccine-induced gp41 and gp140 High responder status., Interpretation: The identified features should be studied further in pursuit of intervention strategies to improve vaccine responses and may be adjusted for in analyses of immune response data to enhance statistical power., Funding: National Institute of Allergy and Infectious Diseases (UM1AI068635 to YH, UM1AI068614 to GDT, UM1AI068618 to MJM, and UM1 AI069511 to MCK), the Duke CFAR P30 AI064518 to GDT, and National Institute of Dental and Craniofacial Research (R01DE027245 to JJK). This work was also supported by the Bill and Melinda Gates Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding sources., Competing Interests: Declaration of interests Y.H. declares contract payments to her institution from the World Health Organization to conduct statistical analysis work (outside the scope of the current work; related to COVID-19 vaccines) and plan to submit the results for publication, within the past 36 months, as well as service to WHV as an SMB (payment directly to her) within the past 36 months. K.E.S. and J.H. declare coverage of travel expenses for attendance at the HVTN Full Group Meeting in 2022 (reimbursement by the HVTN); K.E.S. additionally declares payment of a registration fee for virtual seminar attendance directly to Keystone Symposium by the HVTN. S.D.R. declares contracts awarded to his institution from Battelle and from Janssen, and grants awarded to his institution from the Gates Medical Research Institute and from the Paul G. Allen Family Foundation, within the past 36 months. P.A.G. declares consulting fees received from Johnson and Johnson within the past 36 months, as well as a patent for a COVID-19 monoclonal antibody that is not yet clinically available. K.W.C. declares funding from the Bill and Melinda Gates Foundation in the form of payments to her institution within the last 36 months. B.D.W. declares grant payments made to his institution within the past 36 months from the following entities: Centers for Disease Control and Prevention, Patient-Centered Outcomes Research Institute, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, National Cancer Institute, and the National Institute of General Medical Studies; an honorarium for delivering an invited webinar to the American Statistical Association: Statistical Learning and Data Science Section; travel support through a grant from the National Institute of Mental Health; and retirement accounts invested in mutual funds operated by Vanguard and by TIAA (he does not choose individual stocks). L.-G.B. declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead Sciences, Janssen, and Merck PTY LTD within the past 36 months, as well as participation on a Data Safety Monitoring Board or Advisory Board for the PrEPVAC study within the past 36 months. G.D.T. declares consulting fees received from Axon and from Janssen (not related to this work), serving as an Advisory Board member for the NIH VRC, UNC CFAR, and Johns Hopkins (not related to this work), and serving as a scientific review member for Gilead (not related to this work), all within the past 36 months, as well as travel as part of research funding (more than 3 years prior, with funding paid to her institution). J.T. declares consulting fees from Vaccitech within the past 36 months., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Potential conflicts of interest. W. H. and J. G. G.-L. report royalties or licenses from Mylan, Laurus Generics, TAD Pharma, and CIPLA Limited. J. G. G.-L. and W. H. are named in the US govern­ment patents on Inhibition of HIV infection through chemoprophylaxis (US patents 9044509B2, 9579333, 9937191, 10335423B2), HIV Post-exposure prophylaxis (US patent 11,191,763 B2), and HIV pre-exposure prophylaxis (US govt patent application 17/628,170). All other authors re­port no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors con­sider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Competing Interests: Competing interests: None declared.

For decades, studies of natural killer (NK) cells have focused on those found in peripheral blood (PBNK cells) as the prototype for NK cell biology. Only recently have researchers begun to explore the diversity of tissue-resident NK (tr-NK) cells. While tr-NK cells were initially identified from mice parabiosis and intravascular staining experiments, they can also be identified by tissue retention markers such as CD69, CD103 and others. More importantly, tr-NK cells have distinct functions compared to PBNK cells. Within the liver, there are diverse subsets of tr-NK cells expressing different combinations of tissue-retention markers and transcription factors, the clinical relevance of which are still unclear. Functionally, liver tr-NK are primed with immediate responsiveness to infection and equipped with regulatory mechanisms to prevent liver damage. When decidual NK (dNK) cells were first discovered, they were mainly characterized by their reduced cytotoxicity and functions related to placental development. Recent studies, however, revealed different mechanisms by which dNK cells prevent uterine infections. The lungs are one of the most highly exposed sites for infection due to their role in oxygen exchange. Upon influenza infection, lung tr-NK cells can degranulate and produce more inflammatory cytokines than PBNK cells. Less understood are gut tr-NK cells which were recently characterized in infants and adults for their functional differences. In this mini-review, we aim to provide a brief overview of the most recent discoveries on how several tr-NK cells are implicated in the immune response against infection., (© 2022 John Wiley & Sons Ltd.)

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 log 10 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., (© 2022. The Author(s).)

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 < 400 copies per mL., 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 (Χ 2 trend P < 0.0001). Of the HIV positive participants, 84.5% (95% CI, 79.0-88.8) knew their HIV positive status, 98.3% (95% CI 95.1-99.4) who knew their status were on ART, and of those on ART, 95.9% (95% CI 91.8-98.0) were virally suppressed. Among all HIV-positives 90.8% (95% CI, 86.3-94.0) had achieved viral suppression, whilst those in the 14-19 year age group were least likely to be virally suppressed at 82.8% (95% CI 65.5-92.4) compared to those in the older age groups. Married women compared to those unmarried were more likely to have achieved viral suppression (PRR) of 1.11 (95% CI 1.05-1.18), P < 0.001., 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. 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., (© 2022. The Author(s).)

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 pol sequences sampled during 2006-2019 from MSM in Coast ( N = 178, 47.9%), Nairobi ( N = 137, 36.8%), and Nyanza ( N = 57, 15.3%) provinces in Kenya. Maximum-likelihood (ML) phylogenetics and Bayesian inference were used to determine HIV-1 clusters, evolutionary dynamics, and virus migration rates between geographic regions. HIV-1 sub-subtype A1 (72.0%) was most common followed by subtype D (11.0%), unique recombinant forms (8.9%), subtype C (5.9%), CRF 21A2D (0.8%), subtype G (0.8%), CRF 16A2D (0.3%), and subtype B (0.3%). Forty-six clusters (size range 2-20 sequences) were found-half (50.0%) of which had evidence of extensive HIV-1 mixing among different provinces. Data revealed an exponential increase in infections among MSM during the early-to-mid 2000s and stable or decreasing transmission dynamics in recent years (2017-2019). Phylogeographic inference showed significant (Bayes factor, BF > 3) HIV-1 dissemination from Coast to Nairobi and Nyanza provinces, and from Nairobi to Nyanza province. Strengthening HIV-1 prevention programs to MSM in geographic locations with higher HIV-1 prevalence among MSM (such as Coast and Nairobi) may reduce HIV-1 incidence among MSM in Kenya., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nduva, Otieno, Kimani, McKinnon, Cholette, Sandstrom, Graham, Price, Smith, Bailey, Hassan, Esbjörnsson and Sanders.)

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., (© The Author(s) 2022. Published by Oxford University Press.)

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 < 180 days post infection and faster CD4 decline below 500 cells/µl (adjusted HR 4.537, 95% CI 1.475-13.954; 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., (© 2022. The Author(s).)

The risk of HIV acquisition is low on a per-contact basis but increased by transmission co-factors such as other sexually transmitted infections (STIs). Human papillomavirus (HPV) is a prevalent STI that most individuals will acquire HPV in their lifetime. Current HPV vaccines can prevent newly acquired infections, but are largely ineffective against established HPV, complicating worldwide eradication efforts. In addition to being the causative agent of cervical cancer, accumulating evidence suggests that HPV infection and/or accompanying cervical inflammation increase the risk of HIV infection in men and women. The fact that immunological features observed during HPV infection overlap with cellular and molecular pathways known to enhance HIV susceptibility underscore the potential interplay between these two viral infections that fuel their mutual spread. Here we review current insights into how HPV infection and the generation of anti-HPV immunity contribute to higher HIV transmission rates, and the impact of HPV on mucosal inflammation, immune cell trafficking, and epithelial barrier function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zayats, Murooka and McKinnon.)

Resting CD4 + T cells are primary targets of early HIV infection events in vivo , but do not readily support HIV replication in vitro . This barrier to infection can be overcome by exposing resting CD4 + T cells to endothelial cells (ECs). ECs line blood vessels and direct T cell trafficking into inflamed tissues. Cell trafficking pathways have been shown to have overlapping roles in facilitating HIV replication, but their relevance to EC-mediated enhancement of HIV susceptibility in resting CD4 + T cells has not previously been examined. We characterized the phenotype of primary human resting CD4 + T cells that became productively infected with HIV when cocultured with primary human blood and lymphatic ECs. The infected CD4 + T cells were primarily central memory cells enriched for high expression of the integrins LFA-1 and VLA-4. ICAM-1 and VCAM-1, the cognate ligands for LFA-1 and VLA-4, respectively, were expressed by the ECs in the coculture. Blocking LFA-1 and VLA-4 on resting CD4 + T cells inhibited infection by 65.4%-96.9%, indicating that engagement of these integrins facilitates EC-mediated enhancement of productive HIV infection in resting CD4 + T cells. The demonstration that ECs influence cellular HIV susceptibility of resting memory CD4 + T cells through cell trafficking pathways engaged during the transmigration of T cells into tissues highlights the physiological relevance of these findings for HIV acquisition and opportunities for intervention.

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. 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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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 (all p < 0.05) were found in women stratified for GI compared to women without. Adjusted linear mixed models showed several pro-inflammatory, chemotactic, growth factors, and adaptive cytokines significantly correlated with higher titers of IgM, IgA and IgG subclasses (p < 0.05). The strong and significant positive correlations between mucosal antibodies and markers of GI suggest that GI may impact mucosal antibody profiles. These findings require further investigation to establish a plausible biological link between the local inflammatory milieu and its consequence on these genital antibodies., (© 2021. The Author(s).)

Objectives: STIs 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., Methods: HIV-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., Results: The 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 (p<0.001), but an increase in chemokines MIG (p=0.020), GRO-α (p<0.001), IP-10 (p<0.001), MIP-1β (p=0.008) and MCP-1 (p=0.005). Principal component analysis showed differences in STI and BV-related inflammatory profiles, but that resolution restored a profile consistent with vaginal health., Conclusions: A comprehensive STI intervention effectively reduced genital inflammation among young women, thereby improving vaginal health and potentially reducing HIV risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Young adolescents in Sub-Saharan Africa (SSA) are at high risk of involvement in sexual risk behaviors; and curable sexually transmitted infections (STI), herpes simplex virus type 2 (HSV-2), human immunodeficiency virus (HIV) and unintended pregnancies remain persistently high in this population. Evidence based strategies are urgently needed to improve these outcomes. The aim of this systematic review was to synthesize the evidence from randomized controlled trials (RCT) to determine whether school-based interventions promote safe sex behaviors, reduce sexual risk behaviors and risk of curable STIs, HSV-2, HIV and unintended pregnancies among young adolescents aged 9-19 years in SSA. Electronic databases were searched for published studies and manual searches were conducted through reviewing of references of cited literature in the English language up to December 2019. Two independent reviewers screened and abstracted the data. We identified 428 articles and data from nine RCTs (N = 14,426 secondary school students) that fulfilled the selection criteria were analysed. Two studies measured pregnancy as an outcome and showed significant declines in unintended pregnancies. Of the five studies that measured HIV/AIDS related-knowledge, condom-use outcomes (normative beliefs, knowledge, and self-efficacy) and attitudes to HIV testing, four showed significant improvements. Of the six studies that measured sexual debut, four reported moderate but non-significant declines and in two studies sexual debut information was either incomplete or unreliable. One study measured curable STIs and found no significant declines; whilst the second study that measured HSV-2 and HIV, no significant declines were observed. This review highlights the need to undertake well-designed research studies to provide evidence on the impact of interventions on curable STIs, HSV-2 and HIV, critical to improving the health of young adolescents., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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 < 0.001), not completing high school (aOR 1.60, 95% CI 1.39-1.85; p < 0.001), not using condoms at first sex (aOR 1.43, 95% CI 1.20-1.70; p < 0.001), consuming alcohol (aOR 1.63, 95% CI 1.15-2.31; p = 0.006) or substances (aOR 1.37, 95% CI 1.31-1.44; p < 0.001), and absence of medical circumcision (aOR 2.05, 95% CI 1.71-2.44; p < 0.001). Risk was lower among those testing for HIV in last 12 months (aOR 0.54, 95% CI 0.36-0.80; p = 0.002). Greater effort is needed to implement innovative programs within settings that are easily accessible and where heterosexual men are likely to be., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Understanding what shapes the latent human immunodeficiency virus type 1 (HIV-1) reservoir is critical for developing strategies for cure. We measured frequency of persistent HIV-1 infection after 5 years of suppressive antiretroviral therapy initiated during chronic infection. Pretreatment CD8+ T-cell activation, nadir CD4 count, and CD4:CD8 ratio predicted reservoir size., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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+ CD127 low Tregs in the endocervix correlated with those in blood (r=0.31, p=0.01), with a higher Treg frequency observed in the endocervix (median 3.8 vs 2.0%, p<0.0001). Most Tregs expressed FOXP3 in both compartments, and CTLA-4 expression was higher on endocervical Tregs compared to blood (median 50.8 vs 6.0%, p<0.0001). More than half (34/62, 55%) of participants displayed a non- Lactobacillus dominant 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 log 10 CD4+ T cells per log 10 Treg, 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ssemaganda, Cholette, Perner, Kambaran, Adhiambo, Wambugu, Gebrebrhan, Lee, Nuhu, Mwatelah, Jahan, Omole, Wanjiru, Gitau, Kimani and McKinnon.)

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., (© 2021 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

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 < 0.001). Lower G-CSF (P = 0.011) and elevated IL-1Rα (P = 0.008) remained significant in adjusted models. Multivariable analyses of plasma samples obtained from NET-EN-detectable women showed a significant increase in IP-10 (P = 0.026) and reductions in TNF-β (P = 0.037), RANTES (P = 0.009), and M-CSF (P < 0.001). While similar growth factor reduction in CVL was noted for both DMPA and NET-EN, similar trends were not observed for endogenous progesterone., Conclusions: Detectable NET-EN was associated with reduced growth factors in the plasma and genital tract; particularly G-CSF and M-CSF. Our results suggest that while NET-EN is not inflammatory, it may have important immunological effects., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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  < .05) protein or pathway differences between groups. Vaginal microbiomes were not significantly different between groups. No differences were observed between age groups in this PTM model, however, these animals may not reflect biological factors contributing to HIV risk such as those found in their human counterparts. This model is therefore not appropriate to explore human adolescent differences in HIV risk. Young women remain a key population at risk for HIV infection, and there is still a need for comprehensive assessment and intervention strategies for epidemic control of this uniquely vulnerable population.

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 = 0.49)., 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., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

There is an urgent need to identify immunological markers of tuberculosis (TB) risk in HIV co-infected individuals. Previously we have shown that TB recurrence in HIV co-infected individuals on ART was associated with markers of systemic inflammation (IL-6, IL1β and IL-1Rα). Here we examined the effect of additional acute inflammation and microbial translocation marker expression on risk of TB recurrence. Stored plasma samples were drawn from the TB Recurrence upon Treatment with HAART (TRuTH) study, in which individuals with previously treated pulmonary TB were screened for recurrence quarterly for up to 4 years. Recurrent TB cases (n = 37) were matched to controls (n = 102) by original trial study arm assignment and ART start date. Additional subsets of HIV infected (n = 41) and HIV uninfected (n = 37) individuals from Improving Recurrence Success (IMPRESS) study were sampled at active TB and post successful treatment completion. Plasma concentrations of soluble adhesion molecules (sMAdCAM, sICAM and sVCAM), lipopolysaccharide binding protein (LBP) and transforming growth factor-beta (TGF-β1, TGF-β2, TGF-β3) were measured by multiplex immunoassays and ELISA. Cytokine data was square root transformed in order to reduce variability. Multivariable analysis adjusted for a number of potential confounders measured at sample time-point: age, BMI, CD4 count, viral load (VL) and measured at baseline: presence or absence of lung cavities, previous history of TB, and WHO disease stage (4 vs 3). The following analytes were associated with increased risk of TB recurrence in the multivariable model: sICAM (aOR 1.06, 95% CI: 1.02-1.12, p = 0.009), LBP (aOR 8.78, 95% CI: 1.23-62.66, p = 0.030) and TGF-β3 (aOR 1.44, 95% CI 1.01-2.05, p = 0.044). Additionally, we observed a positive correlation between LBP and sICAM (r= 0.347, p<0.0001), and LBP and IL-6, identified to be one of the strongest predictors of TB risk in our previous study (r=0.623, p=0.03). These data show that increased risk of TB recurrence in HIV infected individuals on ART is likely associated with HIV mediated translocation of microbial products and the resulting chronic immune activation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pillay, Lewis, Rambaran, Yende-Zuma, Archary, Gengiah, Govender, Hassan-Moosa, Samsunder, Abdool Karim, McKinnon, Padayatchi, Naidoo and Sivro.)

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 < 0.0001). Over time, FSWs reported increased condom use, particularly with regular partners, more frequent prior HIV testing, and were less likely to report a history of vaginal discharge (P < 0.0001). In adjusted analyses compared with 2008, HIV prevalence decreased in 2011 (aPR 0.64; 95% CI: 0.46-0.90), 2012 (aPR 0.58; 95% CI: 0.41-0.81), 2013 (aPR 0.53; 95% CI: 0.38-0.73), 2014 (aPR 0.48; 95% CI: 0.34-0.67), 2015 (aPR 0.50; 95% CI: 0.35-0.70), 2016 (aPR 0.40; 95% CI: 0.28-0.57), and 2017 (aPR 0.33; 95% CI: 0.22-0.50)., Conclusion: HIV prevalence has decreased among FSW accessing SWOP in Nairobi, Kenya. This decline is consistent with the scale-up of HIV prevention and treatment efforts, both in FSWs and in the general population., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2021. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Establishment of persistent human immunodeficiency virus type 1 (HIV-1) reservoirs occurs early in infection, and biomarkers of infected CD4+ T cells during acute infection are poorly defined. CD4+ T cells expressing the gut homing integrin complex α4β7 are associated with HIV-1 acquisition, and are rapidly depleted from the periphery and gastrointestinal mucosa during acute HIV-1 infection., Methods: Integrated HIV-1 DNA was quantified in peripheral blood mononuclear cells obtained from acutely (Fiebig I-III) and chronically infected individuals by sorting memory CD4+ T-cell subsets lacking or expressing high levels of integrin β7 (β7negative and β7high, respectively). HIV-1 DNA was also assessed after 8 months of combination antiretroviral therapy (cART) initiated in Fiebig II/III individuals. Activation marker and chemokine receptor expression was determined for β7-defined subsets at acute infection and in uninfected controls., Results: In Fiebig I, memory CD4+ T cells harboring integrated HIV-1 DNA were rare in both β7high and β7negative subsets, with no significant difference in HIV-1 DNA copies. In Fiebig stages II/III and in chronically infected individuals, β7high cells were enriched in integrated and total HIV-1 DNA compared to β7negative cells. During suppressive cART, integrated HIV-1 DNA copies decreased in both β7negative and β7high subsets, which did not differ in DNA copies. In Fiebig II/III, integrated HIV-1 DNA in β7high cells was correlated with their activation., Conclusions: β7high memory CD4+ T cells are preferential targets during early HIV-1 infection, which may be due to the increased activation of these cells., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

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., Competing Interests: The authors have declared that no competing interests exist.

Transitions aims to understand the human immunodeficiency virus (HIV) risk at critical transition points in the sexual life course of adolescent girls and young women (AGYW) who engage in casual sex, transactional sex, and sex work. In this article, we present the Transitions study methods. The Transitions study has the following objectives: (1) to describe how the characteristics and length of the transition period and access gap vary across two epidemiological contexts (Mombasa, Kenya, and Dnipro, Ukraine); (2) to understand how the risk of HIV varies by length and characteristics of the transition period and access gap across epidemiologic contexts; and (3) to assess the extent to which HIV infections acquired during the transition period and access gap could mitigate the population-level impact of focused interventions for female sex workers and explore the potential marginal benefit of expanding programs to reach AGYW during the transition period and access gap. Cross-sectional biobehavioral data were collected from young women aged 14 to 24 years who were recruited from locations in Mombasa County, Kenya, and Dnipro, Ukraine, where sex work took place. Data are available for 1,299 Kenyan and 1,818 Ukrainian participants. The survey addressed the following areas: timing of transition events (first sex, first exchange of sex for money or other resources, self-identification as sex workers, entry into formal sex work, access to prevention program services); sexual behaviors (condom use, anal sex, sex under the influence of drugs or alcohol); partnerships (regular and first-time clients, regular and first-time transactional sex partners, and husbands and boyfriends); alcohol use; injection and non-injection illicit drug use; experience of violence; access to HIV prevention and treatment program; testing for sexually transmitted and blood-borne infections and HIV; and reproductive health (pregnancies, abortions, contraceptives). HIV and hepatitis C virus prevalence data were based on rapid test results. Mathematical modeling will be used to generate projections of onward HIV transmission at specific transition points in the sexual life course of AGYW. Taken together, these data form a novel data resource providing comprehensive behavioral, structural, and biological data on a high-risk group of AGYW in two distinct sociocultural and epidemiologic contexts., (Copyright © 2020 Cheuk, Mishra, Balakireva, Musyoki, Isac, Pavlova, Bhattacharjee, Lorway, Pickles, Ma, Gichangi, Sandstrom, McKinnon, Lazarus, Moses, Blanchard and Becker.)

Background: Sexually transmitted infections (STIs) and Human immunodeficiency virus (HIV) share a complex bidirectional relationship, however, population prevalence and the association between the presence of STIs and HIV in a high HIV burden district in KwaZulu-Natal, South Africa is not known., Methods: A total of 9812 participants aged 15-49 years were enrolled in a cross-sectional population-based household survey. Participants completed a structured questionnaire and provided first-pass urine (males) or self-collected vulvo-vaginal swabs (females) for the detection of STIs., Results: Prevalence of herpes simplex virus type-2 (HSV-2) was 57.8%, syphilis was 1.6%, Neisseria gonorrhoeae was 2.8%, Chlamydia trachomatis was 7.1%, Trichomonas vaginalis was 9.0%, Mycoplasma genitalium was 5.5% and HIV was 36.3%. HIV positive status was associated with an increased probability of having M. genitalium (aPR = 1.49, 95% CI 1.02-2.19) among males and syphilis (aPR = 2.54, 95% CI 1.32-4.86), N. gonorrhoeae (aPR = 2.39, 95% CI 1.62-3.52), T. vaginalis (aPR = 1.70, 95% CI 1.43-2.01) and M. genitalium (aPR = 1.60, 95% CI 1.15-2.22) among females. HIV viral load ≥400 copies per mL was associated with an increased probability of N. gonorrhoeae (aPR = 1.91, 95% CI 1.36-2.70), C. trachomatis (aPR = 1.52, 95% CI 1.12-2.05) and M. genitalium (aPR = 1.83, 95% CI 1.27-2.63)., Conclusions: The high prevalence of STIs and the association between STIs and HIV, and HIV viral load underscores the public health implications of sustained transmission risk of STIs and HIV. These findings highlight the urgent need for expanding STI surveillance and implementing interventions to monitor and reduce the STI burden., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.

Introduction: We performed a cross-sectional study of HIV-uninfected men and women who inject drugs from the ALIVE cohort to examine if black men and women who inject drugs have higher levels of CD4+ T cells expressing the integrin heterodimer α4β7 compared to white men and women., Materials and Methods: Flow cytometry was used to examine expression of α4β7 and other markers associated with different functional CD4+ T cell subsets in both men and women who inject drugs., Results: Higher levels of α4β7, CCR5, and CCR6 were observed on CD4+ T cells from black participants compared with white participants. In a multivariable model, α4β7 expression differed by race, but not sex, age, or other factors., Discussion: Black men and women express higher percentages of α4β7 expressing CD4+ T cells, which may play a role in HIV disease., Competing Interests: SM has received speaker fees from Gilead Sciences that was not related to this work. The authors have no other conflicts of interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.