Search

Background: We evaluated the prognostic usefulness of interferon γ release assays (IGRAs) for active tuberculosis and mortality in Kenyan human immunodeficiency virus type 1 (HIV-1)-infected women and their infants.Methods: Prevalence and correlates of Mycobacterium tuberculosis-specific T-SPOT.TB IGRA positivity were determined during pregnancy in a historical cohort of HIV-1-infected women. Hazard ratios, adjusted for baseline maternal CD4 cell count (aHR(CD4)), were calculated for associations between IGRA positivity and risk of active tuberculosis and mortality over 2-year postpartum follow-up among women and their infants.Results: Of 333 women tested, 52 (15.6%) had indeterminate IGRA results. Of the remaining 281 women, 120 (42.7%) had positive IGRA results, which were associated with a 4.5-fold increased risk of active tuberculosis (aHR(CD4), 4.5; 95% confidence interval [CI], 1.1-18.0; P = .030). For immunosuppressed women (CD4 cell count, <250 cells/μL), positive IGRA results were associated with increased risk of maternal mortality (aHR(CD4), 3.5; 95% CI, 1.02-12.1;), maternal active tuberculosis or mortality (aHR(CD4), 5.2; 95% CI, 1.7-15.6; P = .004), and infant active tuberculosis or mortality overall (aHR(CD4), 3.0; 95% CI, 1.0-8.9; P = .05) and among HIV-1-exposed uninfected infants (aHR(CD4), 7.3; 95% CI, 1.6-33.5; P = .01).Conclusions: Positive IGRA results for HIV-1-infected pregnant women were associated with postpartum active tuberculosis and mortality among mothers and their infants. [ABSTRACT FROM AUTHOR]

Escape from cytotoxic T lymphocyte (CTL) responses toward HIV-1 Gag and Nef has been associated with reduced control of HIV-1 replication in adults. However, less is known about CTL-driven immune selection in infants as longitudinal studies of infants are limited. Here, 1,210 gag and 1,264 nef sequences longitudinally collected within 15 months after birth from 14 HIV-1 perinatally infected infants and their mothers were analyzed. The number of transmitted founder (T/F) viruses and associations between virus evolution, selection, CTL escape, and disease progression were determined. The analyses indicated that a paraphyletic-monophyletic relationship between the mother-infant sequences was common (80%), and that the HIV-1 infection was established by a single T/F virus in 10 of the 12 analyzed infants (83%). Furthermore, most HIV-1 CTL escape mutations among infants were transmitted from the mothers and did not revert during the first year of infection. Still, immune-driven selection was observed at approximately 3 months after HIV-1 infection in infants. Moreover, virus populations with CTL escape mutations in gag evolved faster than those without, independently of disease progression rate. These findings expand the current knowledge of HIV-1 transmission, evolution, and CTL escape in infant HIV-1 infection and are relevant for the development of immune-directed interventions in infants.IMPORTANCEDespite increased coverage in antiretroviral therapy for the prevention of perinatal transmission, paediatric HIV-1 infection remains a significant public health concern, especially in areas of high HIV-1 prevalence. Understanding HIV-1 transmission and the subsequent virus adaptation from the mother to the infant's host environment, as well as the viral factors that affect disease outcome, is important for the development of early immune-directed interventions for infants. This study advances our understanding of vertical HIV-1 transmission, and how infant immune selection pressure is shaping the intra-host evolutionary dynamics of HIV-1., Competing Interests: The authors declare no conflict of interest.

Studying vertical human immunodeficiency virus (HIV) transmission enables the impact of passively transferred antibodies on HIV transmission and pathogenesis to be examined. Using phage display of HIV envelope peptides and peptide enzyme-linked immunosorbent assay (ELISA), we found that, in infants who acquired HIV, passive antibody responses to constant region 5 (C5) were associated with improved survival in 2 cohorts. In a combined analysis, C5 peptide ELISA activity was correlated directly with survival and estimated infection time and inversely with set point viral load. These results suggest that preexisting C5-specific antibodies may be correlated with the survival of infants living with HIV, motivating additional research into their protective potential., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

This study evaluated the impact of human immunodeficiency virus (HIV) and combination antiretroviral therapy (cART) on immune activation during pregnancy in a Zambian cohort of HIV-exposed but uninfected children followed up from birth. Activated CD8+ T cells (CD38+ and HLA-DR+) were compared among HIV-uninfected (n = 95), cART experienced HIV-infected (n = 111), and cART-naive HIV-infected (n = 21) pregnant women. Immune activation was highest among HIV-infected/cART-naive women but decreased during pregnancy. Immune activation HIV-infected women who started cART during pregnancy was reduced but not to levels similar to those in HIV-uninfected women. The effects of elevated maternal immune activation in pregnancy on subsequent infant health and immunity remain to be determined., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: In low and middle income countries, human immunodeficiency virus (HIV) exposed, uninfected (HEU) infants demonstrate higher morbidity and mortality than their unexposed counterparts. To determine possible immune correlates of this effect, we investigated the impact of in utero HIV exposure on the uninfected neonatal immune milieu and maternal factors mediating these abnormalities in a cohort of vaginally delivered mother-infants. Samples of delivery and cord blood plasma were selected from 22 Kenyan HIV-infected women and their HIV exposed uninfected (HEU) infants drawn from the pre-ARV era, while 19 Kenyan HIV-uninfected (HU) women and their infants were selected from a control cohort., Results: Compared to HU cord plasma, HEU cord plasma contained significantly higher levels of pro-inflammatory cytokines interleukins (IL)-6 and -8 (both p < 0.001) and significantly lower levels of CXC motif chemokine 11 (CXC11) (p < 0.001). Mediation analysis demonstrated that maternal HIV infection status was a significant determinant of infant IL-8 responses: HEU status was associated with a ninefold higher infant:mother (cord:delivery) plasma levels of IL-8 (p < 0.005), whereas maternal viral load was negatively associated with HEU IL-8 levels (p = 0.04) and not associated with HEU IL-6 levels., Conclusions: Exposure to maternal HIV infection drives an increase in prenatal IL-8 that is partially mediated by maternal cytokine levels. Differences between maternal and infant cytokine levels strongly suggest independent modulation in utero, consistent with prenatal immune activation. Elevated pro-inflammatory signals at birth may interfere with T cell responses at birth and subsequently influence immune maturation and the risk of morbidity and mortality in HEU infants.

Introduction: Spontaneous interferon-γ (IFNγ) released detected by enzyme-linked immunospot (ELISpot) assays may be a biological phenomenon. Markers of immune activation levels were assessed as correlates of high background among individuals in Kenya., Methods: Couples concordantly seronegative for HIV-1 were enrolled. IFN-γ ELISpot assays were conducted and negative control wells were categorized as having either high or low background (≥50 and <50 SFU/10 6 peripheral blood mononuclear cells [PBMC], respectively). PBMC were stained for CD4, CD8, and immune activation markers (CD38 and HLA-DR) and analyzed using flow cytometry. Proportions of activated T-cells were compared between those with low and high background by Mann-Whitney U test. Correlates of background SFU and immune activation were assessed using regression models., Results: Among 58 individuals, 14 (24%) had high background. Frequencies of CD4 + CD38 + HLA-DR + and CD8 + CD38 + HLA-DR + cells were higher in individuals with high background compared to those with low background (P = 0.02). Higher background SFU was associated with history of sexually transmitted infections (P = 0.03), and illness in the past 3 months (P = 0.005), in addition to increased levels of activated CD4 + and CD8 + cells (P range = 0.008-0.03). Female gender and male circumcision decreased levels of CD4 + and CD8 + immune activation (P range = 0.002-0.03). Additionally, higher background SFU and activated CD4 + and CD8 + cells were individually associated with positive ELISpot responses to HIV-1 peptide pools (P range = 0.01-0.03)., Conclusions: These findings suggest that increased basal immune responses may be a biological mechanism contributing to higher background ELISpot SFU. Systematic exclusion of data from individuals with increased background in IFN-γ release assays may bias results in population-based studies., (© 2018 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd.)

Background: HIV-1 infection may impair transplacental antibody transfer to infants. The impact of highly active antiretroviral treatment (ART) given during pregnancy on transplacental antibody transport is unknown., Methods: HIV-1 infected pregnant women with CD4 counts between 200 - 500 were randomized to short-course zidovudine (ZDV) or triple ART at 32 weeks gestation for prevention of mother-to-child HIV-1 transmission. Levels of maternal antibody against measles, pneumococcus and rotavirus at delivery, and antibody transfer to the baby through cord blood, were compared between trial arms., Results: Overall, 141 and 148 women were randomized to triple ART and ZDV, respectively; cord blood was available for a subset (n = 20 in triple ART and n = 22 in ZDV). Maternal antibody levels to all pathogens during pregnancy and at delivery were not significantly different between arms. Within each arm, antibody levels at delivery were lower than at enrolment. For all antibodies, a woman's levels before delivery were an important predictor of amount transferred to her infant. Women on triple ART transferred higher levels of pathogen-specific antibodies when compared with women on short course ZDV., Conclusions: Women on triple ART transferred higher levels of pathogen-specific antibodies compared with women on ZDV alone.

Background: Exclusive breastfeeding (EBF) is recommended for 6 months after delivery as the optimal infant feeding method and is especially important for prevention of mother-to-child HIV transmission (PMTCT). However, EBF promotion efforts among HIV-infected mothers in sub-Saharan Africa have achieved mixed success and require context-specific interventions., Methods: HIV-positive, pregnant women from six clinics in Nairobi were enrolled into a clinic-level, before-after counseling intervention study. All women received standard perinatal and HIV care. Women in the intervention arm were offered three counseling sessions that promoted EBF, described its benefits, and explained breastfeeding techniques. Mother-infant pairs were followed until 14 weeks postpartum, with infant HIV testing at 6 weeks. EBF prevalence at 14 weeks postpartum was compared between study arms using log-binomial regression. Proportions of 6-week HIV-free survival and 14-week infant survival were assessed using Cox regression. Risk estimates were adjusted for clinic, relationship status, and antiretroviral therapy., Results: Between 2009 and 2013, 833 women were enrolled of whom 94% planned to practice EBF for 6 months and 95% were taking therapeutic or prophylactic antiretrovirals. Median age was 27 years; median CD4 count was 403 cells/μL. EBF prevalence at 14 weeks postpartum was 86% in the control and 81% in the intervention group (p = 0.19). No differences were observed between groups for 6-week HIV-free survival and 14-week infant survival., Conclusion: Women who received breastfeeding counseling were not more likely to breastfeed exclusively, in part due to high overall EBF prevalence in this study population. The high EBF prevalence is an important finding, given recent efforts to promote EBF in Kenya.

Objective: The effects of sex hormones on the immune defenses of the female genital mucosa and its susceptibility to infections are poorly understood. The injectable hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may increase the risk for HIV-1 acquisition. We assessed the local concentration in the female genital mucosa of cationic polypeptides with reported antiviral activity in relation to DMPA use., Methods: HIV-1-uninfected women were recruited from among couples testing for HIV in Nairobi, Kenya. Cervicovaginal secretion samples were collected, and the concentrations of HNP1-3, LL-37, lactoferrin, HBD-2, and SLPI were measured by enzyme-linked immunosorbent assays. Levels of cationic polypeptides in cervicovaginal secretions were compared between women who were not using hormonal contraception and those using DMPA, oral, or implantable contraception., Results: Among 228 women, 165 (72%) reported not using hormonal contraception at enrollment, 41 (18%) used DMPA, 16 (7%) used an oral contraceptive, and 6 (3%) used a contraceptive implant. Compared with nonusers of hormonal contraception, DMPA users had significantly higher mean levels of HNP1-3 (2.38 vs. 2.04 log₁₀ ng/mL; P = 0.024), LL-37 (0.81 vs. 0.40 log10 ng/mL; P = 0.027), and lactoferrin (3.03 vs. 2.60 log₁₀ ng/mL; P = 0.002), whereas SLPI and HBD-2 were similar., Conclusions: Although all analyzed cationic polypeptides have intrinsic antiviral capacity, their interaction and cumulative effect on female genital mucosa susceptibility to infections in vivo has yet to be unraveled. This study suggests a potential mechanism underlying the effect of DMPA on the innate immune defenses, providing a rationale to investigate its effect on HIV-1 acquisition risk.

Background: A safe, effective vaccine for breastfeeding infants born to HIV-1-positive mothers could complement antiretroviral therapy (ART) for prevention of mother-to-child transmission of HIV-1. To date, only a few HIV-1 vaccine candidates have been tested in infants., Trial Design: A phase I/II randomized controlled trial PedVacc 002 was conducted to determine the safety and immunogenicity of a single, low dose of MVA.HIVA vaccine delivered intramuscularly to healthy 20-week-old infants born to HIV-1-positive mothers in Nairobi, Kenya., Methods: Pregnant HIV-1-positive women in the 2nd/3rd trimester of gestation were enrolled, provided with ART and self-selected their infant-feeding modality. Infants received nevirapine and cotrimoxazole prophylaxis. At 20 weeks of age, eligible HIV-1-negative infants were randomized to vaccine versus no-treatment arms and followed to 48 weeks of age for assessments of vaccine safety, HIV-1-specific T-cell responses and antibodies to routine childhood vaccines., Results: Between February and November 2010, 182 mothers were screened, 104 were eligible and followed on ART during pregnancy/postpartum, of whom 73 had eligible infants at 20 weeks postpartum. Thirty-six infants were randomized to vaccine and 37 to no treatment. Eighty-four percent of infants breastfed, and retention at 48 weeks was 99%. Adverse events were rare and similar between the two arms. HIV-1-specific T-cell frequencies in interferon-γ ELISPOT assay were transiently higher in the MVA.HIVA arm (p=0.002), but not above the threshold for a positive assay. Protective antibody levels were adequate and similar between arms for all routine childhood vaccines except HBV, where 71% of MVA.HIVA subjects compared to 92% of control subjects were protected (p=0.05)., Conclusions: This trial tested for the first time an MVA-vectored candidate HIV-1 vaccine in HIV-1-exposed infants in Africa, demonstrating trial feasibility and vaccine safety, low immunogenicity, and compatibility with routine childhood vaccinations. These results are reassuring for use of the MVA vector in more potent prime-boost regimens., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This article describes results from a cross-sectional study among HIV-infected children 15 months to 12 years of age who were receiving antiretroviral therapy. We found a low prevalence of measles IgG seropositivity (45.7%) and identified CD4% ≥ 25 as a predictor. Most HIV-infected children on ART were not measles seropositive and might benefit from revaccination.

Objective: To determine neonatal immunologic factors that correlate with mother-to-child-transmission of HIV-1., Design: This case-control study compared cord blood natural killer (NK) and T-cell populations of HIV-1 exposed infants who subsequently acquired infection by 1 month (cases) to those who remained uninfected by 1 year of life (controls). Control specimens were selected by proportional match on maternal viral load., Methods: Cryopreserved cord blood mononuclear cells (CBMCs) were thawed and stained for multiparameter flow cytometry to detect NK and T-cell subsets and activation status. CBMCs were also used in a viral suppression assay to evaluate NK cell inhibition of HIV-1 replication in autologous CD4 T cells., Results: Cord blood from cases contained a skewed NK cell repertoire characterized by an increased proportion of CD16CD56 NK cells. In addition, cases displayed less-activated CD16CD56 NK cells and CD8 T cells, based on HLA-DRCD38 costaining. NK cell suppression of HIV-1 replication ex vivo correlated with the proportion of acutely activated CD68CD16CD56 NK cells. Finally, we detected a higher proportion of CD27CD45RA effector memory CD4 and CD8 T cells in cord blood from cases compared with controls., Conclusion: When controlled for maternal viral load, cord blood from infants who acquired HIV-1 had a higher proportion of CD16CD56 NK cells, lower NK cell activation and higher levels of mature T cells (potential HIV-1 targets) than control infants who remained uninfected. Our data provide evidence that infant HIV-1 acquisition may be influenced by both innate and adaptive immune cell phenotypes and activation status.

Background: Infants born to HIV-1 infected mothers may have increased risk for tuberculosis (TB), but the prevalence of TB infection in this population is undefined. In contrast to tuberculin skin tests that are confounded by recent bacille Calmette-Guérin (BCG) vaccination, TB interferon gamma release assays (IGRAs) do not cross-react with BCG and enable detection of TB infection in infancy., Methods: In a nested observational cohort of HIV-1 infected Kenyan mothers and their infants, we conducted T-SPOT.TB assays on cryopreserved peripheral blood mononuclear cells from 6-month-old infants without prior active TB. Maternal and infant correlates of infant TB infection were assessed., Results: One hundred and eight-two infants were tested with T-SPOT.TB. Of 128 infants with determinate T-SPOT.TB results, the prevalence of a positive T-SPOT.TB was 10.9% [95% confidence interval (CI): 6.1-17.7%]. All infants were BCG-vaccinated and 7.0% were HIV-1 infected. Positive infant T-SPOT.TB was associated with maternal active TB (odds ratio: 15.5, 95% CI: 1.3-184; P = 0.04) and prolonged infant fever (>1 month) (odds ratio: 18.8, 95% CI: 1.6-223; P = 0.03)., Conclusions: We observed a high prevalence of TB infection in 6-month-old HIV-1 exposed infants. Improved TB detection and prevention are warranted in HIV-1 exposed infants at high risk for active TB disease.

Individual and sexual partner characteristics may increase the risk of abnormal cervical cytology among women in human immunodeficiency virus (HIV)-discordant relationships. Papanicolaou smears were obtained in a prospective cohort of Kenyan HIV-discordant couples. Of 441 women, 283 (64%) were HIV-infected and 158 (36%) were HIV-uninfected with HIV-infected partners. Overall, 79 (18%) had low-grade and 25 (6%) high-grade cervical abnormalities. Male herpes simplex virus type 2 (HSV-2) seropositivity and lower couple socioeconomic status were associated with cervical abnormalities (p < 0.05). HIV-uninfected women with HIV-infected male sex partners (CD4 > 350 cells/µL) had the lowest prevalence of high-grade cervical lesions. HIV-infected women (CD4 > 350 cells/µL) and HIV-uninfected women with HIV-infected partners (CD4 ≤ 350 cells/µL) were at similar intermediate risk (p > 0.05), and HIV-infected women (CD4 ≤ 350 cells/µL) had significantly higher risk of high-grade cervical abnormalities (p = 0.05). Women in HIV-discordant relationships have high rates of cervical lesions and this may be influenced by couple-level factors, including HIV status and CD4 count of the infected partner.

Despite global efforts to reduce measles incidence, outbreaks continue to occur in developing countries where HIV-1-infected adults represent a vulnerable population. Immunization campaigns have targeted children, although little is known about the levels of measles protection in adult populations in Kenya. The objective of this study was to determine seroprevalence and titers of measles IgG among HIV-1-infected and uninfected adults in Nairobi, Kenya. The presence of anti-measles IgG was measured in cryopreserved serum of 257 HIV-1-infected and 367 uninfected adults using a commercial ELISA (Enzygnost, Germany). The measles IgG concentration was calculated for those samples that were positive. Overall, 96% of adults were measles seropositive and the mean measles IgG concentration among those who were seropositive was 4134 mIU/ml, which is well above previously reported protective levels. There was no statistical difference in seroprevalence or antibody concentration between the HIV-infected and HIV-uninfected groups. While local vaccination efforts and circulating measles infection likely contribute to this high measles seroprevalence rate, these data are unique to an urban population and may not reflect a country-wide distribution. Our results suggest that reduced immunity among HIV-1-infected adults is not a major contributor to measles resurgence in Kenya., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Maternal antiretroviral treatment (ART) is recommended for prevention of mother-to-child HIV-1 transmission (PMTCT), including in women with high CD4 + cell counts. Within a pediatric HIV-1 vaccine trial PedVacc 002, we assessed hematologic profiles of infants born to mothers receiving ART. All mothers had CD4 + cell counts of >350 mm -3 ; 93% received zidovudine-containing ART; infants received nevirapine up to 6 weeks and cotrimoxazole after 6 weeks. Among 84 infants at 19 weeks, 58% had hematologic toxicity; 44% had neutropenia and 23% had anemia. Breastfeeding was associated with 3.8-fold higher risk of neutropenia (RR 3.8, 95% CI 1.03-14.1, p = 0.008). Hematologic monitoring and PMTCT regimen selection are important for optimizing infant outcomes., Competing Interests: COMPETING INTERESTS: GJ-S reports grants from NIH, CDC and BMGF and royalties from UpToDate, outside the submitted work. IN reports a grant from University of Nairobi, during the conduct of the study. Other authors disclose no potential conflicts of interest.

Background: The synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1) is well known, but lack of knowledge about the epidemiology of HSV-2 acquisition in HIV-1-discordant couples hampers development of HSV-2 prevention interventions that could reduce HIV-1 transmission., Methods: HIV-1-discordant couples were enrolled in Nairobi, Kenya, and followed for up to 2 years. HSV-2 status was determined using HerpeSelect HSV-2 ELISA. Correlates of prevalence and incidence were assessed. RESULTS.: Of 469 HIV-1-discordant couples, at baseline, 353 (75.3%) were affected by HSV-2, of which 189 (53.5%) were concordantly HSV-2 seropositive and 164 (46.5%) were HSV-2-discordant. Prevalence was lowest among HIV-1-uninfected men (39.9%) compared to HIV-1-infected women (64.8%), HIV-1-infected men (66.7%), and HIV-1-uninfected women (68.5%). During follow-up, HSV-2 seroincidence was 14.9 per 100 person-years. Incidence was 1.6-fold higher among females compared to males (95% confidence interval [CI], 1.00-2.48) and 2.5-fold higher in HIV-1-infected compared to uninfected women (95% CI, 1.12-5.74). At least 30% of incident HSV-2 infections originated from an outside partner., Conclusions: The high HSV-2 prevalence and incidence in HIV-1-discordant couples in sub-Saharan Africa suggest HSV-2 treatment and prevention could be an effective targeted strategy to reduce HSV-2 and HIV-1 transmission in this high-risk population.

Natural killer (NK) cells play an important role in the containment of HIV replication during primary infection, though their functions are impaired during chronic HIV infection. Infants experience more rapid HIV disease progression than adults, but contributions of infant NK cells to containing HIV infection are unknown. The aim of this study was to determine the impact of HIV infection on infant NK cell phenotype by evaluating samples and data from a cohort study of women and their infants, conducted in Nairobi, Kenya between 1999 and 2003. The percentage and phenotype of NK cells was evaluated longitudinally by multi-parameter flow cytometry over the first year of life in HIV-infected (HIV+, = 16), HIV-exposed uninfected (HIV-EU, n = 6), and healthy unexposed controls (HIV-, n = 4). At birth, NK subset distributions based on expression of CD56 and CD16 did not differ between HIV+, HIV-EU, or HIV- infants. However, HIV infection was associated with a subsequent decline in NK cells as a percentage of total lymphocytes (p < 0.001), and an expanding proportion of CD56-CD16+ NK cells (p < 0.001). Activated CD38(bright)CD69+ NK cells were more frequent in the HIV+ infants, followed by HIV-EU and HIV- infants, in both CD56(dim) (p = 0.005) and CD56(bright) compartments (p = 0.03). HIV infection and exposure was also associated with a significant decline in the percentage of perforin-expressing NK cells in the CD56(dim) compartment over the first year of life, with HIV+ infants losing approximately 2.5% (p < 0.001) and HIV-EU infants losing 3.0% (p = 0.01) of perforin+ cells per month. Thus, infant HIV infection is associated with alterations in NK cell subsets, activation, and cytolytic potential that could contribute to their poor control over HIV infection. Furthermore, exposure to HIV infection in infants who escaped infection is also associated with alterations in NK cells that may contribute to the reduced ability to fight infections that is observed in HIV-EU infants.

Objective: Cervicovaginal HIV-1-neutralizing immunoglobulin A (IgA) was associated with reduced HIV-1 acquisition in a cohort of commercial sex workers. We aimed to define the prevalence and correlates of HIV-1-neutralizing IgA from HIV-1-exposed seronegative (HESN) women in HIV-1-serodiscordant relationships., Methods: HIV-1-serodiscordant couples in Nairobi were enrolled and followed quarterly up to 2 years, and women in concordant HIV-1-negative relationships were enrolled as controls. Cervicovaginal, seminal, and blood samples were collected at enrollment and follow-up. Cervicovaginal IgA was assessed for HIV-1-neutralizing activity by a peripheral blood mononuclear cell-based assay using an HIV-1 clade A primary isolate., Results: HESN women in discordant relationships had significantly more HIV-1-neutralizing IgA detected in genital secretions compared with control women [36 of 155 (23%) vs. four of 70 (6%), respectively; odds ratio (OR) 5.0; 95% confidence interval (CI) 1.70-14.64; P = 0.003]. These responses persisted over time in all available follow-up cervicovaginal samples from women with detectable HIV-1-neutralizing IgA at baseline. Partner median HIV-1 plasma viral load was lower among women who had HIV-1-neutralizing IgA compared with women without detectable activity (4.3 vs. 4.8 log(10) copies/ml, respectively; OR 0.70; 95% CI 0.51-0.94; P = 0.02). A similar trend was found with partner seminal viral load (OR 0.57; 95% CI 0.32-1.02; P = 0.06)., Conclusion: HESN women were five times more likely to have neutralizing IgA in cervicovaginal secretions than low-risk control women, and these responses were inversely associated with partner viral load. These observations support the existence of antiviral activity in the mucosal IgA fraction following sexual HIV-1 exposure.

A number of studies of highly exposed HIV-1-seronegative individuals (HESN) have found HIV-1-specific cellular responses. However, there is limited evidence that responses prevent infection or are linked to HIV-1 exposure. Peripheral blood mononuclear cells (PBMC) were isolated from HESN in HIV-1-discordant relationships and low-risk controls in Nairobi, Kenya. HIV-1-specific responses were detected using gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assays stimulated by peptide pools spanning the subtype A HIV-1 genome. The HIV-1 incidence in this HESN cohort was 1.5 per 100 person years. Positive ELISpot responses were found in 34 (10%) of 331 HESN and 14 (13%) of 107 low-risk controls (odds ratio [OR] = 0.76; P = 0.476). The median immunodominant response was 18.9 spot-forming units (SFU)/10(6) peripheral blood mononuclear cells (PBMC). Among HESN, increasing age (OR = 1.24 per 5 years; P = 0.026) and longer cohabitation with the HIV-1-infected partner (OR = 5.88 per 5 years; P = 0.003) were associated with responses. These factors were not associated with responses in controls. Other exposure indicators, including the partner's HIV-1 load (OR = 0.99 per log(10) copy/ml; P = 0.974) and CD4 count (OR = 1.09 per 100 cells/μl; P = 0.238), were not associated with responses in HESN. HIV-1-specific cellular responses may be less relevant to resistance to infection among HESN who are using risk reduction strategies that decrease their direct viral exposure.

Objective: Breast milk is a major route of infant HIV infection, yet the majority of breast-fed, HIV-exposed infants escape infection by unknown mechanisms. This study aimed to investigate the role of HIV-specific breast milk cells in preventing infant HIV infection., Design: A prospective study was designed to measure associations between maternal breast milk HIV-specific interferon-γ (IFN-γ) responses and infant HIV-1 detection at 1 month of age., Methods: In a Kenyan cohort of HIV-infected mothers, blood and breast milk HIV-gag IFN-γ ELISpot responses were measured. Logistic regression was used to measure associations between breast milk IFN-γ responses and infant HIV infection at 1 month of age., Results: IFN-γ responses were detected in breast milk from 117 of 170 (69%) women. IFN-γ responses were associated with breast milk viral load, levels of macrophage inflammatory protein (MIP) 1α, MIP-1β, regulated upon activation, normal T-cell expressed, and secreted and stromal-cell derived factor 1 and subclinical mastitis. Univariate factors associated with infant HIV infection at 1 month postpartum included both detection and breadth of breast milk IFN-γ response (P = 0.08, P = 0.04, respectively), breast milk MIP-1β detection (P = 0.05), and plasma (P = 0.004) and breast milk (P = 0.004) viral load. In multivariate analyses adjusting for breast milk viral load and MIP-1β, breast milk IFN-γ responses were associated with an approximately 70% reduction in infant HIV infection [adjusted odds ratio (aOR) 0.29, 95% confidence interval (CI) 0.092-0.91], and each additional peptide pool targeted was associated with an approximately 35% reduction in infant HIV (aOR 0.65, 95% CI 0.44-0.97)., Conclusion: These data show breast milk HIV-gag-specific IFN-γ cellular immune responses are prevalent and may contribute to protection from early HIV transmission. More broadly, these data suggest breast milk cellular responses are potentially influential in decreasing mother-to-child transmission of viruses.

The C868T single nucleotide polymorphism in the CD4 receptor encodes an amino acid substitution of tryptophan for arginine in the third domain. Previous studies suggest that C868T increases the risk of HIV-1 acquisition; however, the influence of this single nucleotide polymorphism (SNP) on disease progression has not been established. The presence of the C868T polymorphism was not statistically significantly associated with HIV-1 disease progression outcomes in a cohort of postpartum Kenyan women.

Background: We determined the consistency of positive interferon-gamma (IFN-γ) release assays (IGRAs) to detect latent TB infection (LTBI) over one-year postpartum in HIV-1-infected women., Methods: Women with positive IGRAs during pregnancy had four 3-monthly postpartum IGRAs. Postpartum change in magnitude of IFN-γ response was determined using linear mixed models., Results: Among 18 women with positive pregnancy IGRA, 15 (83%) had a subsequent positive IGRA; 9 (50%) were always positive, 3 (17%) were always negative, and 6 (33%) fluctuated between positive and negative IGRAs. Women with pregnancy IGRA IFN-γ>8 spot forming cells (SFCs)/well were more likely to have consistent postpartum IGRA response (odds ratio: 10.0; 95% confidence interval (CI): 0.9-117.0). Change in IFN-γ response over postpartum was 10.2 SFCs/well (95% CI: -1.5-21.8 SFCs/well)., Conclusion: Pregnancy positive IGRAs were often maintained postpartum with increased consistency in women with higher baseline responses. There were modest increases in magnitude of IGRA responses postpartum.

Although CD8(+) T cells play an important role in the containment of adult HIV-1 replication, their role in infant HIV-1 infection is not as well understood. Impaired HIV-specific CD8(+) T cell responses may underlie the persistently high viral loads observed in infants. We examined the frequency and phenotype of infant HIV-specific CD8(+) T cells in 7 HIV-infected antiretroviral therapy-naïve infants during the first 2 years of life, using class I HLA tetramers and IFN-γ-ELISPOT. The frequency (0.088-3.9% of CD3(+)CD8(+) cells) and phenotype (CD27(+)CD28(-), CD45RA(+/-), CD57(+/-), HLA-DR(+), CD95(+)) of infant HIV-specific CD8(+) T cells were similar to reports in adults undergoing early infection. Unlike adults, at 23-24 months post-infection a high frequency of HIV-specific CD8(+) T cells expressed HLA-DR (mean 80%, range 68-85%) and CD95 (mean 88%, range 79-96%), suggesting sustained activation and vulnerability to apoptosis. Despite comparable expansion of HIV-specific CD8(+) T cells of a similar phenotype to adults during early infection, infant T cells failed to contain HIV-1 replication, and remained persistently activated and vulnerable to apoptosis during chronic infection.

Despite more than 2 decades of research, an effective vaccine that can prevent HIV-1 infection in populations exposed to the virus remains elusive. In the pursuit of an HIV-1 vaccine, does prevention of exposure to maternal HIV-1 in utero, at birth or in early life through breast milk require special consideration? This article reviews what is known about the immune mechanisms of susceptibility and resistance to mother-to-child transmission (MTCT) of HIV-1 and summarizes studies that have used passive or active immunization strategies to interrupt MTCT of HIV-1. Potentially modifiable infectious cofactors that may enhance transmission and/or disease progression (especially in the developing world) are described. An effective prophylactic vaccine against HIV-1 infection needs to be deployed as part of the Extended Program of Immunization recommended by the World Health Organization for use in developing countries, so it is important to understand how the infant immune system responds to HIV-1 antigens, both in natural infection and presented by candidate vaccines., (Copyright © 2010 Elsevier Inc. All rights reserved.)

We examined associations between maternal human leukocyte antigen (HLA) and vertical human immunodeficiency virus type 1 (HIV-1) transmission in a perinatal cohort of 277 HIV-infected women in Nairobi. HLA class I genes were amplified by using sequence-specific oligonucleotide probes, and analyses were performed using logistic regression. Maternal HLA-A*2301 was associated with increased transmission risk before and after adjusting for maternal viral load (unadjusted: odds ratio [OR], 3.21; 95% confidence interval [CI], 1.42-7.27; P = .005; Pcorr = 0.04; adjusted: OR, 3.07; 95% CI, 1.26-7.51; P =.01; Pcorr is not significant). That maternal HLA-A*2301 was associated with transmission independent of plasma HIV-1 RNA levels suggests that HLA may alter infectivity through mechanisms other than influencing HIV-1 load.

Background: : HIV-1-infected children have lower response rates after measles and tetanus immunization than uninfected children. We determined the extent to which highly active antiretroviral therapy (HAART) augments vaccine immunity and promotes responses to revaccination., Methods: : Previously immunized, antiretroviral-naive HIV-1-infected children were evaluated for immunity against measles and tetanus. After 6 months on HAART, children meeting CD4% criteria (>15%) who were persistently antibody negative were revaccinated and immunity was reassessed., Results: : At enrollment, among 90 children with mean age of 4.9 years, 67% had negative measles IgG and 22% negative tetanus IgG. Among 62 children completing 6 months on HAART, 17 (40%) of 43 without protective measles IgG converted and 10 (53%) of 19 positive children lost measles responses (P = 0.3). Children who lost responses had significantly lower measles antibody concentrations than those who remained measles IgG positive during follow-up (7.1 vs. 20.3 mg/mL; P = 0.003). Three (23%) of 13 children negative for tetanus IgG spontaneously seroconverted on HAART, while 15 (31%) of 49 children lost tetanus antibody (P = 0.008). There was a nonsignificant trend for an association between spontaneous measles seroconversion and lower baseline HIV-1 viral load (P = 0.06). Tetanus seroconversion was associated with older age (P = 0.03). After revaccination, positive responses were observed in 78% and 75% of children reimmunized against measles and tetanus, respectively., Conclusions: : After 6 months of HAART, more than half of previously immunized children still lacked positive measles antibody. With increased use of HAART in pediatric populations, revaccination against measles and tetanus should be considered to boost response rates and immunization coverage.

Objective: Several co-infections have been shown to impact the progression of HIV-1 infection. We sought to determine if treatment of helminth co-infection in HIV-1-infected adults impacted markers of HIV-1 disease progression., Design: To date, there have been no randomized trials to examine the effects of soil-transmitted helminth eradication on markers of HIV-1 progression., Methods: A randomized, double-blind, placebo-controlled trial of albendazole (400 mg daily for 3 days) in antiretroviral-naive HIV-1-infected adults (CD4 cell count >200 cells/microl) with soil-transmitted helminth infection was conducted at 10 sites in Kenya (ClinicalTrials.gov NCT00130910). CD4 and plasma HIV-1 RNA levels at 12 weeks following randomization were compared in the trial arms using linear regression, adjusting for baseline values., Results: Of 1551 HIV-1-infected individuals screened for helminth infection, 299 were helminth infected. Two hundred and thirty-four adults were enrolled and underwent randomization and 208 individuals were included in intent-to-treat analyses. Mean CD4 cell count was 557 cells/microl and mean plasma viral load was 4.75 log10 copies/ml at enrollment. Albendazole therapy resulted in significantly higher CD4 cell counts among individuals with Ascaris lumbricoides infection after 12 weeks of follow-up (+109 cells/microl; 95% confidence interval +38.9 to +179.0, P = 0.003) and a trend for 0.54 log10 lower HIV-1 RNA levels (P = 0.09). These effects were not seen with treatment of other species of soil-transmitted helminths., Conclusion: Treatment of A. lumbricoides with albendazole in HIV-1-coinfected adults resulted in significantly increased CD4 cell counts during 3-month follow-up. Given the high prevalence of A. lumbricoides infection worldwide, deworming may be an important potential strategy to delay HIV-1 progression.

Background: Mother-child human leukocyte antigen (HLA) concordance and maternal HLA homozygosity may increase the risk of vertical transmission of human immunodeficiency virus type 1 (HIV-1) risk by reducing infant immune responses., Methods: We analyzed mother-child HLA concordance and maternal HLA homozygosity in a Kenyan perinatal cohort receiving antenatal zidovudine. HLA concordance was scored as the number of shared class I alleles, and relative risk estimates were adjusted for maternal HIV-1 load., Results: Among 277 mother-infant pairs, HIV-1 transmission occurred in 58 infants (21%), with in utero transmission in 21 (36%), peripartum transmission in 26 (45%), and transmission via breast-feeding in 11 (19%). With increased concordance, we observed a significant increase in the risk of transmission overall (adjusted hazard ratio [aHR], 1.3 [95% confidence interval {CI}, 1.0-1.7]; P = .04 in utero (adjusted odds ratio, 1.72 [95% CI, 1.0-1.7]; P = .04), and via breast-feeding (aHR, 1.6 [95% CI, 1.0-2.5]; P = .04). Women with homozygosity had higher plasma HIV-1 RNA levels at 32 weeks of gestation (5.1 vs. 4.8 log(10) copies/mL; P = .03) and an increased risk of transmission overall (aHR, 1.7 [95% CI, 1.1-2.7]; P = .03) and via breast-feeding (aHR, 5.8 [95% CI, 1.9-17.7]; P = .002)., Conclusion: The risks of overall, in utero, and breast milk HIV-1 transmission increased with HLA concordance and homozygosity. The increased risk may be due to reduced alloimmunity or less diverse protective immune responses.

Breastmilk chemokines have been associated with increased HIV-1 RNA levels in breastmilk and altered risk of mother-to-child HIV-1 transmission. To characterize CC and CXC chemokines in breastmilk postpartum, we collected breastmilk specimens at regular intervals for 6 months after delivery from women with and without HIV-1 infection and used commercial ELISA kits to measure breastmilk concentrations of MIP-1alpha, MIP-1beta, RANTES, and SDF-1alpha. Among 54 HIV-1-infected and 26 uninfected women, mean chemokine levels were compared cross-sectionally and longitudinally at days 5 and 10, and months 1 and 3 postpartum. For both HIV-1-infected and uninfected women, breastmilk chemokine levels were highest at day 5 for MIP-1alpha, MIP-1beta, and SDF-1alpha, and subsequently decreased. RANTES levels remained constant over the follow-up period among HIV-1-uninfected women, and increased moderately among HIV-1-infected women. For MIP-1beta and RANTES, breastmilk levels were significantly higher among HIV-1-infected women compared to uninfected women early postpartum. In addition, HIV-1-infected women transmitting HIV-1 to their infant had consistently higher breastmilk RANTES levels than those who did not transmit, with the greatest difference observed at 1 month (2.68 vs. 2.21 log10 pg/mL, respectively; p = 0.007). In summary, all four chemokines were most elevated within the first month postpartum, a period of high transmission risk via breastmilk. MIP-1beta and RANTES levels in breastmilk were higher among HIV-1-infected women than among uninfected women, and breastmilk RANTES was positively associated with vertical transmission in this study, consistent with results from our earlier cohort.