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Summary: Genital cytomegalovirus (CMV) reactivation is common during the third trimester of pregnancy. We hypothesized that cervical CMV shedding may increase risk of spontaneous preterm birth (sPTB) through the release of inflammatory cytokines in the cervix. We conducted a nested case–control analysis to determine the relationship between CMV shedding and sPTB using data and samples from a prospective cohort study in western Kenya. Women who delivered between 28 + 0 and 33 + 6 weeks gestation were matched by gestational age at sample collection to controls who delivered ≥ 37 + 0 weeks. Levels of CMV DNA and interleukin (IL)‐1 beta (β), IL‐6, IL‐8 and tumor necrosis factor (TNF)‐α were measured in cervical swabs. We used conditional logistic regression to assess relationships between CMV shedding, cervical cytokine levels and sPTB. Among 86 cases and 86 matched controls, cervical CMV levels were not significantly associated with sPTB [odds ratio (OR) = 1·23, 95% confidence interval (CI) = 0·59–2·56], but were significantly associated with higher levels of cervical IL‐6 (β = 0·15, 95% CI = 0·02–0·29) and TNF‐α (β = 0·14, 95% CI = 0·01–0·27). In univariate analysis, higher odds of sPTB was associated with higher cervical IL‐6 levels (OR = 1·54, 95% CI = 1·00–2·38), but not with other cervical cytokines. In this cohort of Kenyan women, we did not find a significant association between cervical CMV shedding and sPTB before 34 weeks. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) type 1-specific cell-mediated immunity of breast milk may influence the likelihood of mother-to-child transmission of HIV-1 via breast-feeding. In breast-milk specimens collected during the first month postpartum from HIV-1-seropositive women in Nairobi, HIV-1 gag-specific cellular responses were detected in 17 (47%) of 36, and env-specific cellular responses were present in 20 (40%) of 50. Peripheral blood lymphocyte responses against either gag or env were detected in 35 (66%) of the 53 subjects, 18 (51%) of whom had positive gag or env responses in their breast milk. In paired analyses of blood and breast milk, the mean magnitude of responses to env or gag stimulation in breast milk was significantly higher than that in blood and remained higher in breast milk after normalization of responses according to CD8+ lymphocyte count. These results suggest that CD8+ lymphocytes present in breast milk have the capacity to recognize HIV-1-infected cells and may be selectively transported to breast milk to reduce either viral replication or transmission in breast milk. [ABSTRACT FROM AUTHOR]

Objectives: Children with HIV may experience adverse neurocognitive outcomes despite antiretroviral therapy (ART). Cytomegalovirus (CMV) is common in children with HIV. Among children on ART, we examined the influences of early HIV viral load and CMV DNA on neurocognition., Design: We determined the association between pre-ART viral load, cumulative viral load, and CMV viremia and neurocognition using data from a cohort study., Methods: Children who initiated ART before 12 months of age were enrolled from 2007 to 2010 in Nairobi, Kenya. Blood was collected at enrollment and every 6 months thereafter. Four neurocognitive assessments with 12 domains were conducted when children were a median age of 7 years. Primary outcomes included cognitive ability, executive function, attention, and motor z scores. Generalized linear models were used to determine associations between HIV viral load (pre-ART and cumulative; N  = 38) and peak CMV DNA (by 24 months of age; N  = 20) and neurocognitive outcomes., Results: In adjusted models, higher peak CMV viremia by 24 months of age was associated with lower cognitive ability and motor z scores. Higher pre-ART HIV viral load was associated with lower executive function z scores. Among secondary outcomes, higher pre-ART viral load was associated with lower mean nonverbal and metacognition z scores., Conclusion: Higher pre-ART viral load and CMV DNA in infancy were associated with lower executive function, nonverbal and metacognition scores and cognitive ability and motor scores in childhood, respectively. These findings suggest long-term benefits of early HIV viral suppression and CMV control on neurocognition., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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.

Age at HIV acquisition may influence viral pathogenesis in infants, and yet infection timing (i.e. date of infection) is not always known. Adult studies have estimated infection timing using rates of HIV RNA diversification, however, it is unknown whether adult-trained models can provide accurate predictions when used for infants due to possible differences in viral dynamics. While rates of viral diversification have been well defined for adults, there are limited data characterizing these dynamics for infants. Here, we performed Illumina sequencing of gag and pol using longitudinal plasma samples from 22 Kenyan infants with well-characterized infection timing. We used these data to characterize viral diversity changes over time by designing an infant-trained Bayesian hierarchical regression model that predicts time since infection using viral diversity. We show that diversity accumulates with time for most infants (median rate within pol = 0.00079 diversity/month), and diversity accumulates much faster than in adults (compare previously-reported adult rate within pol = 0.00024 diversity/month [1]). We find that the infant rate of viral diversification varies by individual, gene region, and relative timing of infection, but not by set-point viral load or rate of CD4+ T cell decline. We compare the predictive performance of this infant-trained Bayesian hierarchical regression model with simple linear regression models trained using the same infant data, as well as existing adult-trained models [1]. Using an independent dataset from an additional 15 infants with frequent HIV testing to define infection timing, we demonstrate that infant-trained models more accurately estimate time since infection than existing adult-trained models. This work will be useful for timing HIV acquisition for infants with unknown infection timing and for refining our understanding of how viral diversity accumulates in infants, both of which may have broad implications for the future development of infant-specific therapeutic and preventive interventions., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: FAM is an Investigator of the Howard Hughes Medical Institute (HHMI)., (Copyright: © 2023 Russell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Infant antibody responses to viral infection can differ from those in adults. However, data on the specificity and function of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in infants, and direct comparisons between infants and adults are limited. Here, we characterize antibody binding and functionality against Wuhan-Hu-1 (B lineage) strain SARS-CoV-2 in convalescent plasma from 36 postpartum women and 14 of their infants infected with SARS-CoV-2 from a vaccine-naïve prospective cohort in Nairobi, Kenya. We find significantly higher antibody titers against SARS-CoV-2 Spike, receptor binding domain and N-terminal domain, and Spike-expressing cell-surface staining levels in infants versus mothers. Plasma antibodies from mothers and infants bind to similar regions of the Spike S2 subunit, including the fusion peptide (FP) and stem helix-heptad repeat 2. However, infants display higher antibody levels and more consistent antibody escape pathways in the FP region compared to mothers. Finally, infants have significantly higher levels of antibody-dependent cellular cytotoxicity (ADCC), though, surprisingly, Spike pseudovirus neutralization titers between infants and mothers are similar. These results suggest infants develop distinct SARS-CoV-2 binding and functional antibody activities and reveal age-related differences in humoral immunity to SARS-CoV-2 infection that could be relevant to protection and COVID-19 disease outcomes., (© 2023. Springer Nature Limited.)

Background: HIV may increase SARS-CoV-2 infection risk and COVID-19 severity generally, but data are limited about its impact on postpartum women and their infants. As such, we characterized SARS-CoV-2 infection among mother-infant pairs in Nairobi, Kenya., Methods: We conducted a nested study of 62 HIV-uninfected and 64 healthy women living with HIV, as well as their HIV-exposed uninfected (N = 61) and HIV-unexposed (N = 64) infants, participating in a prospective cohort. SARS-CoV-2 serology was performed on plasma collected between May 1, 2020-February 1, 2022 to determine the incidence, risk factors, and symptoms of infection. SARS-CoV-2 RNA PCR and sequencing was also performed on available stool samples from seropositive participants., Results: SARS-CoV-2 seropositivity was found in 66% of the 126 mothers and in 44% of the 125 infants. There was no significant association between SARS-CoV-2 infection and maternal HIV (Hazard Ratio [HR] = 0.810, 95% CI: 0.517-1.27) or infant HIV exposure (HR = 1.47, 95% CI: 0.859-2.53). Maternal SARS-CoV-2 was associated with a two-fold increased risk of infant infection (HR = 2.31, 95% CI: 1.08-4.94). Few participants (13% mothers, 33% infants) had symptoms; no participant experienced severe COVID-19 or death. Seroreversion occurred in about half of mothers and infants. SARS-CoV-2 sequences obtained from stool were related to contemporaneously circulating variants., Conclusions: These data indicate that postpartum Kenyan women and their infants were at high risk for SARS-CoV-2 infection and that antibody responses waned over an average of 8-10 months. However, most cases were asymptomatic and healthy women living with HIV did not have a substantially increased risk of infection or severe COVID-19., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Begnel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A multitude of enzyme-linked immunosorbent assays (ELISAs) has been developed to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies since the coronavirus disease 2019 pandemic started in late 2019. Assessing the reliability of these assays in diverse global populations is critical. This study compares the use of the commercially available Platelia Total Ab Assay (Bio-Rad) nucleocapsid ELISA to the widely used Mount Sinai spike IgG ELISA in a Kenyan population seroprevalence study. Using longitudinal plasma specimens collected from a mother-infant cohort living in Nairobi, Kenya between May 2019 and December 2020, this study demonstrates that the two assays have a high qualitative agreement (92.7%) and strong correlation of antibody levels (R 2  = 0.973) in repeated measures. Within this cohort, seroprevalence detected by either ELISA closely resembled previously published seroprevalence estimates for Kenya during the sampling period and no significant difference in the incidence of SARS-CoV-2 antibody detection by either assay was observed. Assay comparability was not affected by HIV exposure status. These data support the use of the Platelia SARS-CoV-2 Total Ab ELISA as a suitable high-throughput method for seroprevalence studies in Kenya., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: Cytomegalovirus (CMV) viremia is associated with mortality in severely ill immunocompetent adults and hospitalized children with HIV (CWH). We measured CMV viremia in HIV-exposed and -unexposed Kenyan children aged 1-59 months discharged from hospital and determined its relationship with postdischarge mortality., Methods: CMV DNA levels were measured in plasma from 1024 children (97 of which were HIV exposed uninfected [HEU], and 15 CWH). Poisson and Cox proportional hazards regression models were used to identify correlates of CMV viremia ≥ 1000 IU/mL 
and estimate associations with 6-month mortality, respectively., Results: CMV viremia was detected in 31% of children, with levels ≥ 1000 IU/mL in 5.8%. HIV infection, age < 2 years, breastfeeding, and midupper arm circumference < 12.5 cm were associated with CMV viremia ≥ 1000 IU/mL. Among HEU children, CMV ≥ 1000 IU/mL (hazard ratio [HR] = 32.0; 95% confidence interval [CI], 2.9-354.0; P = .005) and each 1-log increase in CMV viral load (HR = 5.04; 95% CI, 1.7-14.6; P = .003) were associated with increased risk of mortality. CMV viremia was not significantly associated with mortality in HIV-unexposed children., Conclusions: CMV levels at hospital postdischarge predict increased risk of 6-month mortality in Kenyan HEU children. CMV suppression may be a novel target to reduce mortality in HEU children., Clinical Trial Registration: NCT02414399., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. 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.)

Pre-existing antibodies that bind endemic human coronaviruses (eHCoVs) can cross-react with SARS-CoV-2, which is the betacoronavirus that causes COVID-19, but whether these responses influence SARS-CoV-2 infection is still under investigation and is particularly understudied in infants. In this study, we measured eHCoV and SARS-CoV-1 IgG antibody titers before and after SARS-CoV-2 seroconversion in a cohort of Kenyan women and their infants. Pre-existing eHCoV antibody binding titers were not consistently associated with SARS-CoV-2 seroconversion in infants or mothers; however, we observed a very modest association between pre-existing HCoV-229E antibody levels and a lack of SARS-CoV-2 seroconversion in the infants. After seroconversion to SARS-CoV-2, antibody binding titers to the endemic betacoronaviruses HCoV-OC43 and HCoV-HKU1, and the highly pathogenic betacoronavirus SARS-CoV-1, but not the endemic alphacoronaviruses HCoV-229E and HCoV-NL63, increased in the mothers. However, eHCoV antibody levels did not increase following SARS-CoV-2 seroconversion in the infants, suggesting the increase seen in the mothers was not simply due to cross-reactivity to naively generated SARS-CoV-2 antibodies. In contrast, the levels of antibodies that could bind SARS-CoV-1 increased after SARS-CoV-2 seroconversion in both the mothers and infants, both of whom were unlikely to have had a prior SARS-CoV-1 infection, supporting prior findings that SARS-CoV-2 responses cross-react with SARS-CoV-1. In summary, we found evidence of increased eHCoV antibody levels following SARS-CoV-2 seroconversion in the mothers but not the infants, suggesting eHCoV responses can be boosted by SARS-CoV-2 infection when a prior memory response has been established, and that pre-existing cross-reactive antibodies are not strongly associated with SARS-CoV-2 infection risk in mothers or infants.

Shared bacteria between maternal breast milk and infant stool, infers that transfer of maternal breast milk microbiota through breastfeeding seeds the establishment of the infant gut microbiome. Whether combination antiretroviral therapy (cART) impacts the breast milk microbiota in women living with HIV is unknown. Since current standard of care for people living with HIV includes cART, it has been difficult to evaluate the impact of cART on the microbiome. Here, we performed a next-generation sequencing retrospective study from pre-ART era clinical trials in Nairobi, Kenya (between 2003-2006 before cART was standard of care) that tested the effects of ART regimens to prevent mother-to-child HIV transmission. Kenyan women living with HIV were randomized to receive either no ART during breastfeeding ( n  = 24) or cART (zidovudine, nevirapine, lamivudine; n  = 25) postpartum. Using linear mixed-effects models, we found that alpha diversity and beta diversity of the breast milk bacterial microbiome changed significantly over time during the first 4 weeks postpartum (alpha diversity P  < 0.0007; beta diversity P  = 0.005). There was no statistically significant difference in diversity, richness, and composition of the bacterial microbiome between cART-exposed and cART-unexposed women. In contrast, antibiotic use influenced the change of beta diversity of the bacterial microbiome over time. Our results indicate that while early postpartum time predicts breast milk microbiome composition, cART does not substantially alter the breast milk microbiota in women living with HIV. Hence, cART has minimal impact on the breast milk microbiome compared to antibiotics use. IMPORTANCE Breastfeeding has important benefits for long-term infant health, particularly in establishing and shaping the infant gut microbiome. However, the impact of combination antiretroviral therapy exposure and antibiotics on the breast milk microbiome in women living with HIV is not known. Here, in a longitudinal retrospective study of Kenyan women living with HIV from the pre-antiretroviral therapy era, we found that antibiotic use significantly influenced breast milk microbiome beta diversity, but antiretrovirals exposure did not substantially alter the microbiome. Given the protective role of breastfeeding in maternal-infant health, these findings fill an important knowledge gap of the impact of combination antiretroviral therapy on the microbiome of women living with HIV.

Background: Cytomegalovirus (CMV) viremia is common in human immunodeficiency virus (HIV) infection and is associated with worse long-term outcomes. To date, no studies have assessed CMV viremia in children diagnosed with HIV in hospital., Methods: We studied CMV viremia and clinical outcomes in 163 Kenyan children aged 2 months to 12 years, diagnosed with HIV in hospital. CMV DNA levels in plasma were measured using quantitative polymerase chain reaction (PCR). Regression models were used to assess associations between CMV viremia ≥1000 IU/mL and the risk of continued hospitalization or death at 15 days, duration of hospitalization, and 6-month mortality., Results: At enrollment, 62/114 (54%) children had CMV viremia, and 20 (32%) were ≥1000 IU/mL. Eleven CMV reactivations were observed after admission. The prevalence and level of CMV viremia were highest in children <2 years and lowest in children ≥5 years old. CMV viremia ≥1000 IU/mL was independently associated with age <2 years (P = .03), higher log10 HIV RNA level (P = .01), and height-for-age z score >-2 (P = .02). Adjusting for age and log10 HIV RNA, the relative risk of death or continued hospitalization at 15 days was 1.74 (95% confidence interval [CI] = 1.04, 2.90), and the hazard ratio of 6-month mortality was 1.97 (95% CI = .57, 5.07) for children with CMV DNA ≥1000 IU/mL compared to lower-level or undetectable CMV DNA. Children with CMV DNA ≥1000 IU/mL were hospitalized a median ~5 days longer than children with lower-level or undetectable CMV DNA (P = .002)., Conclusions: In this nested observational study, CMV viremia was common in hospitalized children with HIV, and levels ≥1000 IU/mL were associated with increased risk of mortality and longer hospitalization., (© 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.)

Abstract: Sustained viral suppression in adolescents and young adults living with HIV (AYALWH) is necessary for epidemic control. We evaluated facility and individual correlates of viral suppression using programmatic data from AYALWH between ages 10 and 24 years at 24 HIV clinics in Kenya. Binomial regression was used to evaluate correlates of viral load (VL) suppression (<1,000 copies/ml). Of 5,316 AYALWH on antiretroviral therapy ≥6 months, 2,081 (39%) had VLs available in the medical record, of which 76% were virally suppressed. In multivariable analyses, antiretroviral therapy initiation among AYALWH older than 10 years was associated with higher viral suppression than initiation younger than 10 years (adjusted risk ratio [aRR] 10-14 = 1.03, 95% confidence interval [CI] 0.97-1.10; aRR 15-19 = 1.30, 95% CI 1.19-1.41; aRR 20-24 = 1.43, 95% CI 1.24-1.63). Facilities with both youth-friendly services (YFS) and trained providers had significantly higher VL suppression compared with facilities without YFS or trained providers (adjusted odds ratio: 2.07, 95% CI: 1.71-2.52). Viral suppression remains suboptimal among AYALWH. YFS and trained providers plus greater use of VL data may help increase viral suppression among AYALWH., (Copyright © 2021 Association of Nurses in AIDS Care.)

Defining immune responses that protect humans against diverse HIV strains has been elusive. Studying correlates of protection from mother-to-child transmission provides a benchmark for HIV vaccine protection because passively transferred HIV antibodies are present during infant exposure to HIV through breast milk. A previous study by our group illustrated that passively acquired antibody-dependent cellular cytotoxicity (ADCC) activity is associated with improved infant survival whereas neutralization is not. Here, we show, in another cohort and with two effector measures, that passively acquired ADCC antibodies correlate with infant survival. In combined analyses of data from both cohorts, there are highly statistically significant associations between higher infant survival and passively acquired ADCC levels (p = 0.029) as well as dimeric FcγRIIa (p = 0.002) or dimeric FcγRIIIa binding (p < 0.001). These results suggest that natural killer (NK) cell- and monocyte antibody-mediated effector functions may contribute to the observed survival benefit and support a role of pre-existing ADCC-mediating antibodies in clinical outcome., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Learning climate greatly affects student achievement. This qualitative study aimed to understand community definitions of climate; share lived experiences of students, faculty, and staff; and define priority areas of improvement in the University of Washington School of Public Health (UWSPH). Between March-May 2019, 17 focus group discussions were conducted-stratified by role and self-identified race/ethnicity, gender and sexual orientation-among 28 faculty/staff and 36 students. Topics included: assessing the current climate, recounting experiences related to roles and identities, and recommending improvements. Transcripts were coded using deductive and inductive approaches. Race/ethnicity, gender, and sexual orientation appeared to affect perceptions of the climate, with nearly all respondents from underrepresented or minoritized groups recounting negative experiences related to their identity. Persons of color, women, and other respondents who identified as lesbian, gay, bisexual, transgender, queer/questioning, intersex, and asexual (LGBTQIA) frequently perceived the climate as "uncomfortable." Most felt that UWSPH operates within a structural hierarchy that perpetuates white, male, and/or class privilege and "protects those in power" while leaving underrepresented or minoritized groups feeling like "the way to move up… is to conform" in order to not be seen as "someone pushing against the system." Improvement priorities included: increasing community responsiveness to diversity, equity, and inclusion; intentionally diversifying faculty/staff and student populations; designing inclusive curricula; and supporting underrepresented or minoritized groups academically, professionally, and psychologically., 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 Gwayi-Chore, Del Villar, Fraire, Waters, Andrasik, Pfeiffer, Slyker, Mello, Barnabas, Moise and Heffron.)

Breast milk is nutritionally and immunologically beneficial in early life but is also a potential source of infection. Little is known about breast milk microbiota of women living with HIV (WLHIV), the impact of severe immunosuppression, and the contribution to mortality of HIV-exposed infants. Here, we performed metagenomic sequencing to characterize the bacterial microbiome and DNA virome of breast milk samples at 1 month postpartum from Kenyan WLHIV who were not receiving combination antiretroviral therapy (cART), 23 women with CD4 counts of <250 and 30 women with CD4 of >500; and additionally, 19 WLHIV with infants that lived and 26 WLHIV with infants that died during the first 2 years of life were included. We found that breast milk bacterial microbiomes in this study population were highly diverse but shared a core community composed of the Streptococcaceae , Staphylococcaceae , Moraxellaceae , and Eubacteriaceae families. The breast milk virome was dominated by human cytomegalovirus (CMV) and included the bacteriophage families Myoviridae , Siphoviridae , and Podoviridae Bacterial microbiome and virome profiles and diversity were not significantly altered by HIV immunosuppression, as defined by a CD4 of <250. CMV viral load was not associated with maternal CD4 counts or infant mortality. In conclusion, we show that the core bacterial and viral communities are resilient in breast milk despite immunosuppression in WLHIV. IMPORTANCE Breastfeeding plays an important role in seeding the infant gut microbiome and mammary health. Although most studies focus on the diverse breast milk bacterial communities, little is known about the viral communities harbored in breast milk. We performed the first breast milk virome study of an HIV population. In this study cohort of Kenyan women living with HIV from the pre-antiretroviral therapy era, we found that breast milk harbors a core bacterial microbiome and a virome dominated by human cytomegalovirus. The virome and bacterial microbiome were not substantially altered by immunosuppression or associated with infant mortality. Together, these findings indicate resilience of the microbial community in breast milk compartmentalization. These findings advance out fundamental understanding of the breast milk core microbiome and virome interactions in the context of HIV disease., (Copyright © 2021 Maqsood et al.)

Developmental screening instruments were designed as diagnostic tools, but there is growing interest in understanding whether select tools can also be used systematically in research to examine intervention impacts on long-term outcomes. As such, this systematic review aims to examine associations between child development assessment tools and educational attainment, academic achievement, or wealth. We included studies identified in PubMed, PsycINFO, and Educational Resources Information Center if they reported an association between at least one tool from a pre-established list and one outcome of interest after age 10. Of 597 studies identified, 11 met inclusion criteria; three examined educational attainment as the outcome of interest, six examined academic achievement, one wealth, and one both educational attainment and wealth. Intelligence tests were utilized in five of the included studies, neuropsychological/executive function or behavior tools were used in five, and one study used tools across the domains. High-quality studies were identified across all three of the domains, but educational attainment and wealth had the greatest proportion of high-quality studies, as compared to academic achievement. Our review demonstrates the potential for certain child development assessment tools to adequately assess long-term outcomes of interest, but additional prospective studies using validated, culturally appropriate tools are needed. PROSPERO registration number: CRD42018092292.

Background: Financial incentives can motivate desirable health behaviors, including adult HIV testing. Data regarding the effectiveness of financial incentives for HIV testing in children, who require urgent testing to prevent mortality, are lacking., Methods: In a five-arm unblinded randomized controlled trial, adults living with HIV attending 19 HIV clinics in Western Kenya, with children 0-12 years of unknown HIV status, were randomized with equal allocation to $0, $1.25, $2.50, $5 or $10. Payment was conditional on child HIV testing within 2 months. Block randomization with fixed block sizes was used; participants and study staff were unblinded at randomization. Primary analysis was intent-to-treat, with predefined primary outcomes of completing child HIV testing and time to testing., Results: Of 452 caregivers, 90, 89, 93, 92 and 88 were randomized to $0, $1.25, $2.50, $5.00, and $10.00, respectively. Of those, 31 (34%), 31 (35%), 44 (47%), 51 (55%), and 54 (61%) in the $0, $1.25, $2.50, $5.00, and $10.00 arms, respectively, completed child testing. Compared with the $0 arm, and adjusted for site, caregivers in the $10.00 arm had significantly higher uptake of testing [relative risk: 1.80 (95% CI 1.15--2.80), P = 0.010]. Compared with the $0 arm, and adjusted for site, time to testing was significantly faster in the $5.00 and $10.00 arms [hazard ratio: 1.95 (95% CI 1.24--3.07) P = 0.004, 2.42 (95% CI 1.55--3.79), P < 0.001, respectively)., Conclusion: Financial incentives are effective in improving pediatric HIV testing among caregivers living with HIV., Registration: NCT03049917.

Stakeholder engagement between researchers, policymakers and practitioners is critical for the successful translation of research into policy and practice. The Counseling and Testing for Children at Home (CATCH) study evaluated a paediatric index case testing model, targeting the children of HIV-infected adults in care in Kenya. Researchers collaborated with stakeholders in the planning, execution and evaluation, and dissemination phases of CATCH. They included a community advisory board, the national HIV programme, County health departments, institutional ethics review bodies, a paediatric bioethics group, facility heads and frontline healthcare workers . Stakeholder analysis considered the power and interest of each stakeholder in the study. All stakeholders had some power to influence the success of the project in the different phases. However, support from institutions with higher hierarchical power increased acceptance of the study by stakeholders lower in the hierarchy. During the planning, execution and evaluation, and dissemination phases, the study benefitted from deliberate stakeholder engagement. Through engagement, changes were made in the approach to recruitment to ensure high external validity, placing recruitment optimally within existing clinic flow patterns. Choices in staffing home visits were made to include the appropriate cadre of staff. Adaptations were made to the consenting process that balanced the child's evolving autonomy and risks of HIV disclosure. Dissemination involved delivering site-specific results in each HIV clinic, local and international conferences and sharing of study tools, resulting in the study approach being scaled up nationally. The deliberate engagement of stakeholders early in intervention development optimized study validity and accelerated adoption of the CATCH approach in nationwide HIV testing campaigns by the Ministry of Health and inclusion of paediatric index-case testing in national HIV testing guidelines. Involving policymakers and frontline healthcare workers throughout the study cycle builds capacity in the implementing team for quick adoption and scale-up of the evidence-based practice., (© The Author(s) 2020. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Mother-to-child transmission of human immunodeficiency virus (HIV) occurs in the setting of maternal and passively acquired antibodies, providing a unique window into immune correlates of HIV risk. We compared plasma antibody binding to HIV antigens between 51 nontransmitting mother-infant pairs and 21 transmitting mother-infant pairs. Plasma antibody binding to a variety of gp41 ectodomain-containing antigens was associated with increased odds of transmission. Understanding the reasons why gp41 ectodomain-targeting antibodies are associated with transmission risk will be important in determining whether they can directly enhance infection or whether their presence reflects a redirecting of the humoral response away from targeting more protective epitopes., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Expansion of access to diagnosis and treatment for human immunodeficiency virus (HIV) and a high incidence of HIV infection in adolescence has resulted in a growing population of adolescents and young adults living with HIV. The prevalence of poor retention in care, insufficient viral suppression and loss to follow-up are higher among adolescents and young adults compared with other age groups. Poor outcomes could be attributed to psychosocial changes during adolescence, but also to poor transitional care from paediatric to adult HIV services. In many countries, transition processes remain poorly defined and unstructured, which may jeopardize treatment adherence and retention. We describe existing definitions of transition and transition frameworks, and key elements of transition as proposed by key national stakeholders in Kenya. Our consensus definition of transition is "a planned process by which adolescents and young adults living with HIV, and their caregivers, are empowered with knowledge and skills to enable them to independently manage their health." Transition should begin soon after disclosure of HIV status until an adolescent gains the necessary knowledge and skills and is willing to move to adult services, or by 25 years of age. Proposed key elements of transition are: target ages for milestone achievement; readiness assessment; caregiver involvement and communication with adult clinics; flexibility to return to adolescent or paediatric clinics; group transition; and considerations for adolescents with special needs. Retention in care, linkage to care and viral suppression are important markers of transition success. Proposed definitions and key elements could provide a framework for structuring transition programmes in other countries., ((c) 2019 The authors; licensee World Health Organization.)

Poor retention in HIV care remains a major problem for Adolescents and Young Adults (AYA). A Standardized Patient (SP) clinical training intervention was developed to improve healthcare worker (HCW) "adolescent-friendly" competencies in Kenya. Professional actors were trained to portray HIV-infected AYA according to standardized scripts. HCWs completed a 2-day SP training that included didactic sessions, 7 video-recorded SP encounters, and group debriefing. AYA health experts rated HCWs by reviewing the video recordings. All HCWs (10/10) reported high satisfaction with the intervention and overall improvement in self-rated competency in caring for HIV-infected AYA. Cases were reported to be realistic and relevant by between 7 and 10 of 10 HCWs. The case on disclosure and adherence was rated as most challenging in communication and making medical decisions by HCWs. Areas identified by SPs for improvement by HCWs included allowing patients time to ask questions, and enabling SP to share sensitive information. The overall ICC by experts was low 0.27 (95% CI: -0.79 to 0.95), however, ICCs in assessment of HIV disclosure 0.78 (95% CI: 0.17-0.98), and sexual behavior 0.97 (95% CI: 0.89-0.99) were high. This intervention was acceptable for Kenyan HCWs and improved self-rated competency in caring for HIV-infected AYA.

Background: Antibody-dependent cellular cytotoxicity (ADCC) has been associated with improved infant outcome in mother-to-child transmission (MTCT) of HIV-1. Epitopes of these ADCC-mediating antibodies remain unidentified. CD4-inducible (CD4i) epitopes on gp120 are common ADCC targets in natural infection and vaccination. We tested whether CD4i epitope-specific ADCC mediated by maternal antibodies or passively-acquired antibodies in infants is associated with reduced MTCT and improved infant survival., Methods: We used variants of CD4i cluster A-specific antibodies, A32 and C11, and a cluster C-specific antibody, 17b, with mutations abolishing Fc-Fc receptor interactions as inhibitors in a competition rapid and fluorometric ADCC assay using gp120-coated CEM-nkr target cells with plasma from 51 non-transmitting and 21 transmitting breastfeeding mother-infant pairs., Findings: Cluster A-specific ADCC was common. Individually, neither A32-like nor C11-like ADCC was statistically significantly associated with risk of MTCT or infected infant survival. In combination, total maternal cluster A-specific ADCC was statistically significantly associated with decreased infected infant survival in a log-rank test (p = 0·017). There was a non-significant association for infant passively-acquired total cluster A-specific ADCC and decreased infected infant survival (p = 0·14). Surprisingly, plasma ADCC was enhanced in the presence of the defective Fc 17b competitor. Defective Fc 17b competitor-mediated maternal ADCC enhancement was statistically significantly associated with reduced infected infant survival (p = 0·011). A non-significant association was observed for passively-acquired infant ADCC enhancement and decreased survival (p = 0·19)., Interpretations: These data suggest that ADCC targeting CD4i epitopes is not associated with protection against breast milk HIV transmission but is associated with decreased survival of infected infants. FUND: This study was funded by NIH grant R01AI076105 and NIH fellowship F30AI136636., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: Adolescents and young adults (AYA) have poorer retention, viral suppression, and survival than other age groups. We evaluated correlates of initial AYA engagement in HIV care at facilities participating in a randomized trial in Kenya., Design: Retrospective cohort study., Methods: Electronic medical records from AYA ages 10-24 attending 24 HIV care facilities in Kenya were abstracted. Facility surveys assessed provider trainings and services. HIV provider surveys assessed AYA training and work experience. Engagement in care was defined as return for first follow-up visit within 3 months among newly enrolled or recently re-engaged (returning after >3 months out of care) AYA. Multilevel regression estimated risk ratios and 95% confidence intervals (CIs), accounting for clustering by facility. Final models adjusted for AYA individual age and median AYA age and number enrolled per facility., Results: Among 3662 AYA records at first eligible visit, most were female (75.1%), older (20-24 years: 54.5%), and on antiretroviral therapy (79.5%). Overall, 2639 AYA returned for care (72.1%) after enrollment or re-engagement visit. Engagement in care among AYA was significantly higher at facilities offering provider training in adolescent-friendly care (85.5 vs. 67.7%; adjusted risk ratio (aRR) 1.11, 95% CI: 1.01-1.22) and that used the Kenyan government's AYA care checklist (88.9 vs. 69.2%; aRR 1.14, 95% CI: 1.06-1.23). Engagement was also significantly higher at facilities where providers reported being trained in AYA HIV care (aRR 1.56, 95% CI: 1.13-2.16)., Conclusion: Adolescent-specific health provider training and tools may improve quality of care and subsequent AYA engagement. Health provider interventions are needed to achieve the '95-95-95' targets for AYA.

Background: While traditional epidemiological approaches have supported significant reductions in malaria incidence across many countries, higher resolution information about local and regional malaria epidemiology will be needed to efficiently target interventions for elimination. The application of genetic epidemiological methods for the analysis of parasite genetics has, thus far, primarily been confined to research settings. To illustrate how these technical methods can be used to advance programmatic and operational needs of National Malaria Control Programmes (NMCPs), and accelerate global progress to eradication, this manuscript presents seven use cases for which genetic epidemiology approaches to parasite genetic data are informative to the decision-making of NMCPs., Methods: The use cases were developed through a highly iterative process that included an extensive review of the literature and global guidance documents, including the 2017 World Health Organization's Framework for Malaria Elimination, and collection of stakeholder input. Semi-structured interviews were conducted with programmatic and technical experts about the needs and opportunities for genetic epidemiology methods in malaria elimination., Results: Seven use cases were developed: Detect resistance, Assess drug resistance gene flow, Assess transmission intensity, Identify foci, Determine connectivity of parasite populations, Identify imported cases, and Characterize local transmission chains. The method currently used to provide the information sought, population unit for implementation, the pre-conditions for using these approaches, and post-conditions intended as a product of the use case were identified for each use case., Discussion: This framework of use cases will prioritize research and development of genetic epidemiology methods that best achieve the goals of NMCPs, and ultimately, inform the establishment of normative policy guidance for their uses. With significant engagement of stakeholders from malaria endemic countries and collaboration with local programme experts to ensure strategic implementation, genetic epidemiological approaches have tremendous potential to accelerate global malaria elimination efforts.

The acceptability of financial incentives for pediatric HIV testing was evaluated in Kenya. Sixty HIV-positive women with children of unknown status were randomized to receive $5, $10 or $15 conditional upon HIV testing. Forty-four (73%) completed child testing, with similar rates across arms. Uptake was significantly higher than a cohort with similar procedures but no incentives (73% vs. 14%, P < 0.001).

Objective: To assess the effect of short message service (SMS) communication on facility delivery, exclusive breastfeeding (EBF), and contraceptive use., Design: Mobile WACh was a three-arm unblinded individually randomised controlled trial., Setting: A public sector maternal child health (MCH) clinic in Nairobi, Kenya., Population: Three hundred women attending antenatal care were randomised, 100 to each arm, and followed for 24 weeks postpartum. Pregnant women, at least 14 years old with access to a mobile phone and able to read SMS were eligible for participation., Methods: Women were randomised (1:1:1) to receive one-way SMS versus two-way SMS with a nurse versus control. Weekly SMS content was tailored for maternal characteristics and pregnancy or postpartum timing., Main Outcome Measures: Facility delivery, EBF, and contraceptive use were compared separately between each intervention arm and the control arm by Kaplan-Meier analysis and chi-square tests using intent-to-treat analyses., Results: The overall facility delivery rate was high (98%) and did not differ by arm. Compared with controls, probability of EBF was higher in the one-way SMS arm at 10 and 16 weeks, and in the two-way SMS arm at 10, 16, and 24 weeks (P < 0.005 for all). Contraceptive use was significantly higher in both intervention arms by 16 weeks (one-way SMS: 72% and two-way SMS: 73%; P = 0.03 and P = 0.02 versus 57% control, respectively); however, this difference was not significant when correcting for multiple comparisons., Conclusion: One-way and two-way SMS improved EBF practices and early contraceptive use. Two-way SMS had an added benefit on sustained EBF, providing evidence that SMS messaging influences uptake of interventions that improve maternal and neonatal health., Source of Funding: Funding was provided by the National Institutes of Health (K12HD001264 to JAU, R01HD080460, K24HD054314 to GJS, and K01AI116298 to ALD), the National Science Foundation (Graduate Research Fellowship to TP and BD), as well as the University of Washington Global Center for Integrated Health of Women Adolescents and Children (Global WACh)., Tweetable Abstract: The Mobile WACh RCT demonstrates that SMS improved practice of exclusive breastfeeding and early postpartum contraception., (© 2018 Royal College of Obstetricians and Gynaecologists.)

Antiretroviral therapy-naive HIV-1 infected infants experience poor viral containment and rapid disease progression compared to adults. Viral factors (e.g. transmitted cytotoxic T- lymphocyte (CTL) escape mutations) or infant factors (e.g. reduced CTL functional capacity) may explain this observation. We assessed CTL functionality by analysing selection in CTL-targeted HIV-1 epitopes following perinatal infection. HIV-1 gag, pol and nef sequences were generated from a historical repository of longitudinal specimens from 19 vertically infected infants. Evolutionary rate and selection were estimated for each gene and in CTL-restricted and non-restricted epitopes. Evolutionary rate was higher in nef and gag vs. pol, and lower in infants with non-severe immunosuppression vs. severe immunosuppression across gag and nef. Selection pressure was stronger in infants with non-severe immunosuppression vs. severe immunosuppression across gag. The analysis also showed that infants with non-severe immunosuppression had stronger selection in CTL-restricted vs. non-restricted epitopes in gag and nef. Evidence of stronger CTL selection was absent in infants with severe immunosuppression. These data indicate that infant CTLs can exert selection pressure on gag and nef epitopes in early infection and that stronger selection across CTL epitopes is associated with favourable clinical outcomes. These results have implications for the development of paediatric HIV-1 vaccines.

Background: Despite expanded programs for prevention of mother-to-child HIV transmission (PMTCT), HIV-infected infants may not be diagnosed until they are ill. Comparing HIV prevalence and outcomes in infants diagnosed in PMTCT programs to those in hospital settings may improve pediatric HIV diagnosis strategies., Methods: HIV-exposed infants <12 months old were recruited from 9 PMTCT sites in public maternal child health (MCH) clinics or from an inpatient setting in Nairobi, Kenya and tested for HIV using HIV DNA assays. A subset of HIV-infected infants <4.5 months of age was enrolled in a research study and followed for 2 years. HIV prevalence, number needed to test, infant age at testing, and turnaround time for tests were compared between PMTCT programs and hospital sites. Among the enrolled cohort, baseline characteristics, survival, and timing of antiretroviral therapy (ART) initiation were compared between infants diagnosed in PMTCT programs versus hospital., Results: Among 1,923 HIV-exposed infants, HIV prevalence was higher among infants tested in hospital than PMTCT early infant diagnosis (EID) sites (41% vs. 11%, p < 0.001); the number of HIV-exposed infants needed to test to diagnose one infection was 2.4 in the hospital vs. 9.1 in PMTCT. Receipt of HIV test results was faster among hospitalized infants (7 vs. 25 days, p < 0.001). Infants diagnosed in hospital were older at the time of testing than PMTCT diagnosed infants (5.0 vs. 1.6 months, respectively, p < 0.001). In the subset of 99 HIV-infected infants <4.5 months old followed longitudinally, hospital-diagnosed infants did not differ from PMTCT-diagnosed infants in time to ART initiation; however, hospital-diagnosed infants were >3 times as likely to die (HR = 3.1, 95% CI = 1.3-7.6)., Conclusions: Among HIV-exposed infants, hospital-based testing was more likely to detect an HIV-infected infant than PMTCT testing. Because young symptomatic infants diagnosed with HIV during hospitalization have very high mortality, every effort should be made to diagnose HIV infections before symptom onset. Systems to expedite turnaround time at PMTCT EID sites and to routinize inpatient pediatric HIV testing are necessary to improve pediatric HIV outcomes.

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: Cytomegalovirus (CMV) infection is associated with adverse outcomes in human immunodeficiency virus (HIV)-exposed infants. Determinants of vertical CMV transmission in the setting of maternal HIV-1 infection are not well-defined., Methods: CMV and HIV-1 levels were measured in plasma, cervical secretions, and breast milk of 147 HIV-1-infected women to define correlates of maternal CMV replication and infant CMV acquisition., Results: Although few women had detectable CMV in plasma (4.8%), the majority had detectable CMV DNA in cervical secretions (66%) and breast milk (99%). There was a strong association between cervical CMV detection during pregnancy and later breast milk levels (β = 0.47; P = .005). Plasma HIV-1 level and CD4 counts were associated with CMV in the cervix and breast milk. However HIV-1 levels within the cervix and breast milk were not associated with CMV within these compartments. Maternal breast milk CMV levels (hazard ratio [HR], 1.4; P = .003) and maternal CD4 < 450 cells/mm(3) (HR, 1.8; P = .008) were independently associated with infant CMV acquisition; each log10 increase in breast milk CMV was associated with a 40% increase in infant infection. The breast milk CMV level required to attain a 50% probability of CMV transmission increased with higher maternal CD4 counts, increasing from 3.55 log10 CMV DNA copies/mL at a CD4 count of 350 cells/mm(3) to 5.50 log10 CMV DNA copies/mL at a CD4 count of 1000 cells/mm(3)., Conclusions: Breast milk CMV levels and maternal CD4 count are major determinants of CMV transmission in the setting of maternal HIV-1. Maternal immune reconstitution or lowering breast milk CMV levels may reduce vertical CMV transmission.

Background: Uremia has long been associated with cognitive deficits. This study explored the importance of the time of measurement of neurocognitive functioning, by directly comparing changes in neurocognitive functioning from immediately after hemodialysis treatment to immediately before treatment., Methods: Twenty-five hemodynamically stable hemodialysis patients and 6 peritoneal dialysis controls completed 2 computer-based assessment batteries (ANAM), one immediately before dialysis and the second upon completion of that dialysis session. Paired sample t-tests were used to compare postdialysis with predialysis neurocognitive functioning scores for both a composite measure of global functioning and the neurocognitive subtests., Results: There was significant improvement in global neuropsychological functioning from predialysis to postdialysis (t (24) = -7.5, p<0.001), showing an average of 18% improvement in the hemodialysis group, with no significant change in the peritoneal dialysis group., Conclusion: This study suggests that computer-based testing can offer information on the cognitive fluctuations of medically complex populations and suggests that the end of the session may be a better time to discuss important and complex health messages with hemodialysis patients. It further implies that some of the neurocognitive impairment that is associated with end-stage renal disease is a consequence of uremia and is improved by hemodialysis.

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.)

Background: Breast-feeding by infants exposed to human immunodeficiency virus type 1 (HIV-1) provides an opportunity to assess the role played by repeated HIV-1 exposure in eliciting HIV-1-specific immunity and in defining whether immune responses correlate with protection from infection., Methods: Breast-feeding infants born to HIV-1-seropositive women were assessed for HLA-selected HIV-1 peptide-specific cytotoxic T lymphocyte interferon (IFN)-gamma responses by means of enzyme-linked immunospot (ELISpot) assays at 1, 3, 6, 9, and 12 months of age. Responses were deemed to be positive when they reached > or = 50 HIV-1-specific sfu/1 x 10(6) peripheral blood mononuclear cells (PBMCs) and were at least twice those of negative controls., Results: A total of 807 ELISpot assays were performed for 217 infants who remained uninfected with HIV-1 at approximately 12 months of age; 101 infants (47%) had at least 1 positive ELISpot result (median, 78-170 sfu/1 x 10(6) PBMCs). The prevalence and magnitude of responses increased with age (P = .01 and P = .007, respectively); the median log(10) value for HIV-1-specific IFN-gamma responses increased by 1.0 sfu/1 x 10(6) PBMCs/month (P < .001) between 1 and 12 months of age. Of 141 HIV-1-uninfected infants with 1-month ELISpot results, 10 (7%) acquired HIV-1 infection (0/16 with positive vs. 10/125 [8%] with negative ELISpot results; P = .6). Higher values for log(10) HIV-1-specific spot-forming units at 1 month of age were associated with a decreased risk of HIV-1 infection, adjusted for maternal HIV-1 RNA level (adjusted hazard ratio, 0.09 [95% confidence interval, 0.01-0.72])., Conclusion: . Breast-feeding HIV-1-exposed uninfected infants frequently had HIV-1-specific IFN-gamma responses. Greater early HIV-1-specific IFN-gamma responses were associated with decreased HIV-1 acquisition.

Human leukocyte antigen (HLA) molecules regulate the cellular immune system and may be determinants of infant susceptibility to human immunodeficiency virus type 1 (HIV-1) infection. Molecular HLA typing for class I alleles was performed on infants followed in a Kenyan perinatal cohort. Early HIV-1 infection status was defined as infection occurring at birth or month 1, while late infection via breast milk was defined as first detection of HIV-1 after 1 month of age. Likelihood ratio tests based on a proportional hazards model adjusting for maternal CD4 T cell count and HIV-1 viral load at 32 weeks of gestation were used to test associations between infant allelic variation and incident HIV-1 infection. Among 433 infants, 76 (18%) were HIV-1 infected during 12 months of follow-up. HLA B*18 was associated with a significantly lower risk of early HIV-1 transmission [relative risk (RR) = 0.26; 95% confidence interval (CI) 0.04-0.82], and none of the 24 breastfeeding infants expressing HLA B*18 who were uninfected at month 1 acquired HIV-1 late via breast milk. We observed a trend toward increased early HIV-1 acquisition for infants presenting HLA A*29 (RR = 2.0; 95% CI 1.0-3.8) and increased late HIV-1 acquisition via breast milk for both Cw*07 and Cw*08 (RR = 4.0; 95% CI 1.0-17.8 and RR = 7.2; 95% CI 1.2-37.3, respectively). HLA B*18 may protect breast-feeding infants against both early and late HIV-1 acquisition, a finding that could have implications for the design and monitoring of HIV-1 vaccines targeting cellular immune responses against HIV-1.