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1.  Maternal HLA Homozygosity and Mother-Child HLA Concordance Increase the Risk of Vertical Transmission of HIV-1 
The Journal of infectious diseases  2008;197(8):1156-1161.
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.
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.
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 log10 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).
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.
PMCID: PMC2689391  PMID: 18462163
2.  HLA-G DNA sequence variants and risk of perinatal HIV-1 transmission 
HLA-G gene is a non-classical MHC class 1 molecule that is highly expressed in the trophoblast at the maternal-fetal interface. In an attempt to elucidate possible immunological mechanisms facilitating protection of infants born to human immunodeficiency virus type (HIV-1) infected mothers, we have been studying genetic variations in the coding and untranslated regions of HLA-G antigen between HIV-1-infected mothers and their infected or uninfected infants. This study investigated whether HLA-G DNA sequence variants are associated with perinatal HIV-1 transmission.
Genomic DNA samples were obtained from a nested case-control study of 34 mother-child pairs co-enrolled in a cohort of the Perinatal AIDS Collaborative Transmission Study in New York. The samples were from two groups predominantly of African-American and Hispanic origin: In the first group, both mother and child were HIV-1-infected; in the second group, only the mother was infected while the child remained uninfected. Genotyping of HLA-G gene were performed on the extracted DNA from peripheral blood mononuclear cells using PCR based sequencing and restriction fragment-length polymorphism analyses.
Among the studied HLA-G exons, dissimilarities in HLA-G DNA sequence variants between the HIV-1 non-transmitting mother child pairs were mostly observed in exon 8-3'-untranslated region at nucleotide positions T3742A, C3743T, G3777C (P = 0.001). Non-transmitting HIV-1 mother child pairs exhibited dissimilarities at nucleotide position C3743T allele with decreased risk of perinatal HIV-1 transmission, compared with HIV-1 transmitting mother-child pairs carrying this allele (odds ratio 0.02 [95% confidence interval 0.00–0.15] P = 0.00001). In addition, heterozygous dissimilarities at nucleotide positions C634G and 714 insT/G in the 5'-upstream regulatory region were observed between the mother child pairs of the HIV-1-non-transmitting group while homozygous similarities of C634C, and either 714insG/G or mother-child pairs with similar 714insT/G were observed among the transmitting group in the same region.
This study identified new variants in the HLA-G gene and provides further evidence that dissimilarities in the HLA-G DNA sequence variants could influence the transmission of HIV-1 from infected mothers to their infants.
PMCID: PMC1634865  PMID: 17059603
3.  Frequent Detection of Escape from Cytotoxic T-Lymphocyte Recognition in Perinatal Human Immunodeficiency Virus (HIV) Type 1 Transmission: the Ariel Project for the Prevention of Transmission of HIV from Mother to Infant 
Journal of Virology  1999;73(5):3975-3985.
Host immunologic factors, including human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL), are thought to contribute to the control of HIV type 1 (HIV-1) replication and thus delay disease progression in infected individuals. Host immunologic factors are also likely to influence perinatal transmission of HIV-1 from infected mother to infant. In this study, the potential role of CTL in modulating HIV-1 transmission from mother to infant was examined in 11 HIV-1-infected mothers, 3 of whom transmitted virus to their offspring. Frequencies of HIV-1-specific human leukocyte antigen class I-restricted CTL responses and viral epitope amino acid sequence variation were determined in the mothers and their infected infants. Maternal HIV-1-specific CTL clones were derived from each of the HIV-1-infected pregnant women. Amino acid substitutions within the targeted CTL epitopes were more frequently identified in transmitting mothers than in nontransmitting mothers, and immune escape from CTL recognition was detected in all three transmitting mothers but in only one of eight nontransmitting mothers. The majority of viral sequences obtained from the HIV-1-infected infant blood samples were susceptible to maternal CTL. These findings demonstrate that epitope amino acid sequence variation and escape from CTL recognition occur more frequently in mothers that transmit HIV-1 to their infants than in those who do not. However, the transmitted virus can be a CTL susceptible form, suggesting inadequate in vivo immune control.
PMCID: PMC104176  PMID: 10196293
4.  Evaluation and treatment of the human immunodeficiency virus-1-exposed infant 
Paediatrics & Child Health  2004;9(6):409-417.
In developed countries, care and treatment are available for pregnant women and infants that can decrease the rate of perinatal human immunodeficiency virus type 1 (HIV-1) infection to 2% or less. The paediatrician has a key role in the prevention of mother-to-child transmission of HIV-1 by identifying HIV-exposed infants whose mothers’ HIV infection was not diagnosed before delivery, prescribing antiretroviral prophylaxis for these infants to decrease the risk of acquiring HIV-1 infection, and promoting avoidance of HIV-1 transmission through human milk. In addition, the paediatrician can provide care for HIV-exposed infants by monitoring them for early determination of HIV-1 infection status and for possible short- and long-term toxicities of antiretroviral exposure, providing chemoprophylaxis for Pneumocystis pneumonia, and supporting families living with HIV-1 infection by providing counselling to parents or caregivers.
PMCID: PMC2721159  PMID: 19657433
Antiretroviral; Diagnosis; HIV-1; HIV-exposed infants; Mother-to-child transmission
5.  Genetic determinants of pediatric HIV-1 infection: vertical transmission and disease progression among children. 
Molecular Medicine  2001;7(9):583-589.
It is very likely that perinatal human immunodeficiency virus type 1 (HIV-1) infection is influenced by a combination of virologic and host factors. A greater understanding of the role played by various risk factors for HIV-1 infection is crucial for the design of new preventive and therapeutic strategies. In recent years, a number of studies have suggested that host genetic factors are important determinants of both the susceptibility to perinatal HIV-1 infection and the subsequent pathogenesis of acquired immunodeficiency syndrome (AIDS). Control of HIV-1 infection involves the processing of specific viral peptides and their presentation to cells of the immune system by highly polymorphic human leukocyte antigen (HLA) alleles. The contribution of multiple HLA class I and II alleles in modulating pediatric HIV/AIDS outcomes has now been confirmed by several independent groups. Penetration of HIV-1 into cells is mediated by interaction between CD4 and chemokine receptors that serve as entry coreceptors. Genetic polymorphisms in chemokine ligand and chemokine receptor genes have recently been associated both with mother-to-child HIV-1 transmission and disease progression in children. These observations suggest a key role for genetic factors in pediatric HIV-1 infection. This article describes the current state of knowledge regarding host genetic influences on pediatric HIV-1 infection and discusses the role of these genes in HIV/AIDS pathogenesis.
PMCID: PMC1950069  PMID: 11778647
6.  Human Leukocyte Antigen B58 Supertype and Human Immunodeficiency Virus Type 1 Infection in Native Africans 
Journal of Virology  2006;80(12):6056-6060.
Human leukocyte antigen (HLA) class I alleles can be grouped into supertypes according to their shared peptide binding properties. We examined alleles of the HLA-B58 supertype (B58s) in treatment-naïve human immunodeficiency virus type 1 (HIV-1)-seropositive Africans (423 Zambians and 202 Rwandans). HLA-B and HLA-C alleles were resolved to four digits by a combination of molecular methods, and their respective associations with outcomes of HIV-1 infection were analyzed by statistical procedures appropriate for continuous or categorical data. The effects of the individual alleles on natural HIV-1 infection were heterogeneous. In HIV-1 subtype C-infected Zambians, the mean viral load (VL) was lower among B*5703 (P = 0.01) or B*5703-Cw*18 (P < 0.001) haplotype carriers and higher among B*5802 (P = 0.02) or B*5802-Cw*0602 (P = 0.03) carriers. The B*5801-Cw*03 haplotype showed an association with low VL (P = 0.05), whereas B*5801 as a whole did not. Rwandans with HIV-1 subtype A infection showed associations of B*5703 and B*5802 with slow (P = 0.06) and rapid (P = 0.003) disease progression, respectively. In neither population were B*1516-B*1517 alleles associated with more favorable responses. Overall, B58s alleles, individually or as part of an HLA-B-HLA-C haplotype, appeared to have a distinctive impact on HIV-1 infection among native Africans. As presently defined, B58s alleles cannot be considered uniformly protective against HIV/AIDS in every population.
PMCID: PMC1472610  PMID: 16731944
7.  Does Severity of HIV Disease in HIV-Infected Mothers Affect Mortality and Morbidity among Their Uninfected Infants? 
Rates of perinatal human immunodeficiency virus (HIV) transmission are higher among HIV-infected mothers with more advanced disease, but effects of maternal disease on HIV-uninfected offspring are unclear. We investigated the hypothesis that the severity of HIV disease and immune dysfunction among mothers is associated with increased morbidity and mortality among their uninfected infants.
In a birth cohort of 620 HIV-uninfected infants born to HIV-infected mothers in Lusaka, Zambia, we investigated associations between markers of more advanced maternal HIV disease and child mortality, hospital admissions, and infant weight through 4 months of age.
Mortality in the cohort of uninfected infants was 4.6% (95% confidence interval [CI], 2.8–6.3) through 4 months of age. Infants of mothers with CD4+ T cell counts of <350 cells/μL were more likely to die (hazard ratio [HR], 2.87; 95% CI, 1.03–8.03) and were more likely to be hospitalized (HR, 2.28; 95% CI, 1.17–4.45), after adjusting for other factors, including maternal death and low birth weight. The most common cause of infant death and hospitalization was pneumonia and/or sepsis. A maternal viral load of >100,000 copies/mL was associated with significantly lower child weight through 4 months of age.
Children born to HIV-infected mothers with advanced disease who escaped perinatal or early breastfeeding-related HIV infection are nonetheless at high risk of mortality and morbidity during the first few months of life. HIV-related immunosuppression appears to have adverse consequences for the health of infants, in addition to risks of vertical transmission.
PMCID: PMC1351118  PMID: 16267740
8.  Longitudinal Assessment of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon Responses during the First Year of Life in HIV-1-Infected Infants 
Journal of Virology  2005;79(13):8121-8130.
Human immunodeficiency virus type 1 (HIV-1) infection results in different patterns of viral replication in pediatric compared to adult populations. The role of early HIV-1-specific responses in viral control has not been well defined, because most studies of HIV-1-infected infants have been retrospective or cross-sectional. We evaluated the association between HIV-1-specific gamma interferon (IFN-γ) release from the cells of infants of 1 to 3 months of age and peak viral loads and mortality in the first year of life among 61 Kenyan HIV-1-infected infants. At 1 month, responses were detected in 7/12 (58%) and 6/21 (29%) of infants infected in utero and peripartum, respectively (P = 0.09), and in ∼50% of infants thereafter. Peaks of HIV-specific spot-forming units (SFU) increased significantly with age in all infants, from 251/106 peripheral blood mononuclear cells (PBMC) at 1 month of age to 501/106 PBMC at 12 months of age (P = 0.03), although when limited to infants who survived to 1 year, the increase in peak HIV-specific SFU was no longer significant (P = 0.18). Over the first year of life, infants with IFN-γ responses at 1 month had peak plasma viral loads, rates of decline of viral load, and mortality risk similar to those of infants who lacked responses at 1 month. The strength and breadth of IFN-γ responses at 1 month were not significantly associated with viral containment or mortality. These results suggest that, in contrast to HIV-1-infected adults, in whom strong cytotoxic T lymphocyte responses in primary infection are associated with reductions in viremia, HIV-1-infected neonates generate HIV-1-specific CD8+-T-cell responses early in life that are not clearly associated with improved clinical outcomes.
PMCID: PMC1143755  PMID: 15956557
9.  Analysis of residual perinatal transmission of hepatitis B virus (HBV) and of genetic variants in human immunodeficiency virus and HBV co-infected women and their offspring 
Despite implementation of universal infant hepatitis B (HB) vaccination, mother-to-child transmission (MTCT) of hepatitis B virus (HBV) still occurs. Limited data are available on the residual MTCT of HBV in human immunodeficiency virus (HIV)-HBV co-infected women.
We assessed the prevalence of HBV infection among HIV-infected pregnant women and the rate of residual MTCT of HBV from HIV-HBV co-infected women and analyzed the viral determinants in mothers and their HBV-infected children.
Study design
HIV-1 infected pregnant women enrolled in two nationwide perinatal HIV prevention trials in Thailand were screened for HB surface antigen (HBsAg) and tested for HBeAg and HBV DNA load. Infants born to HBsAg-positive women had HBsAg and HBV DNA tested at 4–6 months. HBV diversity within each HBV-infected mother-infant pair was analyzed by direct sequencing of amplified HBsAg-encoding gene and cloning of amplified products.
Among 3,312 HIV-1 infected pregnant women, 245 (7.4%) were HBsAg-positive, of whom 125 were HBeAg-positive. Of 230 evaluable infants born to HBsAg-positive women, 11 (4.8%) were found HBsAg and HBV DNA positive at 4–6 months; 8 were born to HBeAg-positive mothers. HBV genetic analysis was performed in 9 mother-infant pairs and showed that 5 infants were infected with maternal HBV variants harboring mutations within the HBsAg “a” determinant, and four were infected with wild-type HBV present in highly viremic mothers.
HBV-MTCT still occurs when women have high HBV DNA load and/or are infected with HBV variants. Additional interventions targeting highly viremic women are thus needed to reduce further HBV-MTCT.
PMCID: PMC3872003  PMID: 23916828
HBs antigen variants; Hepatitis B vaccine failure; HIV pregnant women; mother-to-child transmission; Thailand
10.  Infant Safety during and after Maternal Valacyclovir Therapy in Conjunction with Antiretroviral HIV-1 Prophylaxis in a Randomized Clinical Trial 
PLoS ONE  2012;7(4):e34635.
Maternal administration of the acyclovir prodrug valacyclovir is compatible with pregnancy and breastfeeding. However, the safety profile of prolonged infant and maternal exposure to acyclovir in the context of antiretrovirals (ARVs) for prevention of mother-to-child HIV-1 transmission (PMTCT) has not been described.
Pregnant Kenyan women co-infected with HIV-1/HSV-2 with CD4 counts > 250 cells/mm3 were enrolled at 34 weeks gestation and randomized to twice daily 500 mg valacyclovir or placebo until 12 months postpartum. Women received zidovudine from 28 weeks gestation and single dose nevirapine was given to women and infants at the time of delivery for PMTCT. Infant blood was collected at 6 weeks for creatinine and ALT. Breast milk specimens were collected at 2 weeks postpartum from 71 women in the valacyclovir arm; acyclovir levels were determined for a random sample of 44 (62%) specimens. Fisher’s Exact and Wilcoxon rank-sum tests were used for analysis.
One hundred forty-eight women were randomized and 146 mother-infant pairs were followed postpartum. PMTCT ARVs were administered to 98% of infants and all mothers. Valacyclovir was not associated with infant or maternal toxicities or adverse events, and no congenital malformations were observed. Infant creatinine levels were all normal (< 0.83 mg/dl) and median creatinine (median 0.50 mg/dl) and infant growth did not differ between study arms. Acyclovir was detected in 35 (80%) of 44 breast milk samples collected at 2 weeks postpartum. Median and maximum acyclovir levels were 2.62 and 10.15 mg/ml, respectively (interquartile range 0.6–4.19).
Exposure to PMTCT ARVs and acyclovir after maternal administration of valacyclovir during pregnancy and postpartum to women co-infected with HIV-1/HSV-2 was not associated with an increase in infant or maternal toxicities or adverse events.
Trial Registration NCT00530777
PMCID: PMC3324503  PMID: 22509337
11.  Impact of HIV-1 infection and pregnancy on maternal health: comparison between perinatally and behaviorally infected young women 
The introduction of combination antiretroviral therapy has resulted in improved survival and quality of life for individuals infected with the human immunodeficiency virus (HIV). There is, as expected, a growing population of perinatally HIV-infected women who are, have been, or will become pregnant. We describe a large cohort of perinatally infected women, compare it with a similar age-matched behaviorally HIV-infected group, and examine factors affecting maternal and infant health.
We reviewed the records of 30 perinatally infected women who gave birth at two hospitals between January 2000 and December 2011. The comparison group comprised behaviorally infected women who delivered at these hospitals during the same period. The outcome measures were differences in CD4 counts and viral load between the cohorts, and comparisons of maternal morbidity, mortality, and mother-to-child HIV transmission.
Median CD4 counts were significantly lower in the perinatal group before, during, and after pregnancy. The median viral load was significantly higher in the perinatal group. Interval prepregnancy to post partum viral load decline was also greater in the behavioral group. Viral load decreases in the perinatal population were not sustained in the post partum period, at which time viral load trended back to prepregnancy levels. There was one mother-to-child HIV transmission in a perinatally infected woman. Over an extended 4 years of follow-up, there were four deaths in the perinatal group and none in the behavioral group.
After delivery, the differences between perinatally and behaviorally infected mothers accentuate, with immunologic deterioration in the former group. The perinatal population may require novel management strategies to ensure outcomes comparable with those observed in the behavioral group.
PMCID: PMC3912851  PMID: 24600295
human immunodeficiency virus infection; pregnancy; maternal health; perinatal infection; behavioral infection
12.  Impact of HLA in Mother and Child on Disease Progression of Pediatric Human Immunodeficiency Virus Type 1 Infection▿  
Journal of Virology  2009;83(19):10234-10244.
A broad Gag-specific CD8+ T-cell response is associated with effective control of adult human immunodeficiency virus (HIV) infection. The association of certain HLA class I molecules, such as HLA-B*57, -B*5801, and -B*8101, with immune control is linked to mutations within Gag epitopes presented by these alleles that allow HIV to evade the immune response but that also reduce viral replicative capacity. Transmission of such viruses containing mutations within Gag epitopes results in lower viral loads in adult recipients. In this study of pediatric infection, we tested the hypothesis that children may tend to progress relatively slowly if either they themselves possess one of the protective HLA-B alleles or the mother possesses one of these alleles, thereby transmitting a low-fitness virus to the child. We analyzed HLA type, CD8+ T-cell responses, and viral sequence changes for 61 mother-child pairs from Durban, South Africa, who were monitored from birth. Slow progression was significantly associated with the mother or child possessing one of the protective HLA-B alleles, and more significantly so when the protective allele was not shared by mother and child (P = 0.007). Slow progressors tended to make CD8+ T-cell responses to Gag epitopes presented by the protective HLA-B alleles, in contrast to progressors expressing the same alleles (P = 0.07; Fisher's exact test). Mothers expressing the protective alleles were significantly more likely to transmit escape variants within the Gag epitopes presented by those alleles than mothers not expressing those alleles (75% versus 21%; P = 0.001). Reversion of transmitted escape mutations was observed in all slow-progressing children whose mothers possessed protective HLA-B alleles. These data show that HLA class I alleles influence disease progression in pediatric as well as adult infection, both as a result of the CD8+ T-cell responses generated in the child and through the transmission of low-fitness viruses by the mother.
PMCID: PMC2748050  PMID: 19605475
13.  Quantitation of HLA Proteins Incorporated by Human Immunodeficiency Virus Type 1 and Assessment of Neutralizing Activity of Anti-HLA Antibodies▿  
Journal of Virology  2007;82(1):428-434.
Human anti-human leukocyte antigen (HLA) antibodies were assessed for neutralizing activity against human immunodeficiency virus type 1 (HIV-1) carrying HLA alleles with matching specificity. Multiparous women carrying anti-HLA antibodies were identified. Plasma samples from those women were confirmed as having antibodies that specifically bound to HLA proteins expressed on the peripheral blood mononuclear cells (PBMCs) of their husbands. A primary HIV-1 isolate was cultured in the husband's PBMCs so that the virus carried matching HLA alleles. To determine the HIV-1-neutralizing activity of anti-HLA antibodies, the infectivity of the virus for GHOST cells (which express green fluorescent protein after HIV infection) was investigated in the presence of a plasma sample positive for the respective anti-HLA antibody. A neutralization assay was also performed using purified immunoglobulin G (IgG) from two plasma samples, and two plasma samples were investigated in the presence of complement. The prerequisite for anti-HLA antibody-mediated neutralization is incorporation of HLA proteins by HIV-1. Therefore, the extent of incorporation of HLA proteins by the primary HIV-1 isolate was estimated. The ratios of HLA class I protein to HIV-1 capsid (p24) protein cultured in the PBMCs of two healthy individuals were 0.017 and 0.054. These ratios suggested that the HIV-1 strain used in the assay incorporated more HLA proteins than gp160 trimers. Anti-HLA antibody-positive plasma was found to contain antibodies that specifically reacted to HIV-1 carrying cognate HLA alleles. However, incubation of HIV-1 with anti-HLA antibody- positive plasma or purified IgG did not show a reduction in viral infectivity. HIV-1-neutralizing activity was also not detected in the presence of complement. This study shows that HIV-1 primary isolates cultured in PBMCs contain significant amounts of HLA proteins. However, the binding of antibodies to those HLA proteins does not mediate a reduction in viral infectivity.
PMCID: PMC2224394  PMID: 17942547
14.  Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission 
AIDS (London, England)  2012;26(16):2007-2016.
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.
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.
In a Kenyan cohort of HIV-infected mothers, blood and breastmilk 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.
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).
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.
PMCID: PMC3718292  PMID: 22948269
breastfeeding; breast milk cytotoxic T lymphocytes; cytokines; early postnatal transmission; infant; MIP-1β; pediatric; sub-Saharan Africa
15.  Role of the Placenta in Adverse Perinatal Outcomes Among HIV-1 Seropositive Women 
Women seropositive for human immunodeficiency virus type 1 (HIV-1) are at an increased risk for a number of adverse perinatal outcomes. Although efforts to reduce mother-to-child transmission of HIV (MTCT) remain a priority in resource-limited countries, HIV testing and treatment have led to steep declines in MTCT in well-resourced countries. Even so, HIV seropositive pregnant women in the United States continue to deliver a disproportionately high number of preterm and low birth weight infants. In this mini-review, we address the role of the placenta in such HIV-related perinatal sequelae. We posit that adverse perinatal outcomes may result from two mutually non-exclusive routes: (1) HIV infection of the placenta proper, potentially leading to impaired maternal-fetal exchange; and (2) infection of the maternal decidual microenvironment, possibly disrupting normal placental implantation and development. Further research into the relationship between HIV-1 infection and placental pathology may lead to the development of novel strategies to improve birth outcomes among HIV-1 seropositive parturients.
PMCID: PMC3940191  PMID: 23657060
Human immunodeficiency virus type 1; placenta; placenta diseases; low birth weight; preterm birth
16.  Maternal Tuberculosis: A Risk Factor for Mother-to-Child Transmission of Human Immunodeficiency Virus 
The Journal of Infectious Diseases  2011;203(3):358-362.
Background. Maternal human immunodeficiency virus (HIV) RNA load, CD4 cell count, breast-feeding, antiretroviral use, and malaria are well-established factors associated with mother-to-child transmission (MTCT) of HIV; the role of maternal tuberculosis (TB), however, has not been well established.
Methods. The study population was 783 HIV-infected Indian mother-infant pair participants in randomized and ancillary HIV-infected cohorts of the Six Week Extended-Dose Nevirapine (SWEN) Study, a study comparing extended nevirapine versus single-dose nevirapine, to reduce MTCT of HIV among breast-fed infants. Using multivariable logistic regression, we assessed the impact of maternal TB occurring during pregnancy and through 12 months after delivery on risk of MTCT.
Results. Of 783 mothers, 3 had prevalent TB and 30 had incident TB at 12 months after delivery. Of 33 mothers with TB, 10 (30%) transmitted HIV to their infants in comparison with 87 of 750 mothers without TB (12%; odds ratio [OR], 3.31; 95% confidence interval [CI], 1.53–7.29; P = .02). In multivariable analysis, maternal TB was associated with 2.51-fold (95% CI, 1.05–6.02; P = .04) increased odds of HIV transmission adjusting for maternal factors (viral load, CD4 cell count, and antiretroviral therapy) and infant factors (breast-feeding duration, infant nevirapine administration, gestational age, and birth weight) associated with MTCT of HIV.
Conclusions. Maternal TB is associated with increased MTCT of HIV. Prevention of TB among HIV-infected mothers should be a high priority for communities with significant HIV/TB burden.
PMCID: PMC3071111  PMID: 21208928
Human immunology  2011;72(4):312-318.
Populations of African ancestry continue to account for a disproportionate burden of human immunodeficiency virus type 1 (HIV-1) epidemic in the US. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in two cohorts: REACH (Reaching for Excellence in Adolescent Care and Health) and HERS (HIV Epidemiology Research Study). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4+ T-cells were examined both separately and combined to represent three categories of HIV-1 disease control (76 “controllers,” 169 “intermediates,” and 93 “non-controllers”). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with one or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and non-genetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV-1 infection span the boundaries of race and viral subtype; while others appear confined within one or the other of those boundaries.
PMCID: PMC3778654  PMID: 21262311
HLA class I; Allele frequency; HIV-1 control; African American
18.  Acute HIV Infection among Kenyan Infants 
Clinical signs and symptoms of acute human immunodeficiency virus (HIV) infection in infants are not well characterized.
Serial clinical assessments and HIV PCR assays were conducted in a cohort of children born to HIV-seropositive mothers from birth to 2 years of age. Acute HIV infection visits were defined as those up to 3 months prior to and including the visit at which HIV DNA was first detected. Noninfection visits included all visits at which the child had test results negative for HIV, including the last visit at which a test result negative for HIV DNA was obtained in children who later acquired HIV infection. Differences in the prevalence of symptoms at acute infection versus noninfection visits were determined overall and were stratified by age at infection (<2 months vs. ≥2 months). HIV RNA was measured serially in infected infants and was compared between infants with and infants without symptoms of acute HIV infection.
There were 125 acute infection visits (among 56 infants) and 3491 noninfection visits (among 306 infants). Acute HIV infection was associated with rash (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1–2.8), failure to thrive (OR, 1.9; 95% CI, 1.0–3.5), and lymphadenopathy (OR, 2.5; 95% CI, 1.4–4.8). Acute HIV infection was associated with lymphadenopathy (OR, 2.6; 95% CI, 1.3–5.0) in infants <2 months of age and with pneumonia (OR, 3.2; 95% CI, 1.1–9.3) and dehydration (OR, 6.0; 95% CI, 1.9–18.5) in infants ≥2 months of age. Infant peak viral load and mortality were not associated with symptoms of acute HIV infection. However, infants with symptoms had higher viral levels later in the course of infection than did those without symptoms (P = .05).
Infants may manifest symptoms early during the course of HIV infection, and symptoms of acute HIV infection may correlate with poor viral control. Rash, failure to thrive, lymphadenopathy, pneumonia, and dehydration may signify acute HIV infection in infants.
PMCID: PMC3310239  PMID: 18171265
19.  Influence of HLA-C Expression Level on HIV Control 
Science (New York, N.Y.)  2013;340(6128):87-91.
A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn’s disease, suggesting a broader influence of HLA expression levels in human disease.
PMCID: PMC3784322  PMID: 23559252
20.  Comparison of Human Immunodeficiency Virus Type 1 Viral Loads in Kenyan Women, Men, and Infants during Primary and Early Infection 
Journal of Virology  2003;77(12):7120-7123.
Steady-state levels of human immunodeficiency virus type 1 (HIV-1) RNA in plasma reached at approximately 4 months postinfection are highly predictive of disease progression. Several studies have investigated viral levels in adults or infants during primary and early infection. However, no studies have directly compared these groups. We compared differences in peak and set point plasma HIV-1 RNA viral loads among antiretrovirus-naive Kenyan infants and adults for whom the timing of infection was well defined. Peak and set point viral loads were significantly higher in infants than in adults. We did not observe any gender-specific differences in viral set point in either adults or infants. However, infants who acquired HIV-1 in the first 2 months of life, either in utero, intrapartum, or through early breast milk transmission, had significantly higher set point HIV-1 RNA levels than infants who were infected after 2 months of age through late breast milk transmission or adults who were infected through heterosexual transmission.
PMCID: PMC156211  PMID: 12768032
21.  HLA-Associated Immune Pressure on Gag Protein in CRF01_AE-Infected Individuals and Its Association with Plasma Viral Load 
PLoS ONE  2010;5(6):e11179.
The human leukocyte antigen (HLA)-restricted cytotoxic T-lymphocyte (CTL) immune response is one of the major factors determining the genetic diversity of human immunodeficiency virus (HIV). There are few population-based analyses of the amino acid variations associated with the host HLA type and their clinical relevance for the Asian population. Here, we identified HLA-associated polymorphisms in the HIV-1 CRF01_AE Gag protein in infected married couples, and examined the consequences of these HLA-selected mutations after transmission to HLA-unmatched recipients.
Methodology/Principal Findings
One hundred sixteen HIV-1-infected couples were recruited at a government hospital in northern Thailand. The 1.7-kb gag gene was amplified and directly sequenced. We identified 56 associations between amino acid variations in Gag and HLA alleles. Of those amino acid variations, 35 (62.5%) were located within or adjacent to regions reported to be HIV-specific CTL epitopes restricted by the relevant HLA. Interestingly, a significant number of HLA-associated amino acid variations appear to be unique to the CRF01_AE-infected Thai population. Variations in the capsid protein (p24) had the strongest associations with the viral load and CD4 cell count. The mutation and reversion rates after transmission to a host with a different HLA environment varied considerably. The p24 T242N variant escape from B57/58 CTL had a significant impact on the HIV-1 viral load of CRF01_AE-infected patients.
HLA-associated amino acid mutations and the CTL selection pressures on the p24 antigen appear to have the most significant impact on HIV replication in a CRF01_AE-infected Asian population. HLA-associated mutations with a low reversion rate accumulated as a footprint in this Thai population. The novel HLA-associated mutations identified in this study encourage us to acquire more extensive information about the viral dynamics of HLA-associated amino acid polymorphisms in a given population as effective CTL vaccine targets.
PMCID: PMC2887364  PMID: 20567513
22.  Male Antenatal Attendance and HIV Testing Are Associated with Decreased Infant HIV Infection and Increased HIV Free Survival 
To investigate the relationship between male involvement in prevention of mother-to-child HIV transmission (PMTCT) services and infant HIV acquisition and mortality a prospective cohort study was undertaken between 1999 and 2005 in Nairobi, Kenya.
HIV-infected pregnant women were enrolled and followed with their infants for 1 year with infant HIV DNA testing at birth, 1, 3, 6, 9 and 12 months postpartum. Women were encouraged to invite male partners for prevention counseling and HIV testing.
Among 456 female participants, 140 (31%) partners attended the antenatal clinic. Eighty-two (19%) of 441 infants tested were HIV infected by one year of age. Adjusting for maternal viral load, vertical transmission risk was lower among women with partner attendance compared to those without (Adjusted hazard ratio [aHR]=0.56, 95% CI 0.33–0.98; P=0.042) and among women reporting versus not reporting previous partner HIV testing (aHR=0.52, 95% CI 0.32–0.84; P=0.008). The combined risk of HIV acquisition or infant mortality was lower with male attendance (aHR=0.55, 95% CI 0.35–0.88; P=0.012) and report of prior male HIV testing (aHR=0.58, 95% CI 0.34–0.88; P=0.01) when adjusting for maternal viral load and breastfeeding.
Including men in antenatal PMTCT services with HIV testing may improve infant health outcomes.
PMCID: PMC3005193  PMID: 21084999
male partners; PMTCT; vertical transmission of HIV; infant mortality; Kenya
23.  Laboratory Abnormalities Among HIV-Exposed, Uninfected Infants: IMPAACT Protocol P1025 
Infant laboratory abnormalities have been associated with exposure to antiretrovirals and to trimethoprim/sulfamethoxazole (TMP/SMX).
We analyzed data from International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) Protocol P1025, a prospective cohort study of human immunodeficiency virus type 1 (HIV)–infected women and their infants. Live-born, singleton, HIV-uninfected infants with at least 6 months of follow-up who represented the first pregnancy on study of HIV-infected mothers with at least 1 prenatal visit, CD4 count, and viral load during pregnancy and who used at least 1 antiretroviral during pregnancy were eligible for inclusion in this analysis.
The study population comprised 1524 infants. During the first 6 months of life, 7.4% of laboratory serious adverse events (SAEs) were related to glucose, 7.2% were related to hemoglobin, 8.7% were related to absolute neutrophil count, and 4.0% were related to total lymphocyte count. The likelihood of laboratory SAEs decreased with increasing age for hemoglobin, absolute neutrophil count, and glucose. Infant preterm birth and current receipt of antiretroviral(s) were the factors with the strongest associations with laboratory SAEs.
The overall frequency of laboratory SAEs was low and decreased with age. Preterm infants are at higher risk of hemoglobin- and total lymphocyte count–related SAEs.
PMCID: PMC3656554  PMID: 23687574
24.  Perinatal Transmission of Major, Minor, and Multiple Maternal Human Immunodeficiency Virus Type 1 Variants In Utero and Intrapartum 
Journal of Virology  2001;75(5):2194-2203.
Previous studies have provided conflicting data on the presence of selective pressures in the transmission of a homogeneous maternal viral subpopulation to the infant. Therefore, the purpose of this study was to definitively characterize the human immunodeficiency virus type 1 (HIV-1) quasispecies transmitted in utero and intrapartum. HIV-1 envelope gene diversity from peripheral blood mononuclear cells and plasma was measured during gestation and at delivery in mothers who did and did not transmit HIV perinatally by using a DNA heteroduplex mobility assay. Children were defined as infected in utero or intrapartum based on the timing of the first detection of HIV. Untreated transmitting mothers (n = 19) had significantly lower HIV-1 quasispecies diversity at delivery than untreated nontransmittting mothers (n = 18) (median Shannon entropy, 0.711 [0.642 to 0.816] versus 0.853 [0.762 to 0.925], P = 0.005). Eight mothers transmitted a single major env variant to their infants in utero, and one mother transmitted a single major env variant intrapartum. Four mothers transmitted multiple HIV-1 env variants to their infants in utero, and two mothers transmitted multiple env variants intrapartum. The remaining six intrapartum- and two in utero-infected infants had a homogeneous HIV-1 env quasispecies which did not comigrate with their mothers' bands at their first positive time point. In conclusion, in utero transmitters were more likely to transmit single or multiple major maternal viral variants. In contrast, intrapartum transmitters were more likely to transmit minor HIV-1 variants. These data indicate that different selective pressures, depending on the timing of transmission, may be involved in determining the pattern of maternal HIV-1 variant transmission.
PMCID: PMC114803  PMID: 11160723
The Journal of pediatrics  2006;149(5):611-616.
To test whether secretory immunoglobulin A (sIgA) to human immunodeficiency virus (HIV) antigens in breast milk of HIV-positive women is associated with protection against HIV transmission among breast-fed infants.
Study design
Nested, case-control design in which HIV-specific sIgA was measured in breast milk collected from 90 HIV-positive women enrolled in a study in Lusaka, Zambia. Milk samples were selected to include 26 HIV-positive mothers with infected infants (transmitters) and 64 mothers with uninfected infants (nontransmitters).
HIV-specific sIgA was detected more often in breast milk of transmitting mothers (76.9%) than in breast milk of nontransmitting mothers (46.9%, P = .009). There were no significant associations between HIV-specific sIgA in breast milk and other maternal factors, including HIV RNA quantities in breast milk, CD4 count, and plasma RNA quantities.
HIV-specific sIgA in breast milk does not appear to be a protective factor against HIV transmission among breast-fed infants.
PMCID: PMC2811256  PMID: 17095329

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