Association between Maternal and Infant Class I and II HLA Alleles and of Their Concordance with the Risk of Perinatal HIV Type 1 Transmission

Abstract

We aimed to investigate the influence of class I and class II HLA specificities and of the concordance between maternal and infant HLA on vertical HIV-1 transmission. HLA typing of samples from mothers and infants enrolled in the Ariel study, a perinatal HIV-1 transmission cohort including 203 mother-infant pairs, was performed by serological and molecular methods. HLA effects were evaluated alone and by multivariate modeling considering also other known predictors of perinatal HIV-1 transmission (maternal viral load, antiretroviral therapy, duration of rupture of membranes, and histological chorioamnionitis). Modest associations were seen with specific HLA markers (increased risk with infant B67 and B58 and maternal DR1; decreased risk with maternal B12), but these were not statistically significant after adjusting for multiple comparisons. Mother-infant concordance at any class I locus was a strong predictor of transmission (odds ratio [OR], 4.16; p = 0.028). Transmission was not associated with class II concordance. Class I HLA concordance retained its importance after adjusting for maternal viral load, antiretroviral therapy, duration of rupture of membranes or histological chorioamnionitis. In multivariate modeling, only class I concordance (OR, 3.59; p = 0.069) and chorioamnionitis (OR, 3.79; p = 0.030) were retained as independent predictors of transmission. HLA alleles, and in particular the class I concordance between maternal and neonatal HLA, may regulate the risk of perinatal HIV-1 transmission.

Human Leukocyte Antigen (HLA) B*18 and Protection against Mother-to-Child HIV Type 1 Transmission

“…18,19,26 Regional differences in HIV-1 subtypes and sub-sequent variability in important CTL epitopes may explain why other studies did not find an association between the B*18 haplotype and HIV-1 transmission. 6,20 In Nairobi and Thailand, predominant subtypes are A and E, respectively, whereas in North America and Europe, subtype B is more common. 6,20 In this study, we hypothesize that infants expressing HLA B*18 may be capable of mounting an effective early and late immune response against HIV-1 through presentation of HIV-1 antigens to infant CTLs.…”

“…6,20 In Nairobi and Thailand, predominant subtypes are A and E, respectively, whereas in North America and Europe, subtype B is more common. 6,20 In this study, we hypothesize that infants expressing HLA B*18 may be capable of mounting an effective early and late immune response against HIV-1 through presentation of HIV-1 antigens to infant CTLs. Other immune mechanisms, such as noncyto-toxic CD8 + T cells and natural killer (NK) cells, may also contribute to an HLA-mediated antiviral effect and control of HIV-1 infection.…”

“…Several associations between specific HLAs and HIV-1 mother-to-child transmission have been described, primarily in non-breast-feeding cohorts in Europe and North America. [1][2][3][4][5][6] These studies focused on class II alleles in European and American children and found that HLAs DQB1*06 and DRB1*03 were associated with increased HIV-1 transmission, and several DQB1 alleles were associated with decreased transmission. [1][2][3][4][5] More limited research has been conducted on HLA associations and vertical HIV-1 transmission among breast-feeding populations from developing countries where the majority of new pediatric HIV-1 infections occur.…”

“…7 The relationship between the A2 supertype and risk of vertical transmission was independent of the protective effect of HLA discordance between mother and child. 6,8 We examined associations between mother-to-child HIV-1 transmission and frequently expressed HLA alleles in a Kenyan perinatal cohort. Special attention was given to defining early and late transmission events to determine effects of HLA on HIV-1 acquisition among breast-feeding infants in sub-Saharan Africa.…”

Genetic Factors that Influence HIV Infection: The Role of the Major Histocompatibility Complex System

“…CTL activity in the maternal peripheral circulation is similar to that in the non-pregnant state and CTLs can appear early in infants, where their presence correlates with slow progressive HIV disease (Pillay and Phillips, 2005). Consequently, an indirect role for CTLs in mother-to-child transmission has been proposed (Polycarpou et al, 2002). Moreover, levels of CTL precursor frequencies specific for pol and nef HIV variants were more frequently found during pregnancy in nontransmitting mothers than in transmitting ones .…”