HLA Class II Antigens and Their Interactive Effect on Perinatal Mother-To-Child HIV-1 Transmission.

HLA class II antigens are central in initiating antigen-specific CD4+ T cell responses to HIV-1. Specific alleles have been associated with differential responses to HIV-1 infection and disease among adults. This study aims to determine the influence of HLA class II genes and their interactive effect on mother-child perinatal transmission in a drug naïve, Mother-Child HIV transmission cohort established in Kenya, Africa in 1986. Our study showed that DRB concordance between mother and child increased risk of perinatal HIV transmission by three fold (P = 0.00035/Pc = 0.0014, OR: 3.09, 95%CI, 1.64-5.83). Whereas, DPA1, DPB1 and DQB1 concordance between mother and child had no significant influence on perinatal HIV transmission. In addition, stratified analysis showed that DRB1*15:03+ phenotype (mother or child) significantly increases the risk of perinatal HIV-1 transmission. Without DRB1*15:03, DRB1 discordance between mother and child provided 5 fold protection (P = 0.00008, OR: 0.186, 95%CI: 0.081-0.427). However, the protective effect of DRB discordance was diminished if either the mother or the child was DRB1*15:03+ phenotype (P = 0.49-0.98, OR: 0.7-0.99, 95%CI: 0.246-2.956). DRB3+ children were less likely to be infected perinatally (P = 0.0006, Pc = 0.014; OR:0.343, 95%CI:0.183-0.642). However, there is a 4 fold increase in risk of being infected at birth if DRB3+ children were born to DRB1*15:03+ mother compared to those with DRB1*15:03- mother. Our study showed that DRB concordance/discordance, DRB1*15:03, children's DRB3 phenotype and their interactions play an important role in perinatal HIV transmission. Identification of genetic factors associated with protection or increased risk in perinatal transmission will help develop alternative prevention and treatment methods in the event of increases in drug resistance of ARV

Reduced cellular susceptibility to in vitro HIV infection is associated with CD4+ T cell quiescence.

HIV preferentially establishes productive infection in activated CD4+ T cells. Since proportions of activated CD4+ T cells vary between individuals, this study aimed to determine if individuals with a greater proportion of activated CD4+ T cells would be more susceptible to in vitro HIV infection.Unstimulated peripheral blood mononuclear cells (PBMC) from various donors were inoculated with HIV(ML1956)in vitro. HIV replication was evaluated by HIV p24 ELISA of culture supernatants and intracellular staining for HIV p24, which was detected by flow cytometry. Baseline T cell phenotypes and infected cell phenotypes were also evaluated by flow cytometry. Ex vivo phenotyping at the time of blood draw showed that elevated T cell activation and reduced Tregs were associated with increased cellular susceptibility to in vitro infection. Furthermore, the infected CD4+ T cell population was enriched for activated cells.These data suggest that CD4+ T cell quiescence provides an environment less conducive to the establishment of HIV infection by limiting the pool of activated target cells

Major HLA class II alleles/allele groups in mothers and their children.

<p>Major HLA class II alleles/allele groups in mothers and their children.</p

PCR and sequencing primers used for genotyping HLA class II genes.

<p>PCR and sequencing primers used for genotyping HLA class II genes.</p

Phenotypes of HIV-infected unstimulated CD4+ T cells.

<p>(A) CD4+ T cells were evaluated for infection by intracellular staining for HIV p24. Cells were gated on singlets, lymphocytes and live cells before discriminating CD4+ T cells. Infected (p24+) and uninfected cells (p24-) were phenotyped for markers of Tregs (defined as CD25^hi, CD127^lo) and T cell activation (CD69, HLA DR). (B) Comparison of T cell phenotypes between infected and uninfected CD4+ T cells (n = 12). Higher frequencies of infected cells were activated (CD69+ HLA DR+, CD69+ HLA DR- or CD69- HLA DR+) or demonstrated a Treg phenotype (CD25^hi CD127^lo) compared to uninfected cells. P-values were calculated using the Wilcoxon signed-rank test for matched pairs.</p

Infection of unstimulated PBMC inoculated with HIV_ML1956.

<p>Graph shows average level of HIV infection of replicate wells as determined by HIV p24 ELISA. Individual patients are represented by their study ID numbers. The number of replicate wells demonstrating productive infection (out of 6) is indicated below the patient study ID numbers.</p