Background:  Mother-infant human leukocyte antigen (HLA) concordance and HLA homozygosity may increase risk of mother-to-child HIV-1 transmission (MTCT) by reducing alloimmune responses against HIV-1-infected maternal cells or recognition of viral mutants that have escaped maternal immunity.

Methods:  To examine the influence of HLA concordance and homozygosity on infant HIV-1 acquisition, HLA typing was performed on mother-infant pairs enrolled in a perinatal HIV-1 study in Nairobi. Women received zidovudine (AZT) at 34 weeks’ gestation and infant blood was collected within 48 hours of delivery and at 1, 3, 6, 9, and 12 months post-partum. Maternal HLA class I typing was conducted following a sequence specific oligonucleotide probe protocol and infant typing performed using amplification refractory mutation system polymerase chain reaction. Mother-child concordancy scores ranging from 3 to 6 were defined by the number of shared class I alleles at A, B, and C loci, and maternal homozygosity was defined as homozygosity at any class I locus versus no homozygosity. Transmission risk was estimated using Cox proportional hazards and logistic regression models.

Results:  Among 300 HIV-1-infected women, 57 (19%) transmitted HIV-1 to their infants, with 21 (37%) infants infected in utero, 26 (47%) between birth and month 1, and 10 (18%) after month 1 via breastfeeding. Women who were homozygous at 1 or more loci had higher plasma HIV-1 RNA at 32 weeks’ gestation (5.0 vs. 4.6 log₁₀ copies/mL, p = 0.03) and, after adjusting for maternal viral load, had a significantly greater risk of HIV-1 transmission overall (adjusted hazard ratio [aHR] = 1.8; 95% confidence interval [CI] 1.1 to 2.9, p = 0.02) and after month 1 (aHR = 4.6, 95%CI 1.6 to 13.5, p = 0.006). With each additional mother-infant concordant allele, we observed a trend toward increased risk of overall mother-to-child HIV-1 transmission (aHR = 1.3; 95%CI 1.0 to 1.6, p = 0.07) and a ~1.6-fold increased late transmission risk via breast milk (aHR = 1.6, 95%CI 1.1 to 2.4, p = 0.03).

Conclusions:  HIV-1 transmission risk via breast milk was increased among mother-infant pairs concordant at >3 HLA class I alleles and among women with HLA homozygosity. These results suggest a role for alloimune responses or HLA diversity in protection against infant HIV-1 acquisition, even in the setting of AZT prophylaxis reducing in utero and intra-partum risk.