Alloimmunity to Class 2 Human Leucocyte Antigens May Reduce HIV-1 Acquisition - A Nested Case-Control Study in HIV-1 Serodiscordant Couples.

Enveloped viruses, including the Human Immunodeficiency Virus-1 (HIV), incorporate host proteins such as human leucocyte antigens (HLA) into their envelope. Pre-existing antibodies against HLA, termed HLA antibodies, may bind to these surface proteins and reduce viral infectivity. Related evidence includes macaque studies which suggest that xenoimmunization with HLA antigens may protect against simian immunodeficiency virus infection. Since HIV gp120 shows homology with class 2 HLA, including shared affinity for binding to CD4, class 2 HLA antibodies may influence HIV acquisition via binding to gp120 on the viral envelope. We conducted a nested case-control study on HIV serodiscordant couples, comparing the frequency of HLA antibodies among highly exposed persistently seronegative controls with those who went on to acquire HIV (HIV-seroconverters). We first performed low resolution HLA typing on 143 individuals who were HIV-infected at enrollment (index partners) and their corresponding sexual partners (115 highly exposed persistently seronegative individuals and 28 HIV-seroconverters). We then measured HLA class 1 and 2 antibodies in the highly exposed persistently seronegative individuals and HIV-seroconverters at early and late timepoints. We analyzed whether such antibodies were directed at HLA specificities of their HIV-infected index partners, and whether autoantibodies or complement-fixing class 2 HLA antibodies were present. Seventy-nine percent of highly exposed persistently seronegative individuals had HLA antibodies; 56% against class 1 and 50% against class 2 alleles. Half of the group of highly exposed persistently seronegative individuals, prior to seroconversion, expressed class 2 HLA antibodies, compared with only 29% of controls (p=0.05). HIV infection was a sensitizing event leading to de novo development of antibodies against HLA-A and HLA-B loci, but not against class 2 loci. HLA autoantibodies were present in 27% of highly exposed persistently seronegative individuals. Complement-fixing class 2 HLA antibodies did not differ significantly between highly exposed persistently seronegative individuals and seroconverters. In multivariable regression, presence of class 2 HLA antibodies at early timepoints was associated with reduced odds of HIV acquisition (odds ratio 0.330, confidence interval 0.112-0.976, p=0.045). These epidemiological data suggest that pre-existing class 2 HLA antibodies were associated with reduced odds of HIV acquisition.

HLA antibody repertoire in infants suggests selectivity in transplacental crossing.

PROBLEM: Late in pregnancy, women produce and transfer high amounts of antibodies to the foetus. During gestation, women produce antibodies against human leukocyte antigens (HLA), including antibodies directed at foetal HLA. There is paucity of data on transplacental crossing, specificity and role of HLA antibodies in pregnancy and new-borns. METHOD OF STUDY: Using highly sensitive Luminex technology, we measured prevalence of IgG HLA antibodies in 30 mother-infant pairs six weeks post-partum. Additionally, in six pregnant women, we measured HLA antibodies longitudinally and HLA-typed infant DNA to assess whether maternal HLA antibodies were directed at infant specificities. RESULTS: Overall, 68% of mothers and 44% of infants expressed HLA-I antibodies and 56% of mothers and 52% of infants expressed HLA-II antibodies. Infants shared up to 78% of antibodies with their mothers, suggesting that the remaining antibodies were self-made. Less than 25% of maternal HLA antibodies were detected in infants, possibly due to selection in transplacental crossing. We detected complement-fixing HLA antibodies in mothers and at low levels in infants. In a third of our pregnant subjects, we detected infant-directed HLA antibodies. CONCLUSION: Our findings raise the possibility of selection in transplacental crossing of HLA antibodies. As HLA antibodies may act as autoantibodies in the neonate, the mechanism of a selective transfer may give important insights into immune tolerance. Findings also suggest that infants start producing their own HLA antibodies in the first weeks of life, which, together with maternally derived antibodies may impact the infant's immune reaction to HLA proteins.