Genetic Risk of HIV Acquisition: Mechanisms of Resilience

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PROJECT SUMMARY/ABSTRACT This new R21 submission is entitled “Genetic Risk of HIV Acquisition: Mechanisms of Resilience”. Soon after the identification of a new disease amongst gay men in Los Angeles and New York, originally called GRID, epidemiological evidence suggested a sexually transmitted infection, which was then confirmed in populations in Haiti and African identified with infection with HIV-1. In addition to infection through sex, intravenous administration of contaminated blood products or drug use could lead to infection, as well as mother to child transmission. Blood infection was identified as the highest risk, with different routes of sexual exposure associated with different identifiable risks of infection. Before antiretroviral drug therapy became available, around one third of babies born to infected mothers were infected, while two thirds were not. Thus, it appeared that epidemiological and behavioral factors could predict HIV-1 susceptibility. However, individuals exposed to HIV infection who had not became infected helped identify the defective Δ32 form of CCR5 receptor which misfolded at the surface of a CD4+ cell and could not be infected, and in homozygote form, led to resistance to infection with R5 using viruses. However, no genome-wide significant polymorphisms were found associated with HIV-1 acquisition, which has led the field to move away from genetic association analyses. We were puzzled from recent studies of sex workers exposed to HIV-1 who did not become infected despite high risk behavior and wondered if genetic resilience to HIV-1 acquisition had been missed. Population genetic methods have developed substantially in recent years, now allowing for powerful, biologically-informative analyses even in moderately-sized gene wide association studies (GWAS). In preliminary data, we reanalyzed the largest GWAS of HIV-1 acquisition and used gene-level enrichment analyses and polygenic risk scoring to identify novel genes and inflammatory markers associated with acquisition risk. We have shown that HIV-1 acquisition is a surprisingly heritable trait, and that certain cytokines are associated with HIV-1 resilience. These findings could lead to potential new ways of preventing HIV-1 infection, including targeted interventions to those at highest risk. In this grant, we will extend our analyses of the genetics of acquisition to validation cohorts including non-European ancestry and determine mechanisms of immunological resilience. A better understanding of biological factors influencing acquisition has the potential to develop our basic comprehension of HIV-1 acquisition, improve prevention strategies and reduce social stigma.