# Genetic Risk of HIV Acquisition: Mechanisms of Resilience

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $254,250

## Abstract

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.

## Key facts

- **NIH application ID:** 10077116
- **Project number:** 1R21AI154956-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** DOUGLAS F NIXON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077116

## Citation

> US National Institutes of Health, RePORTER application 10077116, Genetic Risk of HIV Acquisition: Mechanisms of Resilience (1R21AI154956-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10077116. Licensed CC0.

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