Over the last two decades, identification of epidemiologic factors associated with HIV-1 infection (e.g., including plasma HIV-1 RNA level, frequency of unprotected sex, and male circumcision) has provided a critical context for developing HIV-1 prevention interventions (anti-retroviral drugs, pre-exposure prophylaxis, and medical male circumcision) to slow the spread of this infection. Moreover, recent studies have identified molecular markers of host inflammation and immune activation as modulators of HIV-1 infection risk, raising the possibility that novel HIV-1 prevention interventions could be targeted at these factors. Such interventions could include targeted adjuvants to augment the effect of novel vaccines or microbicides; or narrow-spectrum anti-inflammatory agents to prevent HIV-1 infection without augmenting other adverse effects from immunosuppression. However, the molecular mechanisms by which host inflammation impacts sexual acquisition of HIV-1 remain poorly understood. Some studies have identified markers of cellular inflammation as risk factors for HIV-1 infection, while others have reported inflammatory factors associated with protection from HIV-1 infection. These data suggest that the role of host inflammation in modifying HIV-1 infection is likely complex. A better understanding of these molecular mechanisms is therefore of critical importance to properly identify targets for novel HIV-1 prevention interventions that won?t inadvertently increase risk of HIV-1 infection. We recently applied a whole genome sequencing approach to data from multiple African HIV-1 serodiscordant heterosexual couples cohorts and successfully identified, and replicated, a novel association between variants in the human gene CD101 and increased HIV-1 acquisition risk. CD101 expression had been previously reported to be an important regulator of T regulatory cells that regulate host immune responses. Thus, these variants offer a unique opportunity to understand how the regulation of host inflammation may modulate HIV-1 acquisition risk. However, we do not know the mechanism by which these variants impact CD101 or T regulator cell function. These CD101 variants could enhance suppression of T cell responses thereby reducing helpful host inflammatory responses; or they could reduce T cell suppression resulting in increased cellular inflammation and accumulation of HIV-1 target cells. Thus, an improved understanding of how CD101 variants impact HIV-1 acquisition risk may provide insight into the complex molecular pathways that link host inflammatory responses and HIV-1 acquisition risk. We propose to use archived samples from the same repository that were originally used to identify this CD101 genetic association with HIV-1 acquisition risk to better understand how these identified variants impact overall inflammation and regulatory T cell function. These studies will provide important clues into the key molecular factors underlying HIV-1 acquisition risk.

Public Health Relevance

The molecular mechanism by which host inflammation modifies the risk of sexually acquiring HIV-1 is poorly understood. We have recently shown that multiple variants in the gene CD101, which modulates T regulatory cell function, contribute to increased risk of HIV-1 infection. We propose to use archived samples to explore how these CD101 variants may influence T cell function and determine if this provides a molecular context to understand the relationship of host inflammation to HIV-1 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI127156-01
Application #
9202767
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Church, Elizabeth S
Project Start
2016-06-10
Project End
2018-05-31
Budget Start
2016-06-10
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$220,382
Indirect Cost
$47,193
Name
University of Washington
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195