Immunogenetic Modulators of Mucosal Protection From HIV-1

Completed

• Conditions: HSV-2 Infection; HIV Infections

• Registration Number: NCT03701802
• Lead Sponsor: University of Washington

Brief Summary

This is a single site, prospective, observational study that seeks to assess changes in mucosal immunity that occur as a result of HIV-1 exposure, HSV-2 infection, and/or pre-exposure prophylaxis (PrEP) usage to prevent HIV-1 acquisition. The study will collect mucosal and peripheral blood samples for a detailed analysis of longitudinal immune responses, while also obtaining samples for genetic characterization to understand how variants in CD101 and UBE2V1 may modulate host mucosal responses and HIV-1 infection risk.

Detailed Description

A challenge to development of HIV-1 vaccines is to better understand the natural immune mechanisms for protection from HIV-1 infection. To this end, immunologists have increasingly appreciated the importance of regulatory T cells in peripheral blood that modulate the magnitude and characteristics of the host inflammatory response including against infectious diseases. The investigators have recently identified specific host genetic variants in the genes CD101 and UBE2V1 that appear to strongly predispose to HIV-1 infection risk and may act through regulatory T cells and other immunologic pathways. Most studies of individuals who are repeatedly HIV-1 exposed but remain seronegative (HESN) have focused on immunological correlates in peripheral blood rather than mucosal immune responses. However, with genital mucosal tissues being the portal of entry for heterosexually transmitted HIV-1 infection, it is critical to understand the role of immunological responses to HIV-1 that occur in the genital mucosa. A valuable model to carry out such studies is offered by evaluation of HIV-Exposed SeroNegative (HESN) individuals, particularly in the context of heterosexual sex with a stable HIV-1 infected partner e.g., HIV-1 serodiscordant couples (SDC). In order to understand how genital exposure to HIV-1 may modulate these immune pathways, HIV-1 serodiscordant couples should be compared to heterosexual partners in concordant HIV-1 negative couples (CNC) where neither partner has HIV-1. This study seeks to address this important knowledge gap by enrolling high-risk HESN with defined heterosexual HIV-1 exposures in the context of serodiscordant partnerships compared to unexposed concordant seronegative controls. The study will prospectively collect mucosal and peripheral blood samples for a detailed analysis of longitudinal immune responses, while also obtaining samples for genetic characterization to understand how variants in CD101 and UBE2V1 may modulate host mucosal responses and HIV-1 infection risk.

Primary Objectives:

* To identify mucosal immunoregulatory mechanisms mediating host response to heterosexual exposure to HIV-1.

* To determine how high priority variants in CD101 and UBE2V1 modify host mucosal responses in HIV-1 exposure and infection.

Secondary Objectives:

* Identify factors (including HIV-1 exposure, host genetic and microbiota) that modify immunoregulatory mechanisms mediating host response to HIV-1

* Evaluate how these immunogenetic regulatory mechanisms influence other infectious and immunological outcomes

* Evaluate the effect of PrEP on early HIV-1 disease

Study Timeline

• Study First Submitted: 2018-09-21
• Study Start: 2018-09-27
• Study First Submitted QC: 2018-10-08
• Study First Posted: 2018-10-10
• Primary Completion: 2020-09-30
• Study Completion: 2020-09-30
• Status Verified: 2020-11
• Last Update Submitted: 2020-11-02
• Last Update Posted: 2020-11-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 812

Inclusion Criteria

Not provided

Read More

Exclusion Criteria

Not provided

Read More

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Prevalence of genital-tract tissue resident memory (TRM) cells	At 6 months of follow-up	We will compare frequency of CD69+ among CD8+ TRM in genital tissues between HIV-1 exposed and HIV-1 unexposed individuals

Secondary Outcome Measures

Name	Time	Method
Prevalence of genital-tract tissue resident memory (TRM) cells in individuals with versus without CD101 immunoglobulin-like (Ig-like) variants.	At 6 months of follow-up	We will compare frequency of CD69+ among CD8+ TRM in genital tissues in individuals with versus without CD101 immunoglobulin-like (Ig-like) variants.

Trial Locations

Locations (1)

Partners in Health, Research and Development; 🇰🇪 Thika, Kenya