Immunogenetic Modulators of Mucosal Protection From HIV-1

Study Overview
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Brief Summary
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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
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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

Official Title
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Immunogenetic Modulators of Mucosal Protection From HIV-1: The Kinga Study

Conditions
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HIV Infections, HSV-2 Infection

Participation Criteria
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Eligibility Criteria
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Inclusion criteria: HIV-1 Uninfected Participants; Age ≥18 and ≤65 and able to provide independent informed consent for research per local regulations and guidelines Able and willing to provide written informed consent to be screened for and to take part in the study Part of a heterosexual couple in which either one or both partners meet the study eligibility criteria for partner (HIV-1 uninfected) participants. Couples are defined by the following criteria: Partners are sexually active (defined as having had vaginal intercourse with the enrolled partner at least 6 times in the last three months) Partners plan to remain in the relationship for the duration of the study period. HIV-1 uninfected status is based on parallel negative HIV-1 rapid tests, both at study screening and at the enrollment visit Able and willing to provide adequate locator information for study retention purposes, as defined by local standard operating procedures HIV-1 Infected Participants; Of legal age to provide independent informed consent for research per local regulations and guidelines. Able and willing to provide written informed consent to be screened for and to take part in the study. Part of a heterosexual couple in which one partner meets the study eligibility criteria for index (HIV-1 infected) participants and the other partner meets the study eligibility criteria for partner (HIV-1 uninfected) participants Current or previous use of antiretroviral therapy with unsuppressed HIV-1 viral load HIV-1 infected based on positive EIA and, when available, detectable viral load. No history of any clinical AIDS-defining diagnoses. Able and willing to provide adequate locator information for study retention purposes, as defined by local standard operating procedures. Exclusion criteria: HIV-1 Uninfected Participants; Abnormal serum creatinine (based on sub-Saharan African normal values) Active and serious infections, including active tuberculosis infection or osteomyelitis and all infections requiring parenteral antibiotic therapy; active clinically significant medical problems including cardiac disease, pulmonary disease, diabetes requiring hypoglycemic medication; and previously diagnosed malignancy expected to require further treatment. Receiving ongoing therapy with any of the following at the time of enrollment: antiretroviral therapy (ART), including nucleoside analogs, nonnucleoside reverse transcriptase inhibitors, protease inhibitors or investigational antiretroviral agents, interferon (alpha, beta, or gamma) or interleukin (e.g., IL-2) therapy, metformin, aminoglycoside antibiotics, amphotericin B, cidofovir, systemic chemotherapeutic agents, other agents with significant nephrotoxic potential, other agents that may inhibit or compete for elimination via active renal tubular secretion (e.g., probenecid), and/or other investigational agent At enrollment, has any other condition that, based on the opinion of the investigator or designee, would preclude provision of informed consent; make participation in the study unsafe; complicate interpretation of study outcome data) Pregnant at the time of screening HIV-1 Infected Participants; Current or previous use of antiretroviral therapy with suppressed HIV-1 viral load Currently enrolled in another HIV-1 treatment trial At enrollment, has any other condition that, based on the opinion of the investigator or designee, would preclude provision of informed consent; make participation in the study unsafe; complicate interpretation of study outcome data; or otherwise interfere with achieving the study objectives. Pregnant at the time of screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| HIV-1 serodiscordant couples<br>Heterosexual couples in which one partner is infected with HIV-1 and the other partner is HIV-1 uninfected | |
| Concordant HIV-1 negative couples<br>Heterosexual couples in which both partners are HIV-1 uninfected | |

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV prevention, PrEP, Tenofovir Disoproxil Fumarate (TDF)/Emtricitabine (FTC)