Immunogenetic Modulators of Mucosal Protection From HIV-1 (Kinga)

November 2, 2020 updated by: Jairam Lingappa, University of Washington

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

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.

Study Overview

Status

Completed

Conditions

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 Type

Observational

Enrollment (Actual)

812

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Kenya
      • Thika, Kenya
        • Partners in Health, Research and Development

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

African heterosexual HIV-serodiscordant (SDC) and HIV-1 concordant negative couples (CNC)

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
HIV-1 serodiscordant couples
Heterosexual couples in which one partner is infected with HIV-1 and the other partner is HIV-1 uninfected
Concordant HIV-1 negative couples
Heterosexual couples in which both partners are HIV-1 uninfected

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prevalence of genital-tract tissue resident memory (TRM) cells
Time Frame: 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
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.
Time Frame: 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.
At 6 months of follow-up

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prevalence of genital-tract tissue resident memory (TRM) cells
Time Frame: At enrollment
We will compare frequency of CD69+ among CD8+ TRM in genital tissues between HIV-1 exposed and HIV-1 unexposed individuals
At enrollment
Prevalence of genital-tract tissue resident memory (TRM) cells in individuals with versus without CD101 immunoglobulin-like (Ig-like) variants.
Time Frame: At enrollment
We will compare frequency of CD69+ among CD8+ TRM in genital tissues in individuals with versus without CD101 immunoglobulin-like (Ig-like) variants.
At enrollment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Washington

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)
Kenya Medical Research Institute

Investigators

  • Study Chair: Jairam Lingappa, MD, PhD, University of Washington

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 27, 2018

Primary Completion (Actual)

September 30, 2020

Study Completion (Actual)

September 30, 2020

Study Registration Dates

First Submitted

September 21, 2018

First Submitted That Met QC Criteria

October 8, 2018

First Posted (Actual)

October 10, 2018

Study Record Updates

Last Update Posted (Actual)

November 3, 2020

Last Update Submitted That Met QC Criteria

November 2, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY00001559
  • R01AI129715 (U.S. NIH Grant/Contract)
  • R01AI131914 (U.S. NIH Grant/Contract)
  • R01AI141435 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

De-identified individual participant data for all outcome measures

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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