Pharmacy and Poisons Board
Protocol No: ECCT/18/05/02 Date of Protocol: 28-02-2018
Study Title:

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

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Study Objectives:

 Primary Objective:

  • To identify mucosal immunoregulatory mechanisms in host response to natural heterosexual exposure to HIV-1.
  • To determine how high priority variants in CD101 and UBE2V1 modify host mucosal responses to HIV-1 exposure and infection.

Secondary Objective:

1) Identify factors influencing immunoregulatory mechanisms in host response to HIV-1

  • To evaluate the impact on host immunoregulatory responses from variation in cofactors including but not limited to
  • sexually transmitted infections and the host microbiome,
  • HIV-1 exposure as defined by the frequency of sexual activity and the HIV-1 viral load in the HIV-1 infected partner, and
  • HIV-1 prevention measures including antiretroviral PrEP provided to the HESN partner, or ART provided to the HIV-1 infected partner.
  • Characteristics of sexual exposures (frequency, type and duration of sex acts)
  • To assess the effect of biological factors such as host genetic factors, microbiome and virome constituents and viral genetic factors on these immunoregulatory responses.
  • To determine how these immunogenetic responses may alter HIV-1 disease progression

 

2) To evaluate how these immunogenetic regulatory mechanisms influence other infectious and immunological outcomes:

  • To assess the role immunoregulatory mechanisms on host response to other infections (e.g., sexually transmitted infections and bacterial vaginosis),
  • To define the role of these immunogenetic regulatory mechanisms in other acute and chronic manifestations of inflammation.

 

3) Evaluate the effect of PrEP on early HIV-1 disease

  • Among initially HIV-1 uninfected individuals in the study who seroconvert to HIV-1, to assess the level of genital tract inflammation present prior to HIV-1 infection.

 

Tertiary Objectives

  • To utilize archived samples from this study for evaluation of immunogenetic and virologic determinants on inflammatory disorders, and HIV-1 and sexually transmitted infection (STI) acquisition, transmission and disease progression including viral phenotype and genotype, HIV-1 co-receptor usage, innate and adaptive immune polymorphisms, human genomic, microbiome and virome constituents and other biological factors.  
Laymans Summary:
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. We have also 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.
Abstract of Study:
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. We have also 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 that we 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 HESN, 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 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. Here we propose 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. We will prospectively obtain mucosal and peripheral blood samples for a detailed analysis of longitudinal immune responses, while also collecting samples for genetic characterization to understand how variants in CD101 and UBE2V1 may modulate host mucosal responses and HIV-1 infection risk.
 
Design: Single study site, prospective, observational cohort.
 
Population: African heterosexual HIV-serodiscordant (SDC) and HIV-1 concordant negative couples (CNC) will be recruited for this study. The exclusion criteria will be current use of ART by HIV-1 infected partners, or PrEP by HIV-1 uninfected partners at the time of screening or prior to enrollment. Inclusion criteria applied to all partners includes age≥18 years, willingness to engage in voluntary couples HIV-1 counseling and testing, to disclose these testing results to their enrolled partner, and to provide samples requested. Among SDC the HIV-1 uninfected partners may be either male or female.
 
Study Size: The study will enroll both partners in 500 heterosexual Kenyan couples:
 
• 300 HIV-1 serodiscordant couples (200 with male, and 100 with female HIV-1 infected partners) and
• 200 HIV-1 concordant seronegative couples (400 HIV-1 negative partners).
 
 
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