Quantitative Measurement and Correlates of the Latent HIV Reservoir in Virally Suppressed Ugandans
Condition: HIV
Study type: Observational

Summary: 
      Background:

      Human Immunodeficiency Virus (HIV) is the virus that causes AIDS. HIV can hide in the blood
      for many years, even in people who have their HIV infection under control. HIV that is hiding
      in the blood is called the latent HIV reservoir. Researchers want to find out more about it
      in this study. This knowledge may help them develop new ways to prevent or control HIV. This
      study will draw its participants from the Rakai Health Sciences Program in rural southwestern
      Uganda.

      Objective:

      - To measure and learn about the latent HIV reservoir in Ugandans with HIV.

      Eligibility:

      - Men and women at least 18 years of age with HIV.

      Design:

        -  Participants will have a medical history and physical exam. Their medical records will
           be reviewed. Researchers will ask participants about their health and recent illnesses.
           Participants able to get pregnant will have their urine tested for pregnancy.

        -  Participants will have their finger pricked to see if they have enough red blood cells
           to be eligible for the study.

        -  If eligible, participants will have blood drawn through a needle in the arm. Their blood
           will also be tested for other diseases.

        -  After the blood draw, participants will be asked to stay seated or lying down if they
           are not feeling well for up to 30 minutes.
    

Detailed description: 
      Despite prolonged antiretroviral therapy (ART), HIV-1 can persist as transcriptionally
      inactive

      proviruses in resting memory CD4+T cells. This latent reservoir has a long half-life, and is
      believed to be the largest impediment to a cure by ART alone. The latent reservoir may be
      established when activated CD4+ T cells become infected and subsequently revert back to a
      resting memory state. A major approach to eradicating HIV-1 involves reversing latency in
      patients on ART. Cells harboring induced proviruses could be lysed by HIV-1-specific
      cytolytic T lymphocytes, while ART blocks new rounds of infection. The descriptions of the
      Berlin patient and Mississippi baby suggest that a functional cure for HIV is possible. This
      has led to an expansion of research examining HIV latency in the context of sustained viral
      suppression with an eye towards developing a possible cure regimen that could be used on a
      large scale. However, it has recently been demonstrated that the latent HIV reservoir could
      be 60 times larger than previously believed. The recent report that two HIV patients
      receiving CCR5competent bone marrow transplants had a reemergence of circulating HIV after
      fully suppressive therapy was discontinued suggests that a functional cure for large groups
      of individuals will continue to be an elusive goal.

      The vast majority of HIV-infected individuals currently live in sub-Saharan Africa where
      fully suppressive ART is expanding rapidly. Due to this expansion, a large number of Africans
      will be eligible candidates for cure treatment when one comes available. However, strategies
      needed to establish a functional cure may differ in African populations due to differences in
      endemic infectious disease load and in cellular immune activation among Africans as compared
      to Western populations. To date, there have been no systematic studies to quantify the latent
      reservoir in HIV-infected Africans. This is a longitudinal, descriptive study to measure the
      size of the latent HIV reservoir in virally suppressed HIV infected individuals residing in
      Uganda and to examine the immunological and virologic correlates of the latent reservoir. The
      study will draw its participants from a National Institutes of Health (NIH) International
      Center for Excellence in Research (ICER) site, located at the Rakai Health Sciences Program
      (RHSP) in rural southwestern Uganda. One group of subjects will be comprised of 90
      HIV-infected patients who are on ART with suppressed viral loads <40 copies per ml over a
      period of 10-18 months, including 20 individuals with a known window of seroconversion (an
      HIV-negative test result no more than 18 months before the first HIV-positive test result). A
      second group will be comprised of 10 HIV infected subjects with suppressed viral load <40
      copies per ml over a period of 10-18 months. Study participation will require a visit with a
      fingerstick hemoglobin screening and a blood draw, once a year for a period of ten years.
      Plasma and cells from the blood will be separated and processed for quantitative viral
      latency, viral clonality analysis, circulating cytokine and chemokine analysis, co-culture,
      and flow cytometric and serologic assays for selected immunological parameters. Viral latency
      results and clonality measurements will be compared within each individual for changes in the
      reservoir size and make-up that might occur over ten years of continual viral suppression in
      order to calculate the T 1/2 or decay rate of the total latent reservoir and it s component
      proviral populations . Samples collected from individuals with known infection dates will be
      used to estimate the formation curve of the latent reservoir. Overall reservoir size and
      decay and formation rates will be interpreted in relation to values previously collected from
      HIV-infected individuals in the United States.
    

Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        The study will draw its participants from an NIH International Center for Excellence in
        Research (ICER) site, located at the Rakai Health Sciences Program (RHSP) in rural
        southwestern Uganda. Since 1994, over 12,000 adults aged 15-49 years of age have been under
        annual surveillance in an open cohort, the Rakai Community Cohort Study (RCCS). Within the
        RCCS, the Rakai Program has conducted multiple observational, basic science, behavioral and
        operations research studies, and has conducted complex community and individual randomized
        HIV and sexually transmitted disease (STD) prevention trials.
      
Keywords: Viral Suppression; Functional Cure; Natural History