Quantitative Measurement and Correlates of the Latent HIV Reservoir in Virally Suppressed Ugandans

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 70 HIV-infected patients who are on ART with suppressed viral loads \<40 copies per ml over a period of 10-18 months. A second group includes 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 third group will be comprised of 10 HIV infected subjects with suppressed viral load \<40 copies per ml over a period of 10-18 months, while not on ART. A fourth group will include 30 individuals living with HIV on ART with suppressed viral loads, who have known windows of seroconversion, and initiated ART early. Study participation will require a visit with a fingerstick hemoglobin screening and a blood draw, once a year for a period of 20 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 20 years of continual viral suppression in order to calculate the T1/2 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.