Proliferation, proliferation, proliferation! Driver of HIV reservoir

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Despite the success of antiretroviral therapy (ART) in managing HIV infection, there is no cure for HIV. The major barrier to curing HIV is the establishment of latently infected CD4+ T cell reservoirs during primary infection. But what mechanism drives the formation of the HIV reservoir? Does the cellular proliferation of latently infected CD4+ T cells and/or de novo infection contribute to the establishment of the HIV reservoir? Dr. Florencia Tettamanti Boshier, a former postdoctoral fellow in Dr. Josh Schiffer’s lab in the Vaccine and Infectious Diseases and Clinical Research Divisions at Fred Hutch, sought to provide insight into questions about HIV reservoir formation using a mathematical model. The findings were published in a recent article in the Journal of Virus Eradication

When HIV enters the human body, it infects mainly CD4+ T cells. As the virus replicates, it infects more cells. Viral replication stops in a small portion of newly infected cells which enter latency and become part of the reservoir. Prior to antiretroviral therapy, the result is a mixture consisting mostly of short-lived cells in which HIV is replicating and longer-lived latently infected cells. With each new cellular infection, HIV integrates into human chromosomal DNA at a unique, random location. If multiple cells are found to harbor HIV DNA in the exact same chromosomal site, then the likelihood this occurred via viral infection is very low. Rather, this indicates that this reservoir cell proliferated and carried along a new copy of HIV DNA to each of its daughter cells. The knowledge gained from quantifying cells with equivalent HIV DNA integration sites allows researchers to distinguish de novo viral infections from clonal proliferation of latently infected cells. Cells that are newly infected consist of a heterogeneous population of integration sites and sequences. On the other hand, latently infected cells that arise from proliferation will share the same viral integration site, making them distinguishable by their repeated “clonal” integration sites.

To investigate the contribution of de novo infection and cellular proliferation of latently CD4+ T cells to the formation of HIV reservoirs during primary infection, the authors developed a mathematical model that simulated “individual CD4+ T cell clones, which are identified through a unique fingerprint created by HIV integration sites”, according to Dr. Schiffer. Their modeling consists of three steps: 1) a deterministic model to recapitulate general trends in viral load, HIV DNA, and CD4+T cell counts during the first several months of infection, 2) a stochastic model to examine whether proliferation of individual infected clones is important for formation of HIV reservoirs, and 3) testing model output against experimental data to validate its predictions.

HIV infection is characterized by a significant decrease in CD4+ T cells concurrent with peak viral load during the first two weeks of infection, followed by the gradual recovery of CD4+ T cells over the next four weeks. In their deterministic model, the authors incorporated data from Females Rising through Education, Support and Health (FRESH), a longitudinal study by the Ragon Institute of MGH, Harvard and MIT. Their model simulations showed that the viral load increased inversely with the decrease in CD4+ T cells during the first two weeks of primary infection and then stabilized after 20-40 days. Their simulations also found a negative correlation between CD4+ T cells counts and the size of the latent reservoir after 30 days of infection. These correlations in study participant data could only be reproduced with the model if cellular proliferation was included.

Overall, this study demonstrated that while viral replication initially seeds the HIV reservoir, clonal cell proliferation is the primary driver of HIV reservoir expansion during early infection, a distinction that has previously remained elusive. Dr. Schiffer summarized, “This paper uses a mathematical model fit to experimental data to make the novel prediction that a majority of reservoir formation occurs during weeks 1-4 after initial infection due to massive proliferation of reservoir cells.” Their results suggest that “these clones have highly variable proliferation rates leading to a small number of massive clones and a massive number of small clones as early as one month into infection,” he added. This is relevant for HIV cure because “the model suggests that anti-proliferative therapies given between weeks 1 and 4 of infection may significantly lower the volume of the reservoir and assist in HIV cure,” Dr. Schiffer concluded. The next steps for this work are to test these therapeutic predictions in relevant animal models of HIV infection.

The work was supported by the National Institutes of Health.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member
Joshua Schiffer contributed to this work.

Tettamanti Boshier FA, Reeves DB, Duke ER, Swan DA, Prlic M, Cardozo-Ojeda EF, Schiffer JT. 2022. Substantial uneven proliferation of CD4+ T cells during recovery from acute HIV infection is sufficient to explain the observed expanded clones in the HIV reservoir. J Virus Erad. 30;8(4):100091.


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