Abstract
The HIV latent reservoir exhibits slow decay on antiretroviral therapy (ART), impacted by homeostatic proliferation and activation. How these processes contribute to the total dynamic while also producing the observed profile of sampled latent clone sizes is unclear. An agent-based model was developed that tracks individual latent clones, incorporating homeostatic proliferation of cells and activation of clones. The model was calibrated to produce observed latent reservoir dynamics as well as observed clonal size profiles. Simulations were compared to previously published latent HIV integration data from 5 adults and 3 children. The model simulations reproduced reservoir dynamics as well as generating residual plasma viremia levels (pVL) consistent with observations on ART. Over 382 Latin Hypercube Sample simulations, the median latent reservoir grew by only 0.3 log10 over the 10 years prior to ART initiation, after which time it decreased with a half-life of 15 years, despite number of clones decreasing at a faster rate. Activation produced a maximum size of genetically intact clones of around one million cells. The individual simulation that best reproduced the sampled clone profile, produced a reservoir that decayed with a 13.9 year half-life and where pVL, produced mainly from proliferation, decayed with a half-life of 10.8 years. These slow decay rates were achieved with mean cell life-spans of only 14.2 months, due to expansion of the reservoir through proliferation and activation. Although the reservoir decayed on ART, a number of clones increased in size more than 4,000-fold. While small sampled clones may have expanded through proliferation, the large sizes exclusively arose from activation. Simulations where homeostatic proliferation contributed more to pVL than activation, produced pVL that was less variable over time and exhibited fewer viral blips. While homeostatic proliferation adds to the latent reservoir, activation can both add and remove latent cells. Latent activation can produce large clones, where these may have been seeded much earlier than when first sampled. Elimination of the reservoir is complicated by expanding clones whose dynamic differ considerably to that of the entire reservoir.
Highlights
Estimates of the latent reservoir half-life under antiretroviral therapy (ART) give a bulk measure of how this collection of cells changes over time [1]
These clones can arise through homeostatic proliferation, or from antigen-induced cellular activation, abbreviated to activation, where the memory cells remaining after antigen mediated cellular proliferation and clearance, arise from an infected cell that has maintained latency [5]
Seeding of the reservoir occurred at primary HIV infection (PHI) and throughout the period prior to ART initiation
Summary
Estimates of the latent reservoir half-life under antiretroviral therapy (ART) give a bulk measure of how this collection of cells changes over time [1]. By comparing integration positions between infected cells, researchers can determine whether these occurred through different infection events (the integration positions are different), or the cells are clones of a previously infected cell which experienced at least one round of cell division (the integration positions are identical, as are the proviral genomes) These clones can arise through homeostatic proliferation, or from antigen-induced cellular activation, abbreviated to activation, where the memory cells remaining after antigen mediated cellular proliferation and clearance, arise from an infected cell that has maintained latency [5]. The relatively high frequencies of some clones in samples of CD4+ T cells, point to very high expansion of these clones to levels that can reach in their millions and that can contribute to viremia [6] These clones can be maintained over many years even in the presence of ART [3]. A description of clonal dynamics will provide a much more detailed analysis of processes affecting the latent reservoir, and how it may be impacted
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