Mechanisms of HIV persistence in HIV reservoirs

Abstract

The establishment and maintenance of HIV reservoirs that lead to persistent viremia in patients on antiretroviral drugs remains the greatest challenge of the highly active antiretroviral therapy era. Cellular reservoirs include resting memory CD4+ T lymphocytes, implicated as the major HIV reservoir, having a half-life of approximately 44 months while this is less than 6 hours for HIV in plasma. In some individuals, persistent viremia consists of invariant HIV clones not detected in circulating resting CD4+ T lymphocytes suggesting other possible sources of residual viremia. Some anatomical reservoirs that may harbor such cells include the brain and the central nervous system, the gastrointestinal tract and the gut-associated lymphoid tissue and other lymphoid organs, and the genital tract. The presence of immune cells and other HIV susceptible cells, occurring in differing compositions in anatomical reservoirs, coupled with variable and poor drug penetration that results in suboptimal drug concentrations in some sites, are all likely factors that fuel the continued low-level replication and persistent viremia during treatment. Latently, HIV-infected CD4+ T cells harboring replication-competent virus, HIV cell-to-cell spread, and HIV-infected T cell homeostatic proliferation due to chronic immune activation represent further drivers of this persistent HIV viremia during highly active antiretroviral therapy.

Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring

“…4, 5 However, HAART does not cure HIV infection, because the virus hides by integrating proviral DNA into cells that can form long living reservoirs, and already formed viruses can persist in lymphatic tissues attached to follicular dendritic cells where they cannot be killed by current therapy. 6, 7 The ability of HAART to bring the acute HIV infection into a chronic status has been associated with other chronic health problems caused by the side effects of the HAART drug cocktail. Moreover, recent global reports indicate a significant increase in HAART resistant population, increasing the demand to find novel drugs with new modes of action.…”

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“…Even though a steady-state level of a very-low viremia was reported among those on ART, the long-term persistence occurs over time, and is not only due to reactivation of the latent virus in specific cells (Martinez-Picado and Deeks, 2016;Peluso et al, 2019). There are a few plausible reasons for the underlying persistency (Kulpa and Chomont, 2015;Mzingwane and Tiemessen, 2017): (i) residual levels of replicative-competent virus that may not be entirely suppressed in drug-penetrable anatomical compartments, (ii) presence of a small pool of cells carrying silent integrated genomes that can potentially reactivate (latent virus), (iii) continuous immune exhaustion and inflammation that fail at controlling virus replication in infected FIGURE 1 | Timeline covers the highlights over the past three decades of HIV/AIDS. The history of HIV/AIDS epidemic begins from the first reported cases in 1981 of an unknown virus.…”

Comparison of tenofovir plasma and tissue exposure using a population pharmacokinetic model and bootstrap: a simulation study from observed data

“…Estimates of positive slopes were excluded from the individual bootstrap estimate, as per Mager & Goller. (7, 8). …”

“…The gastrointestinal tract contains gut-associated lymphoid tissue (GALT), a well-described mucosal reservoir of viral persistence (6) that potentially limits the ability to achieve cure if those therapies do not achieve effective concentrations in the GALT. (7) Structures within both the male and female genital tracts may also serve as viral reservoirs (reviewed in (8)).…”