HIV Persistence on Antiretroviral Therapy and Barriers to a Cure

Abstract

HIV persists within the body despite successful suppression of virus replication with antiretroviral therapy (ART). HIV lurks in latent and active reservoirs, leading to rebound of virus spread if ART is interrupted. The latent HIV reservoir is a natural consequence of the life cycle of HIV, with integration of HIV into the genomes of cells that are or later enter the resting state, resulting in transcriptionally quiescent provirus. Resting CD4 T cells comprise the majority of the latent reservoir, although new evidence points to additional, smaller cellular reservoirs of latent HIV. An alternate, so-called active reservoir of HIV also exists within cells such as those found the B cell follicle of lymph nodes, where expression of HIV RNA can be found, again despite the full suppression of viremia and viral replication. Multiple factors such as the degree of virus exposure, timing of ART, and host factors can influence the size and characteristics of the HIV reservoir. Constructing effective strategies for HIV eradication and measuring their impact will require a sophisticated knowledge of the HIV reservoir.

Evaluating the Intactness of Persistent Viral Genomes in Simian Immunodeficiency Virus-Infected Rhesus Macaques after Initiating Antiretroviral Therapy within One Year of Infection

“…KEYWORDS SIV, single-genome sequencing, genome intactness, genomic integrity, persistent viral reservoir V irus that persists despite long-term combination antiretroviral therapy (cART), including provirus in latently infected resting memory CD4 ϩ T cells, represents the primary barrier to more-definitive treatment of HIV infection (1)(2)(3). This reservoir has an extremely long half-life (4,5) such that even after years of cART and undetectable plasma viremia, treatment interruption almost invariably results in viral recrudescence (6)(7)(8)(9). Thus, a major goals in HIV cure research are to identify and eradicate the viral reservoir that contributes to rebound viremia or to reduce it to levels that can be sustainably controlled by the immune system, allowing the safe cessation of cART.…”

Nuclear Transit and HIV LTR Binding of NF-κB Subunits Held by IκB Proteins: Implications for HIV-1 Activation

“…While many HIV LARs for use in "shock and kill" strategies to attack and deplete the reservoir of long term latently infected cells have been studied, none have really been proven to be clinically safe and effective [1][2][3][4][5][6]16,18,19]. This unfortunate experience suggests that it might be helpful to pursue mechanistically novel latency activation technologies for use in "shock and kill."…”

“…While combination antiretroviral therapy (cART) can effectively control disease in a patient infected with HIV-1, cART does not cure a patient of the infection, due to the existence of a persistent reservoir of long-lived latently infected cells, largely CD4+ memory T cells (recently reviewed in [1][2][3][4]). Considerable interest has centered on developing ways to attack, deplete, and ideally eliminate the long-lived reservoir of latently infected cells.…”

Extracellular Vesicles in Smoking-Mediated HIV Pathogenesis and their Potential Role in Biomarker Discovery and Therapeutic Interventions

“…CD4 T cells, cells of the myeloid lineage (monocytes and macrophages) and dendritic cells [42][43][44][45]. Monocytes and macrophages are considered one of the most suitable cells for studying viral latency due to their long lifespan, as well as their ubiquitous presence throughout the body, including the brain [43,45,46]. EVs derived from monocytes and macrophages potentially have a profound effect on recipient cells [47,48].…”