Abstract
HIV-1 eradication strategies aim to achieve viral remission in the absence of antiretroviral therapy (ART). The development of an HIV-1 cure remains challenging due to the latent reservoir (LR): long-lived CD4 T cells that harbor transcriptionally silent HIV-1 provirus. The LR is stable despite years of suppressive ART and is the source of rebound viremia following therapy interruption. Cure strategies such as “shock and kill” aim to eliminate or reduce the LR by reversing latency, exposing the infected cells to clearance via the immune response or the viral cytopathic effect. Alternative strategies include therapeutic vaccination, which aims to prime the immune response to facilitate control of the virus in the absence of ART. Despite promising advances, these strategies have been unable to significantly reduce the LR or increase the time to viral rebound but have provided invaluable insight in the field of HIV-1 eradication. The development and assessment of an HIV-1 cure requires robust assays that can measure the LR with sufficient sensitivity to detect changes that may occur following treatment. The viral outgrowth assay (VOA) is considered the gold standard method for LR quantification due to its ability to distinguish intact and defective provirus. However, the VOA is time consuming and resource intensive, therefore several alternative assays have been developed to bridge the gap between practicality and accuracy. Whilst a cure for HIV-1 infection remains elusive, recent advances in our understanding of the LR and methods for its eradication have offered renewed hope regarding achieving ART free viral remission.
Highlights
Infection with human immunodeficiency virus type-1 (HIV-1) requires life-long adherence to antiretroviral therapy (ART) due to the presence of latently infected cells that are central to viral persistence and rebound viremia following ART interruption (Chun et al, 1997, 1998, 1999; Finzi et al, 1997; Perelson et al, 1997; Wong et al, 1997; Davey et al, 1999; Rosenbloom et al, 2017)
This study showed that inhibition of this long non-coding RNA (lncRNA) with small interfering RNAs could induce apoptosis in HIV-1 infected macrophages, indicating the potential of targeting lncRNAs as a novel therapeutic approach to aid the clearance of the latent reservoir (LR) in all cell types (Boliar et al, 2019)
The use of antiretroviral therapy has succeeded in reducing HIV-1 mortality but cannot eliminate the virus due to the persistent and stable LR
Summary
Infection with human immunodeficiency virus type-1 (HIV-1) requires life-long adherence to antiretroviral therapy (ART) due to the presence of latently infected cells that are central to viral persistence and rebound viremia following ART interruption (Chun et al, 1997, 1998, 1999; Finzi et al, 1997; Perelson et al, 1997; Wong et al, 1997; Davey et al, 1999; Rosenbloom et al, 2017). An effective cure for HIV-1 infection has been achieved twice via CCR5 32/ 32 hematopoietic stem cell transplantation and in both cases latently infected cells were eliminated and replaced with HIV-1 resistant donor cells (Hutter et al, 2009; Gupta et al, 2019) Whilst this method is not feasible for widespread use, its repeated success proves the principle that HIV-1 cure strategies must either eliminate (sterilizing cure) or silence (functional cure) the LR. Proposed cure strategies such as “shock and kill” aim to eliminate the LR by utilizing latency reversing agents (LRAs) during ART mediated virus suppression to drive expression of HIV1 from latently infected cells, exposing those cells to viral cytopathic effects or immune clearance whilst limiting de novo infections (Deeks, 2012). We will focus on the mechanisms that facilitate the establishment and maintenance of the HIV-1 LR, some of the prominent methods proposed to achieve a cure and the developments and challenges on the way to measuring their success
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