Measuring the Success of HIV-1 Cure Strategies

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.

Editing of the TRIM5 Gene Decreases the Permissiveness of Human T Lymphocytic Cells to HIV-1

“…Despite an increased focus from the HIV-1 research community on cure research in recent years [ 67 ], aiming in particular at eliminating latent reservoirs [ 3 ], we are still far from a sterilizing or functional cure. Similarly, and despite some recent conceptual advances such as novel strategies to elicit the production of broadly neutralizing antibodies [ 68 ], vaccine prospects remain seemingly out of reach [ 69 , 70 ]. The field of HIV-1 drug research continues to show impressive progress, such as the ongoing emergence of long-acting antiviral drugs [ 71 ] and of the HIV-1 capsid protein as a novel drug target [ 72 ].…”

Editing of the TRIM5 gene decreases the permissiveness of human T lymphocytic cells to HIV-1

“…Despite an increased focus from the HIV-1 research community on cure research in recent years [67], aiming in particular at eliminating latent reservoirs [3], we are still far from a sterilizing or functional cure. Similarly, and despite some recent conceptual advances such as novel strategies to elicit the production of broadly-neutralizing antibodies [68], vaccine prospects remain seemingly out of reach [69,70]. The field of HIV-1 drug research continues to show impressive progresses, such as the ongoing emergence of long-acting antiviral drugs [71] and of the HIV-1 capsid protein as a novel drug target [72].…”

HCMV Antivirals and Strategies to Target the Latent Reservoir

“…The immune system would then be able to recognise and clear these otherwise latently infected cells. This strategy, termed ‘shock and kill’, is also being widely investigated as a therapeutic tool to target HIV-1 latency [ 88 , 89 ]. In essence, epigenetic modifiers have been used to reactivate HIV-1 gene expression in latently infected cells to allow them to be targeted by pre-existing or newly induced HIV-1 specific immune responses.…”