Block-And-Lock Strategies to Cure HIV Infection

Abstract

Today HIV infection cannot be cured due to the presence of a reservoir of latently infected cells inducing a viral rebound upon treatment interruption. Hence, the latent reservoir is considered as the major barrier for an HIV cure. So far, efforts to completely eradicate the reservoir via a shock-and-kill approach have proven difficult and unsuccessful. Therefore, more research has been done recently on an alternative block-and-lock functional cure strategy. In contrast to the shock-and-kill strategy that aims to eradicate the entire reservoir, block-and-lock aims to permanently silence all proviruses, even after treatment interruption. HIV silencing can be achieved by targeting different factors of the transcription machinery. In this review, we first describe the underlying mechanisms of HIV transcription and silencing. Next, we give an overview of the different block-and-lock strategies under investigation.

Silencing integrated SIV proviral DNA with TAR‐specific CRISPR tools

“…This work is part of a larger project aimed at developing a translatable, proof‐of‐concept cure strategy for HIV that utilizes highly specific CRISPR/dead Cas9 reagents to inactivate virus replication in both latently and actively infected cells using a “block and lock” approach, whereby viral transcription is “blocked,” “locking” proviruses in deep latency 1,2 . Here, we target a critical step in HIV transcription, that is, the interaction of the Tat protein with the TAR element in the nascent viral RNA.…”

“…However, cART does not affect the reservoir of latently infected cells, which is not sensitive to antivirals and not detected by the immune system, leading in most cases to virus rebound from this reservoir when therapy is interrupted. One strategy to potentially achieve a functional cure is the “block and lock” approach, which aims at locking out proviruses in a deep latency that prevents viral reactivation by inhibiting viral transcription 1,2 . thereby suppressing the residual viremia arising from reactivation of latently infected cells.…”

A Computational Approach for the Prediction of Treatment History and the Effectiveness or Failure of Antiretroviral Therapy

“…Contemporary research studies focus on the investigation of both HIV-1 and host factors to develop vaccines against HIV-1, which may represent the basis for the novel therapeutic approaches [4,5,33]. While developing new strategies of treatment can be beneficial for HIV-1 prevention and cure, antiretroviral treatment is still used worldwide, so the approaches leading to its optimization still can have an impact on the improvement of HIV-1 therapy strategies.…”

“…These two factors lead to a high mutation rate of HIV-1 [3]. Currently, the role of multiple HIV-1 proteins in HIV-1/AIDS disease pathogenesis and progression is under investigation, including the role of its structural proteins, as well as HIV-1 trans-activator of transcription (tat) protein [4,5]. These studies are essential because they might have an impact on the development of HIV-1 vaccines and novel therapeutic approaches (such as, for instance, "block-and-lock strategies").…”

“…ATV, Atazanavir; APV, Amprenavir; DRV, Darunavir; FPV, Fosamprenavir; IDV, Indinavir; LPV, Lopinavir; NFV, Nelfinavir; RTV, Ritonavir, SQV, Saquinavir; TPV, Tipranavir; 2 period of drug exposure: weeks, average (standard deviation) 3 AUC/ROC: area under the ROC curve obtained in leave-one-out cross-validation (LOO CV); AUC/ROC 20 , area under the ROC curve obtained in fivefold CV;4 HIV-1 PR inhibitors were taken in combination with other antiretroviral drug(s); 5 N/A data are not available.…”