Block and Lock HIV Cure Strategies to Control the Latent Reservoir

Abstract

The HIV latent reservoir represents the major challenge to cure development. Residing in resting CD4+ T cells and myeloid cells at multiple locations in the body, including sanctuary sites such as the brain, the latent reservoir is not eliminated by ART and has the ability to reactivate virus replication to pre-therapy levels when ART is ceased. There are four broad areas of HIV cure research. The only successful cure strategy, thus far, is stem cell transplantation using naturally HIV resistant CCR5 32 stem cells. A second potential cure approach uses gene editing technology, such as zinc-finger nucleases and CRISPR/Cas9. Another two cure strategies aim to control the HIV reservoir, with polar opposite concepts; The "shock and kill" approach, which aims to "shock" or reactivate the latent virus and then "kill" infected cells via targeted immune responses. Lastly, the "block and lock" approach, which aims to enhance the latent virus state by "blocking" HIV transcription and "locking" the HIV promoter in a deep latent state via epigenetic modifications. "Shock and kill" approaches are a major focus of cure studies, however we predict that the increased specificity of "block and lock" approaches will be required for the successful development of a sustained HIV clinical remission in the absence of ART. This review focuses on the current research of novel "block and lock" approaches being explored to generate an HIV cure via induction of epigenetic silencing. We will also discuss potential future therapeutic delivery and the challenges associated with progressing "block and lock" cure approaches as these move toward clinical trials.

NF-κB sub-pathways and HIV cure: A revisit

“…“block and lock” and “shock and kill”, have been proposed for a cure of HIV. The “block and lock” strategy aims to suppress HIV transcriptional machinery to induce a deep silent state, followed by anticipated epigenetic modifications of HIV promoter for induction of a permanently silent transcriptional state so that viral rebound cannot occur or is significantly delayed if ART is ceased [ 16 , 5 , 17 ]. It is not known whether deep latency can be achieved and whether provirus integration sites impact the induction of deep latency as interestingly observed in the elite controllers [18] .…”

Clinical Manifestations and Epigenetic Regulation of Oral Herpesvirus Infections

“…In the “shock and kill” paradigm, HIV-infected cells are treated with histone deacetylase, DNA methyltransferase and/or histone methyltransferase inhibitors to induce reactivation of the virus from latency, which makes the infected cells and the virus visible for the immune system to eliminate the latent viral pools [ 17 , 172 , 173 ]. Alternatively, the “block and lock” paradigm aims to push latent HIV reservoirs into tight latency through inhibition of Tat-dependent transcription [ 17 , 174 ]. Epigenetic drugs have also been tested in the context of other chronic viral infections, such as in the use of bromodomain and extra-terminal domain (BET) inhibitors to target HPV and herpesvirus infections [ 175 , 176 ].…”

Microglia: The Real Foe in HIV-1-Associated Neurocognitive Disorders?

“…On the contrary, the use of TLR antagonists such as chloroquine is thought to lower immune activation. Treatments with hydroxychloroquine or chloroquine have been evaluated in the clinical setting in ART-treated [ 139 ] and ART-naïve patients [ 139 ] and was reported to reduce immune activation, albeit with little or no effect on CD4 + T cell recovery. However, in a randomized trial in naïve, non-progressing patients, hydroxychloroquine treatment resulted in the worsening of CD4 + T cell loss [ 140 ].…”