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.

Keywords: HIV; block-and-lock; cure; latency.

Figure 1

The HIV LTR promoter in active and latent state. (a) HIV Tat induces active transcription by binding the TAR RNA element in the LTR promoter and recruiting several transcription activating proteins. P-TEFb releases and activates RNAPII by CDK9-mediated phosphorylation. PBAF ensures open nucleosome-free chromatin. NF-κB and other transcription factors as NFAT, LEF-1 and SP-1 bind to the HIV LTR. An active chromatin landscape is maintained by histone methyl transferases (HMT) and histone acetyl transferases (HAT). (b) In latent cells, HIV transcription is inhibited by multiple mechanisms. Several proteins required for effective transcription are sequestered in an inactive state. For instance RNAPII is sequestered by DSIF and NELF, NF-κB by IκB, and P-TEFb by 7SK snRNP and HEXIM1. Furthermore, transcriptional repressors as LSF, YY1 and CBF bind the LTR promoter. A repressive chromatin landscape is formed by HMT, histone deacetylases (HDAC) and DNA methyl transferases (DNMT). Finally, BAF positions Nuc-1 downstream of the TSS, inhibiting transcription elongation. Tat; transactivator of transcription, TAR; transactivation response RNA, P-TEFb; positive transcription elongation factor b, RNAPII; RNA polymerase II, CDK9; cyclin dependent kinase 9, PBAF; polybromo-associated BAF, NF-κB; nuclear factor kappa b, NFAT; nuclear factor of activated cells, LEF-1; lymphoid enhancer-binding factor 1, SP-1; specificity protein 1, HMT; histone methyl transferase, HAT; histone acetyl transferase, DSIF; DRB sensitivity inducing factor, NELF; negative elongation factor, IκB; inhibitors of NF-κB, 7SK snRNP; 7SK small nuclear RNA, HEXIM-1; Hexamethylene bisacetamide-induced protein, LSF; late SV40 factor, YY1; yin yang 1, CBF; C-promoter binding factor, LTR; long terminal repeat, HDAC; histone deacetylase, DNMT; DNA methyl transferase, BAF; BRG-associated factor, Nuc-1; nucleosome 1, TSS; transcription start site. Green symbols represent factors promoting active transcription, while red symbols are transcriptional repressors.