HIV-1 transcriptional modulation: novel host factors and prospective therapeutic strategies

Abstract

Purpose of review This review highlights advances in HIV transcription and epigenetic latency mechanisms and outlines current therapeutic approaches to eliminate or block the HIV-1 latent reservoir. Recent findings Novel host factors have been reported to modulate HIV-1 transcription and latency. Chromatin affinity purification strategies followed by mass spectrometry (ChAP-MS) identified the chaperone protein p32 to play an important role in HIV-1 transcriptional regulation via interactions with the viral transcriptional activator Tat. Similarly, an shRNA screen identified the methyltransferase SMYD5 contributing to HIV-1 transcriptional activation also by modulating Tat activity. These new factors, among others, represent potential druggable targets that could be explored in the ‘block-and-lock’ or ‘shock-and-kill’ approaches. Summary The HIV-1 latent reservoir is established early after infection, persists during antiretroviral therapy, and is the source of viral rebound after treatment interruption. An HIV cure requires either eliminating this reservoir or blocking latent proviral reactivation in the absence of antiretroviral therapy (ART). Understanding the mechanisms and key-players modulating HIV transcriptional and reactivation may facilitate therapeutic advancements. Here we summarize, the latest findings on host factors’ roles in HIV transcriptional regulation.

Chronic HIV Transcription, Translation, and Persistent Inflammation

“…HIV-1 transcriptional regulation and chronic expression of HIV RNAs. The combinatorial mechanisms that contribute to HIV-1 transcription and latency have been extensively studied and reviewed [85][86][87][88]. Briefly, the 5 ′ long terminal repeat (LTR) functions as an enhancer and promoter that recruits host cell transcription factors, chromatin remodeling complexes and RNAP II to initiate transcription.…”

“…Transcription elongation is facilitated by the viral factor Tat, which binds an RNA stem loop structure, TAR, at the 5 ′ end of the initiated transcript and recruits the P-TEFb complex to enhance RNAP II activity [89][90][91]. Epigenetic regulation, the recruitment of repressive transcription complexes, the lack of transcriptional activators, limited RNAP II activity, and promoter interference are some of the mechanisms that contribute to latency [85][86][87][88]92]. However, much of the persistent proviral sequences found in PWH on ART are defective, harboring mutations that alter LTR function, major splice donor sequences and the psi packaging element [16,17,88,93].…”

HIV-1 Proviral Genome Engineering with CRISPR-Cas9 for Mechanistic Studies

“…The binding of these TFs to their cognate cis-elements at the provirus facilitates several steps in the transcriptional program, leading to latency reactivation through the action of RNA Polymerase II (Pol II) and co-activators, such as the P-TEFb kinase. Upon recruitment to the HIV-1 promoter [20][21][22][23], P-TEFb phosphorylates Pol II and factors that stabilize Pol II pausing [24][25][26][27][28], to facilitate Pol II pause release, which is as a key rate-limiting step for the early induction of HIV-1 transcription [27,[29][30][31][32]. During the host phase, Tat is expressed, which promotes the transition to the viral phase for robust HIV-1 gene transcription (Figure 1).…”

HIV-1 Transcription and Latency in the Spotlight

“…Thus, we felt the time was right to have an updated overview of the field, with a focus on recent discoveries and future research ideas. The need for these updates is further justified by the increasing recognition that both viral and host factors could be valid targets of pharmacological interventions for either permanent silencing or reactivation from latency for the elimination of reservoir cells [ 5 ].…”