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Review
. 2024 May 1;19(3):124-132.
doi: 10.1097/COH.0000000000000849. Epub 2024 Mar 12.

Persistent HIV-1 transcription during ART: time to reassess its significance?

Céline Fombellida-Lopez  1   2 , Ben Berkhout  1 , Gilles Darcis  2   3 , Alexander O Pasternak  1
Affiliations
Review

Persistent HIV-1 transcription during ART: time to reassess its significance?

Céline Fombellida-Lopez et al. Curr Opin HIV AIDS. .

Abstract

Purpose of review: Despite suppressive antiretroviral therapy (ART), HIV-1 reservoirs persist and reignite viral replication if therapy is interrupted. Persistence of the viral reservoir in people with HIV-1 (PWH) is the main obstacle to an HIV-1 cure. The reservoirs are not transcriptionally silent, and viral transcripts can be detected in most ART-treated individuals. Here, we review the recent progress in the characterization of persistent HIV-1 transcription during ART.

Recent findings: Evidence from several studies indicates that, although cell-associated unspliced (US) HIV-1 RNA is abundantly expressed in ART-treated PWH, intact full-length US transcripts are rare and most US RNA is derived from defective proviruses. The transcription- and translation-competent defective proviruses, previously considered irrelevant, are increasingly being linked to residual HIV-1 pathogenesis under suppressive ART. Recent data suggest a continuous crosstalk between the residual HIV-1 activity under ART and the immune system. Persistent HIV-1 transcription on ART, despite being mostly derived from defective proviruses, predicts viral rebound upon therapy interruption, suggesting its role as an indicator of the strength of the host antiviral immune response that is shaping the viral rebound.

Summary: In light of the recent findings, the significance of persistent HIV-1 transcription during ART for the long-term health of PWH and the cure research should be reassessed.

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Conflict of interest statement

There are no conflicts of interest.

Figures

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FIGURE 1
FIGURE 1
A simplified schematic representation of HIV-1 splicing. Upper panels: HIV-1 open reading frames. Lower panels: the main representatives of unspliced, incompletely spliced, and multiply spliced HIV-1 RNA classes. Gag and Pol proteins are expressed from the 9 kb unspliced RNA. The other HIV-1 proteins are expressed from either incompletely (Vif, Vpr, Env, and Vpu) or multiply (Tat, Rev, and Nef) spliced RNAs. Rev response element (RRE) is present in unspliced and incompletely spliced RNAs but not in multiply spliced RNAs. Exons are shown by bars and introns by dashed lines. (Figure adapted from [37]; reproduced with permission from Elsevier.).
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