Nature Communications Mol Virol 2019

Molecular Virology Publish in mBio, Journal of the American Society for Microbiology

In a recent study, the Molecular Virology Group uncovers a critical step to purge latently infected cells that constitute the major barrier to a cure for HIV-1 infection.

The life cycle of HIV-1 requires integration of a DNA copy into the genome of the host cell. Transcription of the viral genes generates RNAs that are exported to the cytoplasm with the contribution of viral and cellular factors to be translated or incorporated in the newly synthesised virions. It has been observed that highly effective antiretroviral therapy, which is able to reduce circulating virus to undetectable levels, cannot fully eradicate the virus from cellular reservoirs that harbor a transcriptionally latent provirus. Thus, persistence of latently infected cells is the major barrier to a cure for HIV-1 infection.

In order to purge these reservoirs of latently infected cells it has been proposed to activate transcription to stimulate the virus to complete its life cycle. This strategy – called “shock-and-kill” – aims at unmasking these reservoirs, making them vulnerable to the immune system. However, the limited success of the approach so far may indicate the additional posttranscriptional restrictions that need to be overcome for full virus reactivation. In this paper the Group identify the cellular protein MATR3 as an essential cofactor of viral RNA processing.

Reactivation of HIV-1 transcription per se is not sufficient to allow completion of a full life cycle, which depends on MATR3 expression. MATR3 is poorly expressed in quiescent CD4+ T lymphocytes that are the major reservoir of latent HIV-1. Cells derived from aviremic HIV-1 patients under antiretroviral therapy didn’t express MATR3, and most importantly, latency-reversing agents proposed for the rescue of latent provirus were ineffective for MATR3 upregulation. To conclude, the work identifies a cellular factor required for full HIV-1 reactivation and points to the revision of the current strategies for purging viral reservoirs that focus only on transcription.

Full HIV-1 reactivation from latency requires transcriptional and post-transcriptional steps. Current latency revsing agents (LRA) used in “shock-and-kill” approaches require postrancriptional steps for the host cofactor MATR3 to fully reactivate HIV-1

PubMed link: This article is Open Source
Sarracino AGharu LKula A2Pasternak AO4Avettand-Fenoel V5Rouzioux CBardina M1De Wit S6Benkirane M7Berkhout B4Van Lint C2Marcello A
Posttranscriptional Regulation of HIV-1 Gene Expression during Replication and Reactivation from Latency by Nuclear Matrix Protein MATR3
mBio Nov 2018, 9 (6) e02158-18; DOI: 10.1128/mBio.02158-18