Journal Article

Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy

O’Doherty, Una, Rehm, Catherine A., Adelsberger, Joseph W., Paxinos, Ellen E., Fauci, Anthony S., Lane, H. Clifford, Imamichi, Hiromi, Dewar, Robin L.

2016

Overview

Despite years of plasma HIV-RNA levels <40 copies per milliliter during combination antiretroviral therapy (cART), the majority of HIV-infected patients exhibit persistent seropositivity to HIV-1 and evidence of immune activation. These patients also show persistence of proviruses of HIV-1 in circulating peripheral blood mononuclear cells. Many of these proviruses have been characterized as defective and thus thought to contribute little to HIV-1 pathogenesis. By combining 5′LTR-to-3′LTR single-genome amplification and direct amplicon sequencing, we have identified the presence of “defective” proviruses capable of transcribing novel unspliced HIV-RNA (usHIV-RNA) species in patients at all stages of HIV-1 infection. Although these novel usHIV-RNA transcripts had exon structures that were different from those of the known spliced HIV-RNA variants, they maintained translationally competent ORFs, involving elements of gag, pol, env, rev, and nef to encode a series of novel HIV-1 chimeric proteins. These novel usHIV-RNAs were detected in five of five patients, including four of four patients with prolonged viral suppression of HIV-RNA levels <40 copies per milliliter for more than 6 y. Our findings suggest that the persistent defective proviruses of HIV-1 are not “silent,” but rather may contribute to HIV-1 pathogenesis by stimulating host-defense pathways that target foreign nucleic acids and proteins.

• Publisher: National Academy of Sciences
• Subject: Anti-Retroviral Agents - therapeutic use / Antiretroviral agents / Antiretroviral drugs / Biological Sciences / Cells / DNA, Viral - genetics / DNA, Viral - metabolism / Gene Expression Regulation, Viral / HIV / HIV Infections - drug therapy / HIV Infections - virology / HIV-1 - drug effects / HIV-1 - genetics / HIV-1 - physiology / Human immunodeficiency virus / Human immunodeficiency virus 1 / Humans / Lentivirus / Leukocytes, Mononuclear - virology / Medical Sciences / Nucleic acids / Pathogenesis / Proteins / Proviruses - drug effects / Proviruses - genetics / Ribonucleic acid / RNA / RNA, Viral - genetics / RNA, Viral - metabolism / Viral Proteins - genetics / Viral Proteins - metabolism