Nonsuppressible viremia during HIV-1 therapy meets molecular virology

TL;DR

This study uncovers the molecular mechanisms behind nonsuppressible viremia in HIV-1 patients, revealing how specific proviral mutations lead to noninfectious virus production despite ART adherence.

Contribution

It identifies mutations in the HIV-1 5'-leader region that cause nonsuppressible viremia by producing noninfectious virus particles, advancing understanding of viral regulation.

Findings

Mutations in the 5'-leader affect RNA splicing and packaging.

Nonsuppressible viremia involves production of noninfectious virus particles.

Mutant viruses lack Env protein and mature capsid, explaining infectivity failure.

Abstract

HIV-1 replication can be suppressed with antiretroviral therapy (ART), but individuals who stop taking ART soon become viremic again. Some people experience extended times of detectable viremia despite optimal adherence to ART. In the issue of the JCI, White, Wu, and coauthors elucidate a source of nonsuppressible viremia (NSV) in treatment-adherent patients clonally expanded T cells harboring HIV-1 proviruses with small deletions or mutations in the 5'-leader, the UTR that includes the major splice donor site of viral RNA. These mutations altered viral RNA-splicing efficiency and RNA dimerization and packaging, yet still allowed production of detectable levels of noninfectious virus particles. These particles lacked the HIV-1 Env surface protein required for cell entry and failed to form the mature capsid cone required for infectivity. These studies improve our understanding of NSV and the regulation of viral functions in the 5'-leader with implications for rationalized care in individuals with NSV.