Genetically Intact but Functionally Impaired HIV-1 Env Glycoproteins in the T-Cell Reservoir

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Antiretroviral therapy (ART) controls HIV infection but does not eradicate the persistent viral reservoir in resting CD4+ T cells.
• HIV resurgence after ART interruption originates from this reservoir, which contains mostly defective or poorly infectious viral genomes.
• Understanding the functional capacity of intact proviruses within the reservoir is crucial for explaining HIV persistence.

Purpose of the Study:

• To investigate the function and expression of HIV envelope glycoproteins (Env) from the viral reservoir in individuals on suppressive ART.
• To determine the impact of Env defects on viral infectivity and fusogenicity.
• To elucidate the mechanisms contributing to the persistence of intact HIV in the T-cell reservoir.

Main Methods:

• Analysis of full-length, genetically intact HIV env sequences from replicative viruses and cell-associated mRNAs in four HIV-infected subjects on ART.
• Assessment of Env protein fusogenicity and infectivity.
• Evaluation of Env protein expression levels.

Main Results:

• HIV Env proteins from the reservoir exhibited extensive variation in fusogenicity and infectivity.
• Strongest functional defects were observed in Env proteins derived from cell-associated mRNAs.
• Impaired Env function was primarily attributed to defects in Env protein expression.

Conclusions:

• Defects in HIV Env expression significantly impair viral infectivity and fusogenicity, contributing to reservoir persistence.
• Impaired Env function may prevent effective viral clearance, allowing infected cells to evade immune or cytopathic mechanisms.
• These findings highlight a key mechanism maintaining the latent HIV reservoir despite effective antiretroviral therapy.