HIV-1 adaptation to low levels of CCR5 results in V3 and V2 loop changes that increase envelope pathogenicity, CCR5...

Area of Science:

• Virology
• Immunology
• Genetics

Background:

• Cell surface CCR5 levels influence human immunodeficiency virus (HIV) evolution, fitness, and disease progression.
• Previous studies showed CCR5 levels affect HIV Envelope-mediated bystander apoptosis.

Purpose of the Study:

• To investigate HIV-1 evolution under conditions of limited CCR5 expression, mimicking host variability.
• To identify specific viral mutations and their functional consequences.

Main Methods:

• HIV-1 adaptation in a T cell line with low CCR5 expression.
• Genomic sequencing to identify mutations.
• Assays to measure virus replication, Maraviroc (MVC) susceptibility, and bystander apoptosis.

Main Results:

• HIV-1 adaptation yielded two key mutations: N302Y and E172K.
• The N302Y mutation accelerated viral replication and increased MVC IC50.
• N302Y also enhanced Envelope-mediated bystander apoptosis in low CCR5 cells and was over-represented in CXCR4-tropic viruses.

Conclusions:

• HIV-1 can adapt to limited CCR5, leading to mutations that enhance viral fitness and alter drug susceptibility.
• The N302Y mutation is a significant finding with implications for HIV pathogenesis and MVC treatment.
• Understanding CCR5 variability is crucial for predicting HIV evolution and treatment outcomes.