Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• The role of CD4 T cell turnover in HIV persistence during antiretroviral therapy (ART) remains unclear.
• Understanding these dynamics is crucial for developing strategies to eradicate HIV reservoirs.

Purpose of the Study:

• To investigate the precise role of CD4 T cell turnover in maintaining HIV persistence under ART.
• To quantify HIV reservoir size and clonality in relation to CD4 T cell dynamics.

Main Methods:

• Directly measured CD4 T cell turnover using heavy water labeling in ART-suppressed HIV-infected and HIV-uninfected individuals.
• Assessed HIV reservoir size via integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA).
• Analyzed HIV reservoir clonality using proviral integration site sequencing.

Main Results:

• ART-suppressed individuals showed similar fractional CD4 T cell replacement rates but lower absolute proliferation rates (except TEM cells) and reduced plasma IL-7 levels compared to HIV-negatives.
• CD4 T cell half-lives decreased with differentiation from naive to effector memory (TEM) cells (3 years to 3 months).
• TEM cells exhibited the fastest replacement rates, highest enrichment of intDNA and caRNA, and most clonal proviral expansion, with evidence of maintenance through cell differentiation.

Conclusions:

• Circulating integrated HIV proviruses are maintained by both slow turnover of immature CD4 subpopulations and clonal expansion/differentiation into effector cells.
• Earlier ART initiation is associated with reduced intDNA, caRNA, and fractional replacement rates, suggesting a benefit in limiting viral persistence.