Background
While prior studies have reported that a smaller and less active HIV reservoir is associated with delayed HIV rebound, it is unclear how these findings extend to the different CD4 cell subsets of the HIV reservoir. We evaluated HIV characteristics within CD4 cell subsets of participants in a prospective analytic treatment interruption (ATI) study.
Methods
A5345 enrolled individuals with HIV who initiated ART either during chronic or early HIV infection and were virally suppressed pre-ATI. Participants were categorized as early (≤3 weeks) or delayed rebounders (≥4 weeks) based on time to confirmed HIV RNA ≥1000 copies/mL during an ATI. Eight participants from each rebound group were included (3 early-treated and 5 chronic-treated per group). Pre-ATI CD4 T cells were sorted by flow cytometry into four subsets for quantification of cell-associated unspliced HIV RNA (CA-RNA) and total DNA (CA-DNA): naïve (Tn), central memory (Tcm), transitional memory (Ttm), and effector memory (Tem). Wilcoxon rank-sum and paired tests were used to evaluate statistical significance.
Results
The median time to viral rebound was 2.6 weeks for the early rebounders and 5.9 weeks for the delayed rebounders. We found that delayed HIV rebounders had numerically lower levels of CA-RNA and CA-DNA across all CD4 T cell compartments. In particular, delayed rebounders had significantly lower CA-DNA levels in the Ttm compartment compared to early rebounders (delayed vs early rebounders: median 66 vs 650 copies/10^6 cells, p=0.02). Within the different CD4 T cell compartments, levels of CA-RNA and CA-DNA were lowest in the Tn compartment (median RNA and DNA 50 copies/10^6 cells) compared to those found in the Tcm (median RNA and DNA 444 and 101 copies/10^6 cells), Ttm (median RNA and DNA 409 and 98 copies/10^6 cells) and Tem (median RNA and DNA 658 and 223 copies/10^6 cells) compartments. We also evaluated levels of relative HIV transcriptional activity by the CA-RNA/CA-DNA ratio and found that delayed viral rebounders had a significantly lower CA-RNA/CA-DNA ratio in Tn cells compared to early rebounders (delayed vs early: median 1 vs 1.1, p=0.02).
Conclusions
In the A5345 prospective treatment interruption trial, delayed viral rebounders had lower levels of pre-ATI intracellular HIV RNA and DNA across CD4 cell compartments. These results provide further evidence that the size and activity of the viral reservoir across CD4 cell subsets may influence the timing of viral rebound.