Background
While early ART initiation has been associated with smaller HIV reservoirs, it is not clear how the timing of ART initiation affects subsets of the “active” HIV-transcribing reservoir.
Methods
We compared temporal changes in various proviruses and HIV transcripts in CD4+T cells isolated from longitudinal blood samples obtained before ART (T1) and at two time points on suppressive ART (T2, T3) from 11 acute-treated PWH (median T2=119 days; T3=295 days) and 10 chronic-treated PWH (median T2=790 days; T3=1641 days). Initiated (TAR), 5’-elongated (R-U5-pre-Gag), mid-elongated (Pol), distal (Nef), completed (PolyA), and multiply spliced (Tat-Rev) HIV RNAs were measured by RT-ddPCR, normalized to cellular transcription and the corresponding HIV DNA levels, and expressed as the change in HIV levels divided by the change in time.
Results
During untreated infection (T1), the acute cohort tended to have higher levels of some HIV DNA regions (P=0.02 for TAR; P=0.07 for Pol) and HIV transcripts (P=0.003 for Pol; median 1296 vs 56 copies/ug; P=0.07 for initiated and P=0.08 for completed RNA). After normalization to HIV DNA, however, the acute cohort showed no difference in elongated, Pol, or completed HIV RNA/DNA and a trend toward lower initiated HIV RNA/DNA (P=0.08). By the first timepoint after ART suppression (T2), levels of multiply spliced HIV RNA were lower in the acute than chronic-treated PWH (P=0.012; median 0 vs. 2.8 copies/ug), while we did not detect differences in other HIV RNA or RNA/DNA levels. From T1 to T2, the decrease in HIV per unit time was greater in the acute than chronic cohort for all HIV DNA regions (all P<0.05) and most HIV transcripts (all P<0.05, except P=0.07 for multiply spliced HIV RNA). The ratio of completed HIV RNA/DNA also tended to decay faster in the acute cohort (P=0.06), while no difference was observed for initiated, elongated, or Pol HIV RNA/DNA.
Conclusions
Levels of TAR HIV DNA and Pol HIV RNA were higher in acute than chronic infection, but paradoxically, HIV transcription initiation tended to be lower in acute infection. After ART, acute-treated PWH showed faster declines in all HIV DNA regions and most HIV transcripts, as well as a trend towards faster decline in completed HIV RNA per provirus. These findings suggest that acute treatment preserves immune responses that are both better at killing infected cells and selectively reducing those that transcribe completed HIV transcripts.
Table or Figure
