Background
It remains unclear how HIV transcription varies with timing of ART initiation, duration of ART, and elite controller status.
Methods
To investigate these questions, we performed a blinded, cross-sectional analysis of 98 PBMC samples from 36 Reservoir Assay Validation and Evaluation Network (RAVEN) program participants, including 4 ART-naïve elite controllers and 32 ART-suppressed participants with HIV (PWH) stratified by timing of ART start (16 early, 16 chronic) and duration of ART suppression (10 short, 8 intermediate, 14 long). Cell associated (CA) initiated (TAR), 5’-elongated (R-U5-pre-Gag), mid-elongated (Pol), distal (Nef), completed (PolyA), and multiply spliced (Tat-Rev) HIV-1 RNAs were measured by RT-ddPCR and normalized to cellular transcription and HIV DNA.
Results
No differences were observed between the early and chronic treated PWH in CD4+ or CD8+T cell counts, HIV DNA, or plasma viral load (VL) on ART. Compared to early and chronic treated PWH, elite controllers tended to have higher CD8+T cell counts (P=0.0008 and 0.064, respectively), lower HIV DNA (P=0.076, 0.014), and higher VL (P=0.0072, 0.0031). In a cross-sectional analysis of all ART-treated PWH, VL was higher in the short and intermediate compared to long ART duration groups (P=0.0044, 0.042), while we did not detect significant differences in CA HIV RNA. Compared to chronic treated PWH, early treated PWH had lower levels of initiated HIV RNA (median 560 vs. 2348 copies/ug; P=0.029) and 5’ elongated HIV RNA (median 14 vs. 50 copies/ug; P=0.0058) and tended to have lower levels of multiply spliced HIV RNA (P=0.062). These findings persisted after normalization to HIV DNA, with lower levels of initiated HIV RNA per provirus (P=0.054) and 5’ elongated HIV RNA per provirus (P=0.049) in early treated PWH. Compared to chronic treated PWH, elite controllers also tended to have lower levels of initiated HIV RNA (P=0.064) and had lower levels of 5’ elongated HIV RNA (P=0.0029), but these differences disappeared or reversed after normalization to HIV DNA.
Conclusions
Elite control was associated with lower infection frequencies but no decrease in HIV transcription per provirus. Early ART start was associated with lower levels of HIV transcriptional initiation but no differences in VL, while increasing duration of ART was associated with lower VL but no detectable changes in CA HIV RNA. Future studies towards HIV-1 cure should target the immune mechanisms that likely underlie these differences.