HIV persistence in tissues on dolutegravir-based therapy is not associated with resistance mutations to dolutegravir

Relatively few studies have investigated HIV-1 persistence in tissues, especially in healthy people-living-with-HIV-1 (PLWH) on a successful antiretroviral regimen containing second generation integrase inhibitors.

In the ANRS EP64 DOLUVOIR, we explore HIV-1 persistence in five accessible anatomical sites in 20 PLWH on an efficient first-line ART regimen containing dolutegravir with virological load <50 copies/mL: PBMCs, rectum, adipose tissue, lymph node and sperm. We quantify total HIV-DNA and cell-associated HIV-1 RNA in different compartments. We sequence HIV-1 DNA for searching drug resistance mutations (DRM) (in RT and INT) and for studying HIV diversity within tissues (ENV). Intact proviral DNA is estimated in PBMCs with an adapted IPDA assay.

Broad ranges of total HIV-DNA and transcripts levels are detected in lymph nodes, PBMCs, adipose tissue and rectum with the highest levels being found in lymph nodes (2.77 log copies HIV-1-DNA/10⁶ cells and 1.50 log copies of HIV-1 cell-associated-RNA/µg RNA). HIV-1 DNA is undetected in all sperm samples (n = 19) except for one (1.52 log copies HIV-1-DNA/106 cells). No difference is noted between the diversity in the four compartments. DRMs to the current regimen are found archived in compartments of six participants. Only two major DRMs to dolutegravir (G118R and R263K) are found archived in two participants. They are the results of APOBEC hypermutations.

Despite ongoing transcriptional activity, persistence of HIV-1 in deep tissues is not associated with the selection of DRMs to dolutegravir on intact proviruses. Our results suggest that the detectable transcriptional activity stems predominantly from defective proviral DNA.