Background:
The gut is a major target for HIV-1 replication and persistence. Tissue-resident memory (TRM) cells play a crucial role in mucosal immunity but this cell population could be affected by HIV-1 replication in mucosa. Their depletion may contribute to a persistent imbalance in mucosal homeostasis and the persistence of HIV-1 in the gut on ART.
Methods:
42 virologically suppressed people living with HIV-1 (PLWH) and 42 uninfected controls were recruited in the ANRS EP61 GALT study. Duodenal, ileal, and colonic biopsies and blood samples were obtained. The frequency and activation/exhaustion phenotype of intestinal-TRM cells was assessed by FACS. Total HIV-1 DNA and residual HIV-1 RNA were quantified in gut samples, and the genetic complexity of HIV-1 quasispecies was assessed by single-molecule real-time next-generation sequencing of env. Recirculating intestinal-TRM cells were defined as CD103+β7hiCD8+ T cells in peripheral blood. The frequency of HIV-1-specific CD8+ T cells among recirculating TRM cells was assessed in 15 PLWH after stimulation with HIV-1 peptide pools and measurement of IFNγ production, degranulation (CD107a), and cell proliferation (CFSE).
Results:
CD4+ and CD8+ TRM cells were significantly depleted in the colonic mucosa of PLWH versus uninfected controls (P=0.015 and P=0.006 for CD4+ and CD8+ TRM cells, respectively), and their frequency correlated negatively with CD4 nadir (ρ=0.41, P=0.020 and ρ=0.37, P=0.037 for CD4+ and CD8+ TRM cells, respectively). TRM cells express overall lower levels of PD-1, TIGIT, KLRG1 and CD57 than non-TRM cells in all 3 gut segments, but levels are highest in the colon. CD4+ and CD8+ TRM cell frequencies were negatively associated with total HIV-1 DNA and residual HIV-1 RNA, while non-TRM cells were associated with quasispecies genetic complexity (Figure). Recirculating CD8+ TRM cells were enriched in HIV-1-specific T cells (P<0.01 for IFNγ+, CD107a+, and CFSEdim cells in recirculating TRM vs total CD8+ T cells).
Conclusions:
The frequencies of CD4+ and CD8+ TRM cells remained reduced in PLWH on ART, particularly in the colon. Irreversible damage may have been inflicted on these cell populations prior to initiation of ART. The loss of these cells could promote the persistence of HIV-1 in the colon. Enrichment of HIV-1-specific cells in recirculating TRM supports persistent antigenic stimulation by HIV-1 antigens in the gut mucosa of PLWH on suppressive ART.
