Immune tolerance properties of the testicular tissue as a viral sanctuary site in ART-treated HIV-infected adults.
HIV persistence in long-lived infected cells and in anatomical sanctuary sites are major hurdles to HIV eradication. Testicular tissue may represent a significant viral sanctuary site as it constitutes an immunologically privileged compartment. We assessed immunotolerance properties of the testicular tissue in individuals receiving suppressive antiretroviral therapy (ART).



Testicular tissue and matched blood samples were collected from six virally suppressed adults and 10 HIV-uninfected controls prior to sex reassignment surgery. T cells were purified from freshly isolated testicular interstitial cell suspensions. T-cell subsets, expression of immune activation markers and HIV DNA were assessed in matched testicular cells and peripheral blood mononuclear cells (PBMCs).



When compared with PBMCs, testes were characterized by a lower CD4 T-cell proportion among total T cells, a decrease in the frequency of naive cells, an increase in the frequency of effector-memory T cells and an increase in CCR5 expression in both the HIV+ and HIV- groups. In HIV-infected individuals on ART, testes displayed higher T-cell immune activation (Coexpression of CD38 and Human Leukocyte Antigen - antigen D Related) than PBMCs. In both groups, testes were characterized by higher frequencies of immunosuppressive CD39 regulatory T cells and a massive increase in CD73 expression on CD8 T cells. In addition, a remarkable increase in indoleamine-pyrrole 2,3-dioxygenase immunosuppressive enzyme involved in tryptophan/kynurenine catabolism was observed in testes versus blood. Rare cells harboring HIV DNA were detected in testes from five out six participants.



These findings suggest that the adenosine and tryptophan/kynurenine immune-metabolic pathways contribute to immune tolerance in testicular tissue. Our results suggest that testes may represent a distinctive HIV sanctuary site during ART.
aDepartment of Biological Sciences and BioMed Research Centre, Université du Québec à Montréal (UQAM) bChronic Viral Illness Service and Research Institute, McGill University Health Centre cFaculty of Medicine, McGill University dDepartment of Microbiology, Infectiology and Immunology, Faculty of Medicine, Université de Montréal, and Centre de recherche du CHUM eMetropolitan Centre for Plastic Surgery, Montreal, Québec fDepartment of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario gDivision of Hematology, McGill University Health Centre, Montreal, Québec, Canada.
Mohammad-Ali
MA
Jenabian
Cecilia T
CT
Costiniuk
Vikram
V
Mehraj
Feras M
FM
Ghazawi
Rémi
R
Fromentin
Joëlle
J
Brousseau
Pierre
P
Brassard
Maud
M
Bélanger
Petronela
P
Ancuta
Reina
R
Bendayan
Nicolas
N
Chomont
Jean-Pierre
JP
Routy
D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D004279:DNA, Viral / Q000032:analysis; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007155:Immunologic Factors / Q000032:analysis; D008297:Male; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013737:Testis / Q000276:immunology* / Q000821:virology*
D044966:Anti-Retroviral Agents; D004279:DNA, Viral; D007155:Immunologic Factors