Objective:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) dependent apoptosis has been implicated in CD4+ T-cell death and immunologic control of HIV-1 infection. We have described a splice variant called TRAILshort, which is a dominant negative ligand that antagonizes TRAIL-induced cell death in the context of HIV-1 infection. HIV-1 elite controllers naturally control viral replication for largely unknown reasons. Since enhanced death of infected cells might be responsible, as might occur in situations of low (or inhibited) TRAILshort, we tested whether there was an association between elite controller status and reduced levels of TRAILshort expression.Design:Cohort study comparing TRAILshort and full length TRAIL expression between HIV-1 elite controllers and viremic progressors from two independent populations.Methods:TRAILshort and TRAIL gene expression in peripheral blood mononuclear cells (PBMCs) was determined by RNA-seq. TRAILshort and TRAIL protein expression in plasma was determined by antibody bead array and proximity extension assay respectively.Results:HIV-1 elite controllers expressed less TRAILshort transcripts in PBMCs (P = 0.002) and less TRAILshort protein in plasma (P < 0.001) than viremic progressors.Conclusion:Reduced TRAILshort expression in PBMCs and plasma is associated with HIV-1 elite controller status.
Bibliographical noteFunding Information:
The authors would like to thank the persons living with HIV who graciously participated in the studies described. A.C.P. and N.W.C. were supported through the Mayo Clinic Foundation. U.N. is supported by the Swedish Research Council establishment grant (2017-01330). S.R.L. was supported by the National Institutes of Health (NIH) Delaney AIDS Research Enterprise (DARE U19 AI096109 and UM1 AI126611-01) and the National Health and Medical Research Council (NHMRC) of Australia (NHMRC program grant and practitioner fellowship to S.R.L.). A.D.B was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health grant numbers (AI110173 and AI120698). H.-P.K. is a Markey Molecular Medicine Investigator and received support as the inaugural recipient of the JoséCarreras/E. Donnall Thomas Endowed Chair for Cancer Research and the Fred Hutch Endowed Chair for Cell and Gene Therapy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.
- CD4-positive T-lymphocytes
- HIV elite controllers
- tumor necrosis factor-related apoptosis-inducing ligand