title: HIV disease progression correlates with the generation of dysfunctional naive CD8(low) T cells.
abstract: HIV infection can result in depletion of total CD4(+) T cells and naive CD8(+) T cells, and in the generation of dysfunctional effector CD8(+) T cells. In this study, we show that naive CD8(+) T cells in subjects with progressive HIV disease express low levels of CD8α and CD8β chains. Such naive CD8(low) T cells display broad signaling defects across the T-cell receptor complex, and their appearance correlates with generalized up-regulation of major histocompatibility complex class I (MHC-I) antigens on peripheral blood mononuclear cells (PBMCs). To explore a causal link between increased MHC-I up-regulation and the generation of naive CD8(low) T cells, we used the humanized SCID-hu Thy/Liv mouse model to show that HIV infection of the thymus and interferon α (IFNα) treatment alone result in MHC-I up-regulation and in the generation of dysfunctional CD3(high)CD8(+)CD4(-) single-positive 8 (SP8) thymocytes with low expression of CD8. We suggest that dysfunctional naive CD8(low) T cells are generated as a result of IFNα-mediated up-regulation of MHC-I on stromal cells in the thymus and antigen-presenting cells in the periphery, and that dysfunction in this naive compartment contributes to the immunodeficiency of HIV disease. This study is registered at www.clinicaltrials.gov as NCT00187512.
authors.affiliation: Division of Experimental Medicine, University of California at San Francisco, San Francisco, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Favre
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Stoddart
authors.forename: Brinda
authors.initials: B
authors.lastname: Emu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hoh
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Martin
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Hecht
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McCune
mesh_terms: D000328:Adult; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology; D018450:Disease Progression; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D006801:Humans; D066298:In Vitro Techniques; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis; D058965:MART-1 Antigen / Q000276:immunology; D008285:Major Histocompatibility Complex; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D015854:Up-Regulation; D019562:Viral Load; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D058965:MART-1 Antigen; C548668:Mlana protein, mouse; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D048051:p38 Mitogen-Activated Protein Kinases