title: Preferential apoptosis of HIV-1-specific CD4+ T cells.
abstract: In contrast to other viral infections such as CMV, circulating frequencies of HIV-1-specific CD4+ T cells in peripheral blood are quantitatively diminished in the majority of HIV-1-infected individuals. One mechanism for this quantitative defect is preferential infection of HIV-1-specific CD4+ T cells, although <10% of HIV-1-specific CD4+ T cells are infected. Apoptosis has been proposed as an important contributor to the pathogenesis of CD4+ T cell depletion in HIV/AIDS. We show here that, within HIV-1-infected individuals, a greater proportion of ex vivo HIV-1-specific CD4+ T cells undergo apoptosis compared with CMV-specific CD4+ T cells (45 vs 7.4%, respectively, p < 0.05, in chronic progressors). The degree of apoptosis within HIV-1-specific CD4+ T cells correlates with viral load and disease progression, and highly active antiretroviral therapy abrogates these differences. The data support a mechanism for apoptosis in these cells similar to that found in activation-induced apoptosis through the TCR, resulting in oxygen-free radical production, mitochondrial damage, and caspase-9 activation. That HIV-1 proteins can also directly enhance activation-induced apoptosis supports a mechanism for a preferential induction of apoptosis of HIV-1-specific CD4+ T cells, which contributes to a loss of immunological control of HIV-1 replication.
authors.affiliation: Clinical Sciences Division, University of Toronto, Toronto, Canada.
authors.forename: Feng Yun
authors.initials: FY
authors.lastname: Yue
authors.forename: Colin M
authors.initials: CM
authors.lastname: Kovacs
authors.forename: Rowena C
authors.initials: RC
authors.lastname: Dimayuga
authors.forename: Xiao Xiao Jenny
authors.initials: XX
authors.lastname: Gu
authors.forename: Paul
authors.initials: P
authors.lastname: Parks
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D003587:Cytomegalovirus / Q000276:immunology; D018450:Disease Progression; D004198:Disease Susceptibility / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005609:Free Radicals / Q000037:antagonists & inhibitors; D015658:HIV Infections / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology; D019014:fas Receptor / Q000276:immunology
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D061945:Caspase Inhibitors; D018984:Epitopes, T-Lymphocyte; D005609:Free Radicals; D007106:Immune Sera; D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D007371:Interferon-gamma; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9