Activation-induced CD4+ T cell death in HIV-positive individuals correlates with Fas susceptibility, CD4+ T cell count, and HIV plasma viral copy number.
The relevance of activation-induced cell death (AICD) of CD4+ T cells to AIDS pathogenesis is unknown. The present study investigates the relationship of AICD to a defined molecular mechanism regulating peripheral T cell homeostasis, Fas-mediated apoptosis, and clinical correlates of the pathogenesis of AIDS. Increased pokeweed mitogen (PWM)-induced AICD (22.8 versus 4.4%, p = 0.006) and Fas-mediated apoptosis (27.7 versus 12.0%, p = 0.002) of CD4+ T cells were observed in HIV+ versus HIV- individuals. Similarly, increased PWM-mediated AICD (16.2 versus 2.2%, p < 0.001) and Fas-mediated apoptosis (25.8 versus 7.6%, p = 0.005) were noted in CD8+ T cells from HIV+ versus HIV- individuals. PWM-induced AICD of CD4+ T cells was blocked (83% median specific inhibition) by Fas-blocking antibodies, whereas PWM-induced AICD of CD8+ T cells was Fas independent. Comparison between PWM- and anti-CD3-mediated AICD of CD4+ T cells indicated that PWM- and not CD3-induced AICD is Fas dependent. HIV+ individuals with an HIV RNA copy number of <30,000 copies/ml had lower PWM-induced AICD of CD4+ T cells than did those with an HIV RNA copy number of >30,000 copies/ml (5.7 versus 22.1%, p = 0.034), and PWM-induced AICD inversely correlated with CD4+ T cell count (R = -0.567, p = 0.043). Initiation of HAART decreased PWM-induced CD4+ T cell AICD from 24.4 to 9.4% posttreatment (p = 0.035). These results demonstrate that PWM-induced AICD of CD4+ T cells from HIV+ individuals is mediated by Fas/FasL, parallels the in vivo susceptibility of the CD4+ T cell to Fas-mediated apoptosis, and correlates with clinical markers of AIDS pathogenesis and response to HAART.
Dockrell
D H
DH
Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
Badley
A D
AD
Algeciras-Schimnich
A
A
Simpson
M
M
Schut
R
R
Lynch
D H
DH
Paya
C V
CV
D019380:Anti-HIV Agents / Q000627:therapeutic use; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D015331:Cohort Studies; D006678:HIV / Q000276:immunology / Q000302:isolation & purification; D018023:HIV Seronegativity; D006679:HIV Seropositivity / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D006801:Humans; D007111:Immunity, Cellular; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation; D011043:Pokeweed Mitogens / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000032:analysis; D019562:Viral Load; D019014:fas Receptor / Q000502:physiology*
D019380:Anti-HIV Agents; D015415:Biomarkers; D011043:Pokeweed Mitogens; D012367:RNA, Viral; D019014:fas Receptor