Excess apoptosis of mononuclear cells contributes to the depressed cytomegalovirus-specific immunity in HIV-infected patients on HAART.
HIV-infected patients on highly active antiretroviral therapy (HAART) have persistently decreased cytomegalovirus (CMV)-specific proliferative responses [lymphocyte proliferation assay (LPA)] in spite of increases in CD4+ T cell counts. Here we demonstrate an association between apoptosis of unstimulated peripheral blood mononuclear cells (uPBMC) and decreased CMV-LPA. HAART recipients had more apoptosis of uPBMC than controls when measured by caspases 3, 8, and 9 activities and by annexin V binding. Patients with undetectable HIV replication maintained significantly higher apoptosis of CD4+ and CD14+ cells compared to controls. CMV-LPA decreased with higher apoptosis of uPBMC in patients only. This association was independent of CD4+ cell counts or HIV replication. Furthermore, rescuing PBMC from apoptosis with crmA, but not with TRAIL- or Fas-pathway blocking agents or with other caspase inhibitors, increased CMV-LPA in HAART recipients. This effect was not observed in uninfected controls, further indicating that the down regulatory effect of apoptosis on cell-mediated immunity (CMI) was specifically associated with the HIV-infected status.
Weinberg
Adriana
A
Department of Pediatrics of the University of Colorado Health Sciences Center, Denver, CO 80220, USA. Adriana.Weinberg@uchsc.edu
Jesser
Renee D
RD
Edelstein
Charles L
CL
Bill
Jerome R
JR
Wohl
David A
DA
D017304:Annexin A5 / Q000097:blood; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000473:pathology* / Q000502:physiology
D017304:Annexin A5; D015853:Cysteine Proteinase Inhibitors