Short Communication: Apoptosis Pathways in HIV-1-Infected Patients Before and After Highly Active Antiretroviral Therapy: Relevance to Immune Recovery

Abstract

Investigations into apoptotic pathways, intrinsic and extrinsic, and the effects of highly active antiretroviral therapy (HAART) on T cell death via those pathways may provide insight into the mechanisms of and barriers to immune recovery. HIV-1-infected patients were enrolled into a randomized, controlled study of the immune effects of a lopinavir/ritonavir (LPV/r)-based versus an efavirenz (EFV)-based HAART regimen in antiretroviral-naive subjects with CD4(+) counts <350 cells/mm(3). Patients were randomized to receive TDF/FTC/EFZ or TDF/FTC plus LPV/r. Fourteen patients were enrolled and 10 patients completed 6 months of therapy as per the protocol. CD4(+) counts were measured before and during HAART therapy. We isolated T cell subsets to measure ex vivo apoptosis by propidium iodide staining. We also assessed caspase activation for the intrinsic and extrinsic pathways of apoptosis, as well as effector caspase activation. We also measured mitochondrial membrane potential. Cells were analyzed by flow cytometry. All patients had increased activation of caspase 8 (extrinsic pathway), caspase 9 (intrinsic pathway), effector caspases 3/7, and low mitochondrial membrane potential at baseline compared to controls. By 4 weeks, there was a decrease in activation of all caspases, but little further decrease by week 24. T cell mitochondrial membrane potential did not increase until week 12, but continued to increase until week 24. The only predictor of CD4(+) count increase was the increase in mitochondrial membrane potential of naive cells at 6 months (r=0.66, p=0.038). This suggests that positive selection of naive CD4(+) T cells in the thymus is the major determinant of CD4(+) recovery.

Tenofovir-Based Highly Active Antiretroviral Therapy Is Associated with Superior CD4 T Cells Repopulation Compared to Zidovudine-Based HAART in HIV 1 Infected Adults

“…Immune reconstitution as a property of HAART has also been associated with the reduction in the cytotoxic effect of naf , vpr, and tat viral proteins on CD4 T cells through the activation of NF-kappa β and TNF- α [ 2 ]. The observed immune recovery in this study may be due to reduction in chronic immune activation, cytolysis, cytotoxic viral proteins, and an increase in thymic function though there is not much data on these parameters for analysis to support this claim [ 2 , 7 , 15 , 26 ]. However the observed higher CD4 T cells absolute count increase in the tenofovir cohort compared to zidovudine cohort may be attributable to the postulated zidovudine induced stasis of CD4 T cells expansion.…”

A transcriptome-based model of central memory CD4 T cell death in HIV infection

“…Previous studies have reported increased apoptosis in total [58, 103, 104] and in T CM [58, 105] CD4 T cells from patients with HIV, which is an explanation of CD4 T cell loss in chronic infection [106]. These and other studies [13, 57–60] inferred apoptosis by demonstrating Annexin V binding to viable cells; however, it has been demonstrated that Annexin V binding can be increased in other cell death pathways [107–110].…”

HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients

“…Multiple studies in HIV-infected patients, SIV and humanized mouse model have demonstrated the presence of uninfected bystander cells dying of apoptosis in HIV infections (20, 37–39). PBMCs derived from HIV-infected patients have also been shown to have a higher percentage of apoptotic phenotype (24, 25, 40, 41). Finally, caspase activation has been recognized as a critical mediator of apoptosis seen in HIV-infected patients as well as animal model systems (20, 38).…”