Phenotypic characteristics and tendency to apoptosis of peripheral blood mononuclear cells from HIV+ long term non progressors

Abstract

The aim of this study was to analyze (i) phenotype, (ii) in vitro spontaneous and induced apoptosis, (iii) glutathione (GSH) intracellular content and (iv) inhibitors of apoptosis of potential therapeutical use in peripheral blood mononuclear cells (PBMC) from HIV+ long term non progressors (LTNP), in comparison with progressors (HIV+P) and seronegative controls (HIV7). Three groups of subjects were studied: 15 HIV+P (patients losing 4150 CD4+/year), 9 LTNP (subjects infected by HIV for at least 7 years without clinical and immunological signs of progression, with a mean of 898 CD4+/mL) and 18 HIV7. All subjects were living in a large community for former drug addicts, and were matched for age and sex.We used flow cytometry for analyzing PBMC phenotype and apoptosis; high performance liquid chromatography for measuring intracellular GSH content. PBMC phenotype of LTNP shared characteristics with those of both HIV7 and HIV+P. Indeed, LTNP showed a normal number CD4+ cells (an inclusioncriteria),butsignificantlyincreasednumbersofCD8+ lymphocytes, activated T cells, CD19+, CD5+ B lymphocytes and CD57+ cells, as well as a decrease in CD19+, CD57 B lymphocytes and CD16+ cells. In LTNP, spontaneous apoptosis was similar to that of HIV7 and significantly lower than that of HIV+P. Adding interleukin-2 (IL-2) or nicotinamide (NAM)significantlydecreasedspontaneousapoptosisinLTNP and HIV+P. Pokeweed mitogen-induced apoptosis was also similar in LTNP and HIV7, but significantly lower than that of HIV+P. In HIV+P, but also in LTNP, spontaneous apoptosis was inversely correlated to the absolute number and percentage of CD4+ cells and directly correlated to the number and percentageofactivatedTcellspresentinperipheralblood.GSH intracellular content was greatly decreased in PBMC from HIV+P and slightly, but significantly, reduced in LTNP. Adding 2-deoxy-D-ribose, an agent provoking apoptosis through GSH depletion, to quiescent PBMC resulted in similar levels of massive cell death in the three groups. This phenomenon was equally prevented in the three groups by N-acetyl-cysteine but not by IL-2.A complex immunological situation seems to occur in LTNP. Indeed, PBMC from LTNP are characterized by a normal in vitro tendencytoundergoapoptosisdespitethepresenceofastrong activation of theirimmune system,unexpectedly similar tothat of HIV+P. Our data suggest that NAM and IL-2 are possible candidates for reducing spontaneous apoptosis in HIV infection.

Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis

“…Third, initiation of antiretroviral therapy that results in immune reconstitution causes a dramatic reduction in T cell apoptosis in lymphoid tissues (24,25). Finally, whereas patients with rapidly progressive HIV disease have high levels of apoptosis, patients with LTNP HIV disease have levels of apoptosis similar to those of HIV-uninfected patients (26)(27)(28). Intriguingly, mechanisms of LTNP defined thus far have identified host and viral means of impaired viral infectivity or replication, yet no mechanism has been defined that impairs the ability of HIV to induce T cell death.…”

Dynamic correlation of apoptosis and immune activation during treatment of HIV infection

“…19 Furthermore, while spontaneous apoptosis is increased in HIV infected patients with progressive disease compared to HIV uninfected patients 18,20 levels of spontaneous apoptosis in patients with long term non progressive HIV infection are similar to that of HIV negative patients. 21,22 Since spontaneous apoptosis is inhibited in vitro by blocking viral replication, it is reasonable to suspect that spontaneous apoptosis in vivo would similarly be decreased. This study supports that hypothesis by showing that levels of spontaneous apoptosis revert to values seen in HIV uninfected patients within 8 days of treatment, and that within this short time frame, CD4 and CD8 T cell counts increase.…”

“…16,17 Increased spontaneous apoptosis has consistently been observed to correlate directly with the rate of disease progression: rapid progressors have the highest rates of spontaneous apoptosis, 18 ± 20 whereas long term non progressors have rates of apoptosis similar to HIV negative subjects. 18,21,22 In addition to enhanced spontaneous apoptosis, peripheral blood mononuclear cells from HIV infected patients and HIV infected monocyte derived macrophages develop the ability to induce apoptosis of autologous CD4 and CD8 T cells. 23 ± 30 This phenomenon, in addition to enhanced susceptibility of T cells from HIV infected patients to undergo Fas mediated apoptosis, 31 ± 36 suggest that the Fas/Fas Ligand (FasL) system is involved in HIV induced apoptosis.…”

HIV-1 Infection and the Aging of the Immune System: Facts, Similarities and Perspectives

“…26 Rare patients, who are able to better control viral replication, defined long-term nonprogressors have HIV-specific CD8þ T cells that retain a strong capacity to proliferate upon antigenic stimulation and that present polyfunctional capacities in terms of cytokine production, 27,28 and have a low tendency to undergo apoptosis. 29 Physiological aging is characterized by a progressive involution of the thymus, and resultant thymic volumes are significantly lower in persons >45 years as compared with younger persons. 30 The production of naïve T cells further declines, and thymic output becomes minimal after the age of 55, 17 even if signs of thymic activity (in terms of production of the T-cell receptor rearrangement excision circlesddefined TRECdand their presence in peripheral blood lymphocytes) can be found also in persons aged >100 years.…”