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

Abstract

T cells from HIV infected patients undergo spontaneous apoptosis at a faster rate than those from uninfected patients, are abnormally susceptible to activation induced cell death (AICD), and undergo increased apoptosis in response to Fas receptor ligation. These observations have led to the hypothesis CD4 T cell apoptosis may be a mechanism of CD4 T cell depletion and the pathogenesis of AIDS. Successful treatment of HIV infected patients is accompanied by quantitative and qualitative improvements in immune function reflecting at least partial reversibility of the underlying pathogenesis of HIV. In this report we correlate improvements in markers of immune function with a decrease in apoptosis, and changes in its regulation. Therapy with nelfinavir plus saquinavir in combination with two nucleoside analogue inhibitors of reverse transcriptase dramatically reduces plasma viremia and increases CD4 T cell counts. Coincident with these improvements, CD38 and HLA-DR coexpression on both CD4 and CD8 T cells decrease, and CD45RA and CD62L coexpression increase. Furthermore, spontaneous apoptosis decreases in both CD4 and CD8 T cells (CD4 apoptosis 17.4 vs 2.6%, P=0.005; CD8 apoptosis 15.0 vs 1.0%, P50.001), as does both Fas mediated apoptosis (CD4 apoptosis 19.0 vs 3.5%, P=0.03; CD8 apoptosis 13.7 vs 1.5%, P=0.002) and CD3 induced AICD (CD4 apoptosis 13.7 vs 3.2%, P=0.001; CD8 apoptosis 29 vs 2.2%, P=0.08). Changes in apoptosis are not associated with changes in Fas receptor expression, but are significantly correlated with changes in activation marker profiles. Although this suggests a possible regulatory role for the apoptosis inhibitory protein FLIP, direct assessment did not reveal quantitative differences in FLIP expression between apoptosis resistant PBL's from HIV negative patients, and apoptosis sensitive PBL's from HIV positive patients. These findings support the hypothesis that apoptosis mediates HIV induced CD4 T cell depletion, but indicate the need for further studies into the molecular regulation of HIV induced apoptosis.

Apoptosis in SIV infection

“…49,101 Interestingly, the enhancement in CD95-mediated T-cell death in rhesus macaques is not associated with either an upregulation of caspase-3 and caspase-8 or a decrease of FLIP-L and FLIP-S. Similarly, Badley et al 105 found that death of T cells from HIV-infected individuals was not associated with a change in the amount of FLIP. T-cell activation occurring in the course of immune responses has been shown to increase sensitivity to CD95-induced apoptosis.…”

“…Antiretroviral therapy is followed by a significant decrease in CD95-induced, activation-induced, and spontaneous apoptosis in ex vivo cultured peripheral blood lymphocytes 60,96 which correlates with decreased immune activation. 105 Thus, effective viral suppression decreases immune activation and apoptosis, thereby contributing to immune reconstitution.…”

To kill or be killed: how HIV exhausts the immune system

“…However, the levels of c-FLIP in purified CD4 þ and CD8 þ T cells from HIV þ donors do not differ from that of noninfected control donors. 110 The TNF/TNF receptors death pathway is also activated in HIV þ individuals, and both CD4 þ and CD8 þ T cells are susceptible to TNFR1-and TNFR2-induced apoptosis. 109 Susceptibility of patients' T cells to TNFR-induced apoptosis is associated with the downregulation of Bcl-2 protein, while there is no increased expression of the two TNFRs on the surface of T cells, and TNFR1-associated death domain (TRADD), receptor interacting protein (RIP) or TNF receptorassociated factor 2 (TRAF-2) expression is not altered by HIVinfection.…”

Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

“…56 Rapid decreases of T-cell apoptosis after treatment with HIV protease inhibitors has been reported by several investigators. 57,58 Additional evidence supporting the critical role of apoptosis in AIDS progression emerges from studies in SIV-infected macaques where lymphocyte apoptosis was found to be associated with the pathogenicity of lentiviral infection. 31,32 Furthermore, an extensive apoptosis in peripheral lymphoid organs during primary SIV infection was previously found to be predictive of the ability of the immune system to control viral replication and disease progression.…”

“…A previous study failed to show different expression of c-FLIP in purified CD4 þ and CD8 þ T cells from HIV-infected patients. 57 The expression of this molecule, however, in HIVspecific CD8 þ T-cell populations is not known. Similarly, the role of other factors regulating the CD95/Fas-induced apoptosis like FADD or Bid that has been described as the link between the Fas signaling and mitochondria 171 is also not known.…”