Apoptosis of CD4+ and CD8+ T Cells Isolated Immediately ex Vivo Correlates with Disease Severity in Human Immunodeficiency Virus Type 1 Infection

Abstract

Apoptosis of CD4+ and CD8+ T cells has been shown in peripheral blood mononuclear cells (PBMCs) from HIV-infected adults analyzed after overnight culture. Because cell death may be an artifact of in vitro culture, and because there is little information on apoptosis in pediatric HIV disease, we undertook a cross-sectional analysis of apoptosis in PBMCs analyzed immediately ex vivo in HIV-infected children and adults. PBMCs from 22 children, four adolescents, and nine adults and seronegative age-matched control subjects were stained for CD4 and CD8 surface markers. Apoptotic cells were detected in a newly characterized flow cytometric assay by diminished forward and increased side scatter. Children with the most advanced disease had 9.9% (SEM 1.8) apoptotic CD4+ T cells above control, significantly higher than in asymptomatic patients [0.4% (SEM 2.3)], those with mild disease [2.2% (SEM 1.83)], and those with moderate disease [2.5 (SEM 3.6)] (p = 0.015). The percentages of both CD4+ and CD8+ T cell apoptosis were directly related to CD4+ T cell depletion (R2 = 0.23; p = 0.006; n = 32 and R2 = 0.2; p = 0.012; n = 30, respectively). Patients who responded to antiretroviral therapy with the greatest increase in CD4+ T cell percentage had the least CD4+ T cell apoptosis (R2 = 0.15; p = 0.1; n = 19). These findings show that the rate or extent of T cell death by apoptosis percentage of T cell apoptosis is significantly increased in HIV-infected children. The observed correlation of both CD4+ and CD8+ T cell apoptosis with CD4+ T cell depletion suggests that apoptosis plays a role in HIV pathogenesis and may be a useful marker of disease activity.

Chemokine-receptor activation by env determines the mechanism of death in HIV-infected and uninfected T lymphocytes

“…Previous studies have demonstrated that CD8 T cells, in addition to CD4 T cells, undergo apoptosis in lymphoid tissue from HIV-infected patients (5,41,42). The conclusion of such studies has been generally that CD8 T-cell death is secondary to their aberrant activation.…”

Biochemical mechanisms of HIV induced T cell apoptosis

“…5,6 Some studies have also shown a correlation between the extent of apoptosis and disease progression, 7,8 suggesting that, in vivo, HIV kills the CD4 + T cell that it infects. These observations argue that the virus is responsible for the depletion of CD4 + T cells.…”

“…40 Apoptosis is seen in PBL of HIV infected individuals in both the CD4 + and CD8 + T cell subsets. 7,8,40,41 A study of a large cohort of HIV-infected individuals at various stages of disease showed that the degree of apoptosis was significantly higher in CD4 + , CD8 + , and B cells, compared to uninfected individuals, and was correlated with disease progression. 7 This study showed a low level of apoptosis in long-term non-progressors and a high level of apoptosis in rapid progressors.…”

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

“…However in general, progression from acute infection is often accompanied by depletion of the CD4 + lymphocytes and this depletion is a major component of the eventual failure of the immune system and hence AIDS pathogenesis. Apoptosis is one mechanism that contributes to depletion of HIV-1 infected and uninfected cells, deterioration of the immune system and progression to AIDS, respectively (Cotton et al, 1997;Gougeon & Montagnier, 1993;Herbein et al, 1998;Joshi et al, 2011;C. J. Li et al, 1995;Zhu et al, 2011).…”