Selective CD4+ T cell deletion after specific activation in HIV-infected individuals; protection by anti-CD28 monoclonal antibodies

Abstract

SUMMARYAIDS is characterized by a progressive decline in the number of CD4 T cells. This is preceded by an early selective defect in the proliferation of these cells to recall antigens [1][2][3], pokeweed mitogen (PWM) [4][5][6] and to superantigens (SAg) [4,7]. In contrast, the proliferative response to phytohaemagglutinin (PHA) remains intact [1,2,5]. We and others have shown that the proliferative defect in response to some stimuli was in fact due to the induction of cell death [4,7]. The activation-induced cell death mechanism that explains the proliferative defects observed in vitro might also account for the progressive in vivo deletion of CD4 T cells. Indeed, studies performed on different models of primates have shown that induction of cell death in CD4 T cells was detected only when T cells were isolated from animals infected with a type of retrovirus that induces an AIDS-like disease [8]. This correlation prompted us to analyse further the mechanism of HIV-induced activation cell death to determine the specificity and rate of induction of cell death. T cells from HIV-infected individuals were activated with superantigens and the V¯T cell receptor (TCR) expression analysed. Data presented here show that cell death is restricted to activated CD4 T cells, and does not affect bystander cells. More importantly, addition of anti-CD28 MoAb specifically inhibited the induction of apoptosis, raising possibilities for therapy.

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

“…73 This association has been observed in cross-sectional 57,74 and longitudinal studies. 46 Indeed, the correlation of apoptosis with activation has been suggested as a mechanism to explain the enhanced CD4 T cell loss seen in HIV positive patients coinfected with other pathogens, 75,76 and the lack of apoptosis in HIV infected chimpanzees (in whom activation does not occur). 77 It remains unknown whether effective antiretroviral therapy, which leads to immune deactivation, is associated with decreases in apoptosis and apoptosis sensitivity.…”

Discordance between Frequency of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon-Producing CD4+T Cells and HIV-1-Specific Lymphoproliferation in HIV-1-Infected Subjects with Active Viral Replication

“…This theory is supported in part by the finding that activated CD4 ϩ T cells are preferentially infected by HIV-1 (36). According to this hypothesis, activation of HIV-1-specific CD4 ϩ T cells early in disease during periods of high-level viremia might lead to their preferential infection and deletion by direct viral cytolysis or might indirectly lead to their death through apoptosis or other bystander mechanisms (10,15,18). The second hypothesis holds that HIV-1-specific CD4 ϩ T cells are present during chronic infection but are dysfunctional and thus there is no measurable HIV-1-specific lymphoproliferation.…”