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Preferential Apoptosis of HIV-1-Specific CD4⁺ T Cells¹

Feng Yun Yue^*, Colin M. Kovacs^*,, Rowena C. Dimayuga, Xiao Xiao Jenny Gu^*, Paul Parks, Rupert Kaul^* and Mario A. Ostrowski^2,*,

^* Clinical Sciences Division and St. Michael’s Hospital, University of Toronto, Toronto, Canada; and Canadian Immunodeficiency Research Collaborative, Toronto, Canada

In contrast to other viral infections such as CMV, circulating frequencies of HIV-1-specific CD4⁺ T cells in peripheral blood are quantitatively diminished in the majority of HIV-1-infected individuals. One mechanism for this quantitative defect is preferential infection of HIV-1-specific CD4⁺ T cells, although <10% of HIV-1-specific CD4⁺ T cells are infected. Apoptosis has been proposed as an important contributor to the pathogenesis of CD4⁺ T cell depletion in HIV/AIDS. We show here that, within HIV-1-infected individuals, a greater proportion of ex vivo HIV-1-specific CD4⁺ T cells undergo apoptosis compared with CMV-specific CD4⁺ T cells (45 vs 7.4%, respectively, p < 0.05, in chronic progressors). The degree of apoptosis within HIV-1-specific CD4⁺ T cells correlates with viral load and disease progression, and highly active antiretroviral therapy abrogates these differences. The data support a mechanism for apoptosis in these cells similar to that found in activation-induced apoptosis through the TCR, resulting in oxygen-free radical production, mitochondrial damage, and caspase-9 activation. That HIV-1 proteins can also directly enhance activation-induced apoptosis supports a mechanism for a preferential induction of apoptosis of HIV-1-specific CD4⁺ T cells, which contributes to a loss of immunological control of HIV-1 replication.

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