Reactivation Kinetics of HIV-1 and Susceptibility of Reactivated Latently Infected CD4+ T Cells to HIV-1-Specific CD8+ T Cells

Victoria E K Walker-Sperling, Valerie J Cohen, Patrick M Tarwater, Joel N Blankson
Journal of Virology 2015, 89 (18): 9631-8

UNLABELLED: The "shock and kill" model of human immunodeficiency virus type 1 (HIV-1) eradication involves the induction of transcription of HIV-1 genes in latently infected CD4(+) T cells, followed by the elimination of these infected CD4(+) T cells by CD8(+) T cells or other effector cells. CD8(+) T cells may also be needed to control the spread of new infection if residual infected cells are present at the time combination antiretroviral therapy (cART) is discontinued. In order to determine the time frame needed for CD8(+) T cells to effectively prevent the spread of HIV-1 infection, we examined the kinetics of HIV transcription and virus release in latently infected cells reactivated ex vivo. Isolated resting, primary CD4(+) T cells from HIV-positive (HIV+) subjects on suppressive regimens were found to upregulate cell-associated HIV-1 mRNA within 1 h of stimulation and produce extracellular virus as early as 6 h poststimulation. In spite of the rapid kinetics of virus production, we show that CD8(+) T cells from 2 out of 4 viremic controllers were capable of effectively eliminating reactivated autologous CD4(+) cells that upregulate cell-associated HIV-1 mRNA. The results have implications for devising strategies to prevent rebound viremia due to reactivation of rare latently infected cells that persist after potentially curative therapy.

IMPORTANCE: A prominent HIV-1 cure strategy termed "shock and kill" involves the induction of HIV-1 transcription in latently infected CD4(+) T cells with the goal of elimination of these cells by either the cytotoxic T lymphocyte response or other immune cell subsets. However, the cytotoxic T cell response may also be required after curative treatment if residual latently infected cells remain. The kinetics of HIV-1 reactivation indicate rapid upregulation of cell-associated HIV-1 mRNA and a 5-h window between transcription and virus release. Thus, HIV-specific CD8(+) T cell responses likely have a very short time frame to eliminate residual latently infected CD4(+) T cells that become reactivated after discontinuation of antiretroviral therapy following potentially curative treatment strategies.

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