HIV infection of primary human T cells is determined by tunable thresholds of T cell activation

Abstract

HIV infection of primary human T cells requires T cell activation signals. However, how strength, duration, and quality of TCR signals affect susceptibility of resting human T cells to HIV infection remains poorly understood. We found that the same threshold and duration of antigen signals that lead to optimal T cell activation are required for HIV to progress beyond the level of reverse transcription within resting T cells. Remarkably, sustained cytokine signaling from the IL-2 receptor following TCR triggering was critical in establishing productive infection. While blockade of TCR signaling pathways with inhibitors of the phosphatidylinositol 3-kinase pathway caused a partial pre-integration block, another inhibitor, rapamycin, completely suppressed the infection. In contrast, cyclosporin A or FK506, inhibitors of NFAT, failed to block infection if the T cells were pre-activated. Collectively, these results bring to light significant parallels between successful HIV infection and optimal thresholds of T cell activation. Furthermore, our results underscore the critical role of IL-2 signaling in establishing productive HIV infection. These findings have important implications for our understanding of the complex interplay of HIV with host factors induced upon T cell activation.

Endothelial Cells Promote Human Immunodeficiency Virus Replication in Nondividing Memory T Cells via Nef-, Vpr-, and T-Cell Receptor-Dependent Activation of NFAT

“…This seems unlikely, since we examined the cells for early, intermediate, and late activation markers, and we found that the p24 high T cells did not express CD25, HLA-DR, or VLA-1 and only small amounts of CD69. Our results using T cells activated by ECs stand in striking contrast to previous studies, which used similar FACS-based techniques to show that viral replication under other conditions is restricted to highly activated T cells (4,44).…”

“…ϩ T cells infected with a vpr-deficient strain (Vpr Ϫ ) that were similarly stimulated underwent multiple cell divisions (44). Vpr can arrest infected cells in G 2 (19,23,49), which is advantageous to the virus because G 2 is the phase of the cell cycle that is optimal for viral replication (18).…”

“…Since activated CD4 ϩ T cells are a primary source of HIV production in vitro (4,44) and in vivo (21,46,65), it is reasonable to hypothesize that ECs support viral replication in TCR-activated T cells. The productively infected cells observed on days 6 and 9 of culture, i.e., the p24 high T cells, could represent the progeny of the cells that had been fully activated and proliferated in response to high-affinity TCR binding to nonself (allogeneic) MHC molecules.…”

Kinetics of Human Immunodeficiency Virus Type 1 Decay following Entry into Resting CD4 + T Cells

“…It remains controversial whether HIV-1 is stable in the preintegration state. The recent discovery that subtle stimulation of resting CD4 ϩ T cells allows HIV-1 to overcome these blocks further highlights the need for a more complete understanding of the finely tuned host-virus interaction in resting CD4 ϩ T cells (13,25,38,41,49). In the study presented here, a novel HIV-1 Env-pseudotyped reporter virus was used to study the fate of HIV-1 in resting CD4…”

Estudio preliminar sobre las alteraciones fenotípicas de las células treg causadas por la infección vih en pacientes adultos infectados

“…Estudios previos han mostrado que las célula s Treg son un objeti vo potencial de la infección por el VIH in vitro (Moreno-Fernandez et al, 2009;Oswald-Richter et al, 2004).…”