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Abstract
Attempts to eradicate HIV have been thwarted by the persistence of a small pool of quiescent memory CD4 T cells that harbor a transcriptionally silent, integrated form of the virus that can produce infectious virions following an anamnestic immune response. Transcription factors downstream of T-cell receptor activation, such as NF-κB/Rel and nuclear factor of activated T cells (NFAT) transcription members, are considered important regulators of HIV transcription during acute HIV infection. We now report studies exploring their precise role as antagonists of HIV latency using cell and primary CD4 T cell models of HIV-1 latency. Surprisingly, RNA interference studies performed in J-Lat CD4 T cells suggested that none of the NFATs, including NFATc1, NFATc2, NFATc3, and NFAT5, played a key role in the reactivation of latent HIV. However, cyclosporin A markedly inhibited the reactivation response. These results were reconciled when calcium signaling through calcineurin was shown to potentiate prostratin induced activation of NF-κB that in turn stimulated the latent HIV long terminal repeat (LTR). Similar effects of calcineurin were confirmed in a primary CD4 T cell model of HIV latency. These findings highlight an important role for calcineurin in NF-κB-dependent induction of latent HIV transcription. Innovative approaches exploiting the synergistic actions of calcineurin and prostratin in the absence of generalized T-cell activation merit exploration as a means to attack the latent viral reservoir.
Highlights
In HIV-infected patients, highly active antiretroviral therapy (HAART) effectively reduces viral loads but cannot eradicate the virus
Upon T-cell receptor (TCR) crosslinking, 5A8 undergoes HIV transcription and induces expression of nuclear factor of activated T cells (NFAT)-dependent cytokines, such as interleukin (IL)2, in a cyclosporin A (CsA)-sensitive manner (Fig. 1c). These findings argue that the calcium-signaling pathway linking TCR crosslinking and calcineurin activation in 5A8 cells is functionally intact, which allow us to analyze in detail the downstream effects of calcineurin on NFAT and NF-kB induction and in latent HIV-1 transcription
We found no compelling evidence that NFAT contributes to the transcriptional activation of latent HIV in a JLat model we recently developed that robustly displays TCRinduced calcium/calcineurin signaling (Figs. 1 and 2)
Summary
In HIV-infected patients, highly active antiretroviral therapy (HAART) effectively reduces viral loads but cannot eradicate the virus. Attempts to stimulate latent provirus expression with anti-CD3 or interleukin (IL)-2 were unsuccessful [1,2]. These disappointing results reflect in part our incomplete understanding of how latent HIV-1 transcription is induced during activation of infected resting CD4 memory cells in vivo. Reactive oxygen species activators that stimulate latent HIV transcription without the undesirable effects of global T-cell activation have been described [4,5]. Of note, both of these strategies involve the induction of NF-kB
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