Reciprocal regulation of the nuclear factor of activated T cells and HIV-1

Abstract

The human immunodeficiency virus type 1 (HIV-1) has evolved to coordinate its replication with the activation state of the host CD4T cell. To this end, it taps into major host cell signaling pathways and their associated transcription factors. Of these, T-cell activation and the transcription factor NF-kB, respectively, have become the best-studied examples. The past several years have revealed compelling evidence that another transcription factor family involved in T-cell activation, the nuclear factor of activated T cells (NFAT), plays an important role in the regulation of HIV-1. Major advances have been made in our understanding of the interaction of HIV-1 with this intriguing transcription factor. The duplicated NF-kB binding sites in the HIV-1 enhancer surprisingly also bind NFAT proteins and appear to be the most important targets for NFAT transactivation of the HIV-1 long terminal repeat. The crystal structure of NFAT1 bound to one of these duplicated sites was solved recently. Interestingly, it showed that NFAT1 binds to this site as a homodimer and occupies the core of the NF-kB site, suggesting mutually exclusive binding and alternate transactivation by these two factors. NFAT also regulates HIV-1 infection indirectly, as it can relieve a block to reverse transcription in quiescent T cells. In turn, HIV-1, and particularly its Tat and Nef gene products, can upregulate NFAT expression and activity. This reciprocal regulation between virus and transcription factor potentially creates a positive feedback loop, which may facilitate the establishment of early HIV-1 infection and, later, the transition from latent to productive infection. The immunosuppressive drug cyclosporin A (CsA) inhibits NFAT activity and thus represents a potential treatment for HIV-1 infection. Recent small-scale clinical trials have yielded optimistic results, suggesting roles for CsA after organ transplantation in HIV-1 þ individuals and as adjunct treatment in stable early HIV-1 infection.

Functional Incompatibility between the Generic NF-κB Motif and a Subtype-Specific Sp1III Element Drives the Formation of the HIV-1 Subtype C Viral Promoter

“…Of the NFAT family members, the NFAT1 homodimer can occupy the complementary sequence of 5 bp in the 3= half of the H-B motif (GGGACTTTCC; the NFAT binding sequence within the H-B motif is underlined) and modulate HIV-1 gene expression (40,41). Due to a partial overlap in the H-B motif, NFAT and NF-B could compete, leading to the mutually exclusive binding and alternate transactivation by these two factors (42). While NFAT1 binding to the H-B site has a negative modulatory effect on NF-B-mediated transactivation from the HIV-1 LTR, NFAT2 binding positively regulates HIV-1 LTR gene expression (43).…”

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

“…For example, APL-induced calcium signaling, which is reduced and shorter in duration than agonist peptide-induced calcium signaling, can contribute to the selective activation of NF-B or of NFAT (30,57). In contrast to the IL-2 promoter, where NFAT binds as a heterodimer with AP-1, NFAT binds in the LTR enhancer as a homodimer (47). Therefore, while IL-2 expression requires both NFAT activation and AP-1 activation (35), HIV replication can occur with the selective activation of NFAT (26).…”

Kinase Control of Latent HIV-1 Infection: PIM-1 Kinase as a Major Contributor to HIV-1 Reactivation

“…PIM-1 was found to enhance NFATc1-dependent transactivation and IL-2 production in Jurkat T cells, while kinase-deficient PIM-1 mutants acted as dominant negative inhibitors. NFAT, in turn, has been described early on to interact with the HIV-1 LTR (49-51) and has been shown to augment LTR transcription via binding to the dual proximal NF-B sites (43,(52)(53)(54). NFAT further has been reported to be required for viral reactivation from latency in primary T cells (7).…”