Activation of human T cell leukemia virus type 1 (HTLV-1) transcription is established through the formation of protein complexes on the viral promoter that are essentially composed of the cellular basic leucine zipper (bZIP) transcription factor cAMP-response element-binding protein (CREB (or certain other members of the ATF/CREB family), the HTLV-1-encoded transactivator Tax, and the pleiotropic cellular coactivators p300/CBP. HTLV-1 bZIP factor (HBZ) is a protein encoded by HTLV-1 that contains a bZIP domain and functions to repress HTLV-1 transcription. HBZ has been shown to repress viral transcription by dimerizing with CREB, which occurs specifically through the bZIP domain in each protein, and preventing CREB from binding to the DNA. However, we previously found that HBZ causes only partial removal of CREB from a chromosomally integrated viral promoter, and more importantly, an HBZ mutant lacking the COOH-terminal bZIP domain retains the ability to repress viral transcription. These results suggest that an additional mechanism contributes to HBZ-mediated repression of HTLV-1 transcription. In this study, we show that HBZ binds directly to the p300 and CBP coactivators. Two LXXLL-like motifs located within the NH 2 -terminal region of HBZ are important for this interaction and specifically mediate binding to the KIX domain of p300/CBP. We provide evidence that this interaction interferes with the ability of Tax to bind p300/CBP and thereby inhibits the association of the coactivators with the viral promoter. Our findings demonstrate that HBZ utilizes a bipartite mechanism to repress viral transcription.Human T-cell leukemia virus type 1 (HTLV-1) 5 is a retrovirus that is the causative agent of adult T-cell leukemia and a neurodegenerative disorder termed tropical spastic paraparesis/HTLV-1-associated myelopathy (1, 2). Following its integration, the provirus utilizes the cellular RNA polymerase II transcription machinery for replication of the viral genome and expression of viral genes. These processes are dependent on the viral transactivator Tax, which is essential for strong activation of HTLV-1 transcription. Tax alone lacks DNA binding activity and is therefore recruited to the viral promoter as part of a complex with the cellular transcription factor CREB or other members of the activating transcription factor/cyclic AMP-responsive element (CRE)-binding protein (ATF/CREB) family (3-6). These proteins carry a basic leucine zipper (bZIP) domain that stimulates protein dimerization and subsequent DNA binding. Dimer formation is specifically mediated through the leucine zipper (ZIP) domain, whereas DNA binding involves the basic region of each binding partner directly contacting the DNA. The Tax-CREB complexes associate with three Tax-responsive elements called viral CREs (vCREs) within the viral promoter that encompasses the U3 region of the 5Ј-long terminal repeat of the provirus. Each vCRE contains a central sequence similar to that of a cellular CRE that is recognized by CREB and flanking GC-rich s...

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The susceptibility of CD4 T cells to human immunodeficiency virus 1 (HIV-1) infection is regulated by glucose and glutamine metabolism, but the relative contributions of these nutrients to infection are not known. Here we show that glutaminolysis is the major pathway fuelling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in T-cell receptorstimulated naïve, as well as memory CD4, subsets and is required for optimal HIV-1 infection. Under conditions of attenuated glutaminolysis, the α-ketoglutarate (α-KG) TCA rescues early steps in infection; exogenous α-KG promotes HIV-1 reverse transcription, rendering both naïve and memory cells more sensitive to infection. Blocking the glycolytic flux of pyruvate to lactate results in altered glucose carbon allocation to TCA and pentose phosphate pathway intermediates, an increase in OXPHOS and augmented HIV-1 reverse transcription. Moreover, HIV-1 infection is Reprints and permissions information is available at www.nature.com/reprints.