Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options

Virus-specific CD8(+) T cells play an important role in controlling viral infections including human immunodeficiency virus (HIV) infection. However, during chronic HIV infection, virus-specific CD8(+) T cells undergo functional exhaustion, lose effector functions and fail to control viral infection. HIV-specific CD8(+) T cells expressing high levels of co-inhibitory molecule programmed death-1 (PD-1) during the chronic infection and are characterized by lower proliferation, cytokine production, and cytotoxic abilities. Although, antiretroviral therapy has resulted in dramatic decline in HIV replication, there is no effective treatment currently available to eradicate viral reservoirs or restore virus-specific T or B-cell functions thatmay complement ART in order to eliminate the virus. In recent years, studies in mice and non-human primate models of HIV infection demonstrated the functional exhaustion of virus-specific T and B cells could be reversed by blockade of interaction between PD-1 and its cognate ligands (PD-L1 and PD-L2). In this review, we discuss recent advances in our understanding of PD-1 pathway in HIV/ SIV infection and discuss the beneficial effects of PD-1 blockade during chronic HIV/SIV infection and its potential role as immunotherapy for HIV/AIDS.Funding Agencies|NIH [R01 A107183, R01 A1074417, RC2CA149086]; University of Malaya Research Grant (UMRG) of the Health and Translational Medicine Research Cluster, University of Malaya, Kuala Lumpur [RP021A-13HTM]</p

Диагностика и рекомендации при наследственных дистрофиях на примере дистрофии Штаргарта

Штаргарта дистрофиянаследственные болезнисетчатки дистрофи

Displacement of SATB1-Bound Histone Deacetylase 1 Corepressor by the Human Immunodeficiency Virus Type 1 Transactivator Induces Expression of Interleukin-2 and Its Receptor in T Cells

One hallmark of human immunodeficiency virus type 1 (HIV-1) infection is the dysregulation of cytokine gene expression in T cells. Transfection of T cells with human T-cell leukemia type 1 or 2 transactivator results in the induction of the T-cell-restricted cytokine interleukin-2 (IL-2) and its receptor (IL-2Rα). However, no T-cell-specific factor(s) has been directly linked with the regulation of IL-2 and IL-2Rα transcription by influencing the promoter activity. Thymocytes from SATB1 (special AT-rich sequence binding protein 1) knockout mice have been shown to ectopically express IL-2Rα, suggesting involvement of SATB1 in its negative regulation. Here we show that SATB1, a T-cell-specific global gene regulator, binds to the promoters of human IL-2 and IL-2Rα and recruits histone deacetylase 1 (HDAC1) in vivo. SATB1 also interacts with Tat in HIV-1-infected T cells. The functional interaction between HIV-1 Tat and SATB1 requires its PDZ-like domain, and the binding of the HDAC1 corepressor occurs through the same. Furthermore, Tat competitively displaces HDAC1 that is bound to SATB1, leading to increased acetylation of the promoters in vivo. Transduction with SATB1 interaction-deficient soluble Tat (Tat 40-72) and reporter assays using a transactivation-negative mutant (C22G) of Tat unequivocally demonstrated that the displacement of HDAC1 itself is sufficient for derepression of these promoters in vivo. These results suggest a novel mechanism by which HIV-1 Tat might overcome SATB1-mediated repression in T cells

Amino functionalized novel cholic acid derivatives induce HIV-1 replication and syncytia formation in T cells

Synthesis of C-11 azido/amino functionalized cholic acid derivatives has been achieved in excellent yields. Contrary to the previous prediction of analogous compounds to be HIV-1 protease inhibitors, in the present study these novel cholic acid derivatives induced host cell fusion during the progress of HIV-1 infection and produced multinucleated giant cells. This is the first report of syncytia induction and enhancement of viral replication in HIV-1 infected T cells by cholic acid derivatives

HIV-1 Tat modulates T-bet expression and induces Th1 type of immune response

The HIV-1 transactivator Tat performs various viral and cellular functions. Primarily, it induces processive transcription from the HIV-1 LTR promoter. However, Tat secreted from infected cells is known to activate uninfected lymphocytes through receptors. To further delineate the specific target genes, extracellular Tat was expressed on the cell membrane of stimulator cells and co-cultured with human PBMCs. Along with induced CD4+ T cell proliferation and IFN-γ secretion, there was strong upregulation of T-bet expression which is majorly implicated in generating TH1 type of immune response. To further delineate the effect of extracellular Tat on HIV replication, both p24 analysis and in vivo GFP expression were performed. There was a significant inhibition of HIV-1 replication in human CEM-GFP cell line and hPBMCs. Thus, for the first time we report that apart from its transactivation activity, extracellular Tat acts as a costimulatory molecule that affects viral replication by modulating host immune response through induction of T-bet expression and IFN-γ secretion

Reciprocal regulation of human immunodeficiency virus-1 gene expression and replication by heat shock proteins 40 and 70

Cellular heat shock proteins (Hsps) are induced upon heat shock, UV irradiation and microbial or viral infection. They are also known to be involved in apoptosis and immune response in addition to their chaperone function. Although some literature exists regarding the role of Hsps in human immunodeficiency virus (HIV)-1 infection, a clear understanding of their role remains elusive. Previously, we have shown that Hsp40, a co-chaperone of Hsp70, interacts with HIV-1 negative regulatory factor (Nef) and is required for Nef-mediated increase in viral gene expression and replication. We now show that Hsp70 is also present in the Nef–Hsp40 complex reported earlier. Furthermore, Hsp70 inhibits viral gene expression and replication; however, Hsp40 can rescue this down regulation of viral gene expression induced by Hsp70. We also show that HIV-1 viral protein R is required for this inhibitory effect of Hsp70 on viral replication. Our data further show that Hsp40 is consistently up regulated in HIV-1 infection, whereas Hsp70 is down regulated after initial up regulation favoring viral replication. Finally, Hsp70 expression inhibits the phosphorylation of cyclin-dependent kinase 9 required for high-affinity binding of HIV-1 transactivator of transcription–positive transcription elongation factor b complex to transactivation response RNA, whereas Hsp40 seems to induce it. Thus, Hsp40 and Hsp70, both closely associated in their chaperone function, seem to act contrary to each other in regulating viral gene expression. It seems that Hsp70 favors the host by inhibiting viral replication, whereas Hsp40 works in favor of the virus by inducing its replication. Thus, differential expression of Hsp40 and Hsp70 reciprocally regulates viral gene expression and replication in HIV-1 infection