The Tussle Between Mycobacteria and Host: To Eat or Not To Eat.

Autophagy is a catabolic process of cellular homeostasis evolutionarily conserved in eukaryotes. To block infection of intracellular bacterial pathogens, metazoans deploy autophagy for pathogen clearance through phago-lysosome formation and specific bactericidal peptides. Although an array of research have publicized the host regulatory factors, the function of bacterial effectors are yet to be understood in detail. In this article, we focus on the autophagic response to one of the most successful intracellular bacteria Mycobacterium tuberculosis.

Tat predominantly associates with host promoter elements in HIV-1-infected T-cells - regulatory basis of transcriptional repression of c-Rel.

HIV-1 Tat is a multifunctional regulatory protein that, in addition to its primary function of transactivating viral transcription, also tends to modulate cellular gene expression, for which the molecular mechanism remains to be clarified. We have reported earlier nuclear factor kappa B (NFκB) enhancer binding activity of Tat and proposed this DNA binding activity as a possible molecular basis for Tat-mediated regulation of cellular gene expression in infected cells. In the present study, we analyzed the genome-wide occupancy of Tat protein on host cell chromatin in HIV-1-infected T-cells to investigate a potential role of Tat on cellular gene expression. The results obtained identify a spectrum of binding sites of Tat protein on the chromatin and reveal that Tat is also recruited on a number of cellular gene promoters in HIV-1-infected T-cells, indicating its possible involvement in the regulation of gene expression of such cellular genes. Tat was identified as a repressor of one such validated gene, c-Rel, because it downregulates the expression of c-Rel in both Tat expressing and HIV-1-infected T-cells. The results also show that Tat downregulates c-Rel promoter activity by interacting with specific NFκB sites on the c-Rel promoter, thus providing a molecular basis of Tat-mediated regulation of cellular gene expression. Thus, in the present study, we have not only identified recruitment sites of Tat on the chromatin in HIV-1-infected T-cells, but also report for the first time that c-Rel is downregulated in HIV-1-infected cells specifically by interaction of Tat with NFκB binding sites on the promoter.

Epigenetic regulation of HIV-1 persistence and evolving strategies for virus eradication.

Despite the intense effort put by researchers globally to understand Human Immunodeficiency Virus (HIV-1) pathogenesis since its discovery 30 years ago, the acquired knowledge till date is not good enough to eradicate HIV-1 from an infected individual. HIV-1 infects cells of the human immune system and integrates into the host cell genome thereby leading to persistent infection in these cells. Based on the activation status of the cells, the infection could be productive or result in latent infection. The current regimen used to treat HIV-1 infection in an AIDS patient includes combination of antiretroviral drugs called Highly Active Anti-Retroviral Therapy (HAART). A major challenge for the success of HAART has been these latent reservoirs of HIV which remain hidden and pose major hurdle for the eradication of virus. Combination of HAART therapy with simultaneous activation of latent reservoirs of HIV-1 seems to be the future of anti-retroviral therapy; however, this will require a much better understanding of the mechanisms and regulation of HIV-1 latency. In this chapter, we have tried to elaborate on HIV-1 latency, highlighting the strategies employed by the virus to ensure persistence in the host with specific focus on epigenetic regulation of latency. A complete understanding of HIV-1 latency will be extremely essential for ultimate eradication of HIV-1 from the human host.

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.