Molecular pathogenesis of human retroviruses: HIV-1 AND HTLV-1

Acquired immunodeficiency syndrome (AIDS)---a disease clinically characterized by fatal opportunistic infections and malignancies---was first described in 1981(Gottlieb et al.1981, Masur et al. 1981). A few years later, the causative retrovirus was isolated (Gallo et al. 1984) and denominated first as HTLV-1 III/LAV, later as human immunodeficiency virus type-1(HIV-1).; In the year 2004, more than 4 million people in the world were infected by HIV. As this infection is lethal, most of them will die within a decade, although a considerable variation exists in the progression time from the non-symptomatic stage to full-blown AIDS. HIV infection is characterized by a depletion of CD4+ cells (Gottlieb ET al. 1981, Fahey et al. 1984) leading ultimately to an aberrant CD4/CD8 ratio. In addition to the quantitative defects, CD4+ cells are defective in their capability to proliferate upon antigen or mitogen stimulation (Gottlieb et al. 1981, Lane et al.1985), and to produce lypmphokines (Murray et al. 1984). Defective NF- and B-cell functions can also be in infected subjects (Lane et al. 1983, Bonavida et al. 1986). This destruction of the immune system favours opportunistic infections (e.g. Pneumocystis carinii, cytomegalovirus, candida albicans, Cryptosporidium, Salmonella, Toxoplasma) [from "thesis Adobe document).; It is perhaps one of the most dreaded viruses today and much current research on AIDS is aimed at understanding the life cycle of HIV. In order to elucidate the mechanism of transcriptional activation in HIV-1 and to design successful new drugs, it is important to determine all the factors associated with the transcription process of HIV. The HIV-1 encoded RNA-binding protein Tat plays an essential role in viral transcription, replication and pathogenesis (reviewed in Jeang and Gatignol, 1994). The HIV transcriptional activator Tat enhances the processivity of RNA polymerase II by recruiting the CyclinT1/CDK9 complex to the TAR RNA element (Kiernan et al, 1999). In addition, Tat synergizes with the histone acetyltransferase p300 and is acetylated by p300 at a single lysine residue (K50) in the TAR RNA binding domain. Tat acetylation by p300 defines a critical step in Tat transactivation that serves to disrupt the Tat/TAR/CyclinT1 complex and helps in recruiting PCAF to the elongating RNA polymerase II (Kiernan et al, 1999, Mujtaba et. al 2002).; HIV-1 transcription and the coactivators involved in the process is the major focus of my thesis. It is divided into 4 chapters, where the first chapter deals with Retrovirus and Human Immunodeficiency Virus-1 in general, since my thesis projects are mainly focused on HIV-1. In Chapter 2 I've discussed the presence of Transcription Transactivation Domain Associated Protein "TRRAP" in the Tat/TAR-RNA transcription complexes. And I provide the first evidence that TRRAP is an essential cofactor for HIV-1 LTR trans-activation and viral replication. In the Chapter 3 I discuss how the Tat-coactivator interactions inhibit NGF- and brain-derived neurotrophic factor-responsive CRE trans-activation and neurotrophin protection against apoptosis in PC12 and IMR-32 neuroblastoma cells. Finally the 4th chapter focuses on HTLV-1 and its protein p30II.