Date of Award
HIV-1, HAART, antiviral drug therapy, IN (antiviral drugs), viral integrase, carboxyl-terminal domain (CTD)
The Human Immunodeficiency Virus Type-1 (HIV-1) is the causative agent of the Acquired Immune Deficiency Syndrome (AIDS). Combination antiviral therapy has proven to be particularly effective at suppressing viral replication, yet complete eradication of the virus from an infected individual remains elusive. Recently, a new class of antiviral drugs targeting the viral integrase (IN) has been added to the HAART (high active antiretroviral therapy) regimen. This novel drug class exerts its inhibitory effect by targeting one aspect of the dual-staged integration reaction. In contrast to the other two viral targets of HAART, the reverse transcriptase (RT) and protease (PR) enzymes, both of which have singular roles in viral replication, IN contributes a plurality of functions to the viral life cycle, thus potentiating the development for further therapeutic intervention. In spite of the intensity of investigation in the field, the mechanistic details of several aspects of IN activity, especially of its ancillary functions remain unclear. This thesis work focuses primarily on dissecting the contribution of the carboxyl-terminal domain (CTD), in particular the terminal 18 amino acid â€˜tailâ€™ of this domain, to both the primary integration activities and secondary functions of IN. This was accomplished by conducting a survey of incremental deletions aimed at gradually removing this region of the protein, and testing the resulting viruses in a number of measurable assays of virologic function. In so doing we identified a number of anomalous mutant phenotypes, the ensuing characterization of which should contribute to better understanding the roles of IN with regard to both its primary and secondary functions in the replicative strategy of HIV-1.
Mohammed, Kevin Dominic, "Dissecting the Contribution of the Carboxyl-Terminal Domain and Tail of HIV-1 Integrase to Viral Dynamics and Enzymatic Function" (2010). Student Theses and Dissertations. 71.