Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus type 1 (HlV-1) is one of the most important challenges for chemotherapy of the early 21 st century. In the absence of an effective vaccine, a combination of inhibitors of HlV-1 reverse transcriptase and protease provide strong support for control of HIV infection. Recently, HlV-1 integrase inhibitors have also been added to this drug regimen. However, a major challenge in developing an effective therapy against HIV-1 is the emergence of multidrug-resistant virus strains, containing mutations in viral enzymes. Therefore, it is essential to obtain detailed mechanistic information on these key viral enzymes for the continued development of better drugs. During HlV-1 replication, the RNA genome is reverse transcribed into an integration competent double stranded DNA by HlV-1 reverse transcriptase. This viral DNA is subsequently integrated into the host genome by the HlV-1 integrase. My long term goal is to decipher the molecular details of interactions between essential viral and cellular enzymes with their nucleic acid substrates during retroviral replication. This is based on my preliminary and published data, where alterations in nucleic acid structure have influenced their recognition by HlV-1 reverse transchptase. The central hypothesis of the proposal is that structures of nucleic acids play an important role during retroviral replication. The rationale of my hypothesis is based on the manner in which retroviral enzymes accommodate conformationally-distinct nucleic acid substrates. Exploiting my nucleoside analog methodology and proposed virology training, I will validate my hypothesis with specific aims: 1) How does the nucleic acid structure/geometry influence HlV-1 integration and 2) How APOBEC3G recognizes the single stranded viral DNA. New and important biochemical data obtained from my studies will facilitate our understanding on the mechanism of HlV-1 replication, which is essential to design better and effective drugs against HIV.
Gaining a deeper understanding of the interaction between HlV-1's nucleic substrates and its viral enzymes will reveal details about virus replication that will allow scientists to design more effective drugs against HIV.
|Balasubramaniam, Muthukumar; Davids, Benem; Addai, Amma B et al. (2017) Measurement of In Vitro Integration Activity of HIV-1 Preintegration Complexes. J Vis Exp :|
|Welch, Jennifer L; Madison, Marisa N; Margolick, Joseph B et al. (2017) Effect of prolonged freezing of semen on exosome recovery and biologic activity. Sci Rep 7:45034|
|Swepson, Chelsie; Ranjan, Alok; Balasubramaniam, Muthukumar et al. (2016) Cocaine Enhances HIV-1 Transcription in Macrophages by Inducing p38 MAPK Phosphorylation. Front Microbiol 7:823|
|Kaneshiro, Bliss; Edelman, Alison; Dash, Chandravanu et al. (2016) Effect of oral contraceptives and doxycycline on endometrial MMP-2 and MMP-9 activity. Contraception 93:65-9|
|Passaro, Ryan Colby; Pandhare, Jui; Qian, Han-Zhu et al. (2015) The Complex Interaction Between Methamphetamine Abuse and HIV-1 Pathogenesis. J Neuroimmune Pharmacol 10:477-86|
|Pandhare, Jui; Dash, Sabyasachi; Jones, Bobby et al. (2015) A Novel Role of Proline Oxidase in HIV-1 Envelope Glycoprotein-induced Neuronal Autophagy. J Biol Chem 290:25439-51|
|Beni, Yousef; Dash, Chandravanu; Parang, Keykavous (2015) Synthesis of ?-triphosphotriester pronucleotides. Tetrahedron Lett 56:2247-2250|
|Addai, Amma B; Pandhare, Jui; Paromov, Victor et al. (2015) Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients. J Leukoc Biol 97:779-90|
|Dash, Sabyasachi; Balasubramaniam, Muthukumar; Villalta, Fernando et al. (2015) Impact of cocaine abuse on HIV pathogenesis. Front Microbiol 6:1111|
|Pandhare, Jui; Addai, Amma B; Mantri, Chinmay K et al. (2014) Cocaine enhances HIV-1-induced CD4(+) T-cell apoptosis: implications in disease progression in cocaine-abusing HIV-1 patients. Am J Pathol 184:927-936|
Showing the most recent 10 out of 20 publications