HIV infection in humans leads to a progressive depletion of CD4+ T cells resulting in immunodeficiency. However, the mechanism by which HIV depletes CD4+ cells specifically remains one of the most important yet unanswered questions in AIDS research. Although HIV selectively infects CD4+ cells, the relatively few infected cells in vivo does not account for the extent of CD4+ T cell depletion. This has led to the idea that the virus is able to kill uninfected bystander CD4+ cells. Several viral and host associated factors have been proposed to play a role in the AIDS pathogenesis like the viral Env glycoprotein, immune activation, host CCR5 genotypic make-up etc. While HIV disease is clearly associated with immune activation and CD4+ T cell decline, the cause and consequence relation of the two has yet to be established. Moreover, the interaction of the viral Env glycoprotein with the host in regulating AIDS progression remains unknown. Hence, in this study, we propose to conduct a comprehensive examination of the host factors like immune activation, CCR5 gene and promoter polymorphism as well as viral determinant like phenotype and genotype of the Env genes derived from HIV-1 infected patients to determine how they play a concerted role in AIDS progression. Importantly, understanding the host and viral factors in disease progression may have diagnostic use for predicting disease outcome as well as developing treatment strategies.
After more than 30 years of research, the mechanism via which HIV infection leads to CD4+ T cell depletion and AIDS development remains unclear. While several viral and host factors have been implicated in AIDS progression in several independent studies, it is not known how these factors collectively determine disease progression rate in HIV infected individuals. Moreover, how virus replication, immune activation and host genetics work in concert to regulate AIDS progression is yet to be elucidated. Hence, in this proposal we will investigate how host and viral factors collectively influence HIV pathogenesis and disease progression. The findings from this study potentially have translational implications for better prognosis and treatment strategies.
| Garg, Himanshu; Joshi, Anjali (2017) Host and Viral Factors in HIV-Mediated Bystander Apoptosis. Viruses 9: |
| Joshi, Anjali; Punke, Erin B; Sedano, Melina et al. (2017) CCR5 promoter activity correlates with HIV disease progression by regulating CCR5 cell surface expression and CD4 T cell apoptosis. Sci Rep 7:232 |
| Joshi, Anjali; Cox, Emily K; Sedano, Melina J et al. (2017) HIV-1 subtype CRF01_AE and B differ in utilization of low levels of CCR5, Maraviroc susceptibility and potential N-glycosylation sites. Virology 512:222-233 |
| Joshi, Anjali; Sedano, Melina; Beauchamp, Bethany et al. (2016) HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients. J Immunol 196:1768-79 |
