Date of Graduation
School of Medicine
Microbiology, Immunology, and Cell Biology
Retroviruses have a great capacity to evolve in order to over come selection pressures in the environment. Such evolutional power comes from the high mutation rate and the high viral titers that can ensue during an infection. Mutation generates variation in the viral genome. In addition, previous reports found that retroviruses recombine at a relatively high rate. These sources of variation can then be exploited by the population to ensure the presence of advantageous mutations, which become amplified during virus propagation. Because the adaptability is based on the evolutionary potential of the virus, it is essential to study the mechanisms employed in this process. Recombination can accelerate the generation of multidrug-resistant HIV-1 and therefore presents challenges to effective antiviral therapy. We determined that HIV-1 recombination rates with markers 1.0, 1.3, and 1.9 kb apart were 42.4, 50.4, and 47.4% in one round of viral replication. Because the predicted recombination rate of two unlinked markers is 50%, we conclude that markers 1 kb apart segregated in a manner similar to two unlinked markers in one round of retroviral replication. These recombination rates are exceedingly high even among retroviruses. To explore how efficiently HIV-1 can assort markers separated by short distances, we developed a flow-cytometry-based system to study recombination. Using this system, we determined that the recombination rates of markers separated by 588, 300, 288, and 103 bp in one round of viral replication are 56, 38, 31, and 12%, respectively, of the theoretical maximum measurable recombination rate. Statistical analyses revealed that at these intervals, recombination rates and marker distances have a near-linear relationship that is part of an overall quadratic fit. Additionally, we examined the effects of target cells and viral accessory proteins on recombination rate. The results indicated that infection of primary T-cells and the presence or absence of accessory proteins had no effect on recombination. These results illustrate the power of recombination in generating viral population variation and predict the rapid assortment of mutations in the HIV-1 genome in infected individuals.
Rhodes, Terence D., "High frequencies of HIV-1 recombination and the evolutionary potential of a hybrid retrovirus" (2006). Graduate Theses, Dissertations, and Problem Reports. 2402.