| HIV-1, causative agent of the devastating pandemic of AIDS, shows incredible sequence variation, providing a substantial challenge for vaccine design. The aim of this thesis is to characterize HIV-1 diversity by examining levels of inter-subtype recombination and APOBEC-mediated proviral hypermutation, and determine its importance, by associating diversity with pathogenesis.;We identified a subset of individuals with high levels of proviral HIV-1 APOBEC-mediated hypermutation, which correlated with CD4+ count. This indicated that APOBEC3F/3G hypermutation may be important in controlling disease progression. Sequencing the APOBEC3G gene revealed three polymorphisms that were significantly associated with hypermutation; two of these were located in the region 5' of the APOBEC3G gene and may control expression. This data suggests that contrary to previous studies, APOBEC-mediated hypermutation may be controlled by increased activity of host APOBEC3G rather than by defects in the viral Vif. We thus suggest that increases in APOBEC3F/G activity may play a protective role in disease progression. The exploitation of these findings may aid in the development of HIV prevention and therapeutic strategies.;The results of this thesis were obtained by sequencing samples collected from subjects enrolled in two cohorts located in Nairobi, Kenya, composed of individuals involved in commercial sex work (CSW) and those who are not. We found, in agreement with previous studies, that CSW were more likely to be infected with recombinant virus than non-sex workers. This suggests that all individuals at high risk for HIV acquisition may be important drivers of viral diversity in the global pandemic and are thus an important target for prevention and intervention strategies. |
