Title: Human immunodeficiency virus type 1 subtype C and hematopoiesis
Description: Human Immunodeficiency virus (HIV) currently infects an estimated 39.5 million people worldwide with seventy percent of those infected individuals living in sub-Saharan Africa. Reports from southern Africa, an area plagued almost exclusively by HIV-1 subtype C (HIV-1C), have shown higher rates of anemia among HIV positive patients when they are compared to similar patients in the United States where most HIV infections are caused by subtype B. This led to the hypothesis of this dissertation that HIV-1C can more readily infect hematopoietic progenitor cells (HPC) and thereby directly constrain hematopoiesis. The hypothesis was explored in three separate aims. The first aim was to determine the effect of HIV-1C infection on hematopoiesis. To explore this aim a cross-sectional analysis of HIV-1C infected African patients and uninfected controls was performed. The results of this study found that HIV-1C infection effected hematopoiesis in a direct manner that has not been described for HIV-1B. The second aim was to examine whether HIV-1C could infect hematopoietic colony-forming cells in vitro , and if this phenotype differed from HIV-1B. The results of this work demonstrated a significant difference in the ability of HIV-1C isolates to infect HPC in vitro . HIV-1C infected HPC populations were also found in vivo . These patients were divided according to their hemoglobin levels and it was found that having an infected HPC population was associated with higher rates of anemia in southern Africa.

This new phenotype was termed hematotropic. The final aim of this project was to explore what part of the virus was responsible for conferring the hematotropic phenotype. It was found that the envelope of HIV-1C is necessary for this hematotropic phenotype. Furthermore, these findings indicated that the expanded cell tropism identified here could be controlled by mutations in the V2 and CD4 binding loop of the viral envelope that allow for greater binding to the CD4 receptor while possibly protecting the virus from neutralization. These findings should be taken into consideration when examining anti-HIV therapy strategies in areas where HIV-1C is prevalent such as southern Africa.