Control of retroviral replication by host cellular factors

Retroviruses are undoubtedly one of the most elegant entities of the world. With modest genomes and intricate architecture, retroviruses are able to invade a species, establish a domicile, evade the immune system and rapidly evolve to successfully replicate in a specialized niche of the host. To establish a productive infection, retroviruses heavily rely on the host factors to successfully complete their replication cycle. Yet, as the retrovirus directs coordination and utilization of various host proteins for its own benefit, it simultaneously must evade interactions with the host antiviral and immune proteins that are in place to limit virus replication.; This dissertation is dedicated to the study of the interactions of host proteins the virus encounters as it infects a cell. In the first chapters, I sought to understand the role of the cellular uracil DNA Glycosylase, UNG2, in the replication cycle of HIV-1. UNG2 is packaged into HIV-1 virions, which led to assumptions that UNG2 must be critical to the HIV-1 lifecycle. However, work by various groups led to discordant conclusions that UNG2 played both positive and negative roles in the viral lifecycle. It appeared to be both essential for reverse transcription (positive) and involved in mediating the antiviral effect of Apobec3G, a cytidine deaminase that generates uracils in the viral DNA during reverse transcription (negative). Using novel strategies, I found that UNG2 is completely dispensible for HIV-1 replication. Moreover, UNG2 does not modulate the loss of infectivity caused by the antiviral, Apobec3G. Finally, in the third chapter I reconstructed part of an ancient, extinct retrovirus (PtERV) that infected chimpanzees, to test the hypothesis that the antiviral factor, human Trim5alpha, played a role in protecting early humans from infection of this virus. I found that human Trim5alpha potently restricts PtERV infectivity. Additionally, the ability of Trim5alpha to restrict PtERV and HIV-1 is mutually exclusive. Therefore, if PtERV did exert a selection on Trim5alpha in the human lineage 4mya for the ability to restrict and protect humans from infection, it has left our species with a version of Trim5alpha that has made us more susceptible to the current pandemic of HIV-1.