Examining the function of primary HIV-1 Nef isolates in the setting of viral control

HIV is a global pandemic. While combination anti-retroviral therapy can block viral replication, HIV establishes latent reservoirs that persist for life. A rare group of HIV-infected individuals called “elite controllers” spontaneously suppress plasma viremia to clinically undetectable levels. Understanding how elite controllers contain HIV could assist in developing more effective interventions, such as vaccines or eradication strategies. The HIV Nef protein is critical for viral pathogenesis and progression to AIDS. Nef modulates cellular proteins to increase viral replication and to evade host immunity. Functional impairment of several HIV proteins has been seen in elite controllers, but prior to my thesis a systematic analysis of Nef had not been done. To explore this, I examined Nef clones from elite controllers and progressors. I observed that Nef clones from controllers displayed significantly lower activity for multiple functions. Furthermore, I identified natural polymorphisms in Nef that contributed to attenuated function and confirmed these by testing Nef mutants. In summary, I have shown that natural sequence variation in Nef results in substantial differences in protein function. Nef clones isolated from elite controllers displayed the poorest activity for multiple functions, indicating that attenuation of Nef may contribute to reduced pathogenesis in these cases. Therapeutic targeting of the Nef domains identified in my studies could contribute to HIV eradication strategies.