Role of HIV Nef in establishment and maintenance of HIV latency

HIV establishes a latent infection in CD4+ T cells that is not affected by current antiretroviral treatments. Because drug withdrawal allows viruses released from these cellular reservoirs to replicate, patients must remain on therapy for life to prevent re-emergence of the progressive disease. Although strategies to cure HIV infection are being discussed, development of an effective approach will require novel treatments that can eradicate reservoirs of latent virus. For this to occur, there is a need for a better understanding of HIV persistence, including knowledge of host and viral mechanisms required to establish and maintain latency. Formation of latent HIV reservoirs is thought to occur, in part, through infection of T cells that are either poorly activated or that revert to a non-activated state prior to death by viral cytopathic or host immune-mediated effects.

This study will investigate the role of the HIV pathogenic protein Nef in the establishment and maintenance of viral latency.

Dr. Mwimanzi hypothesizes that the Nef protein functions as a molecular “switch”, which regulates the activation threshold of virus-infected T cells. Using in vitro cell culture systems and panels of Nef variants that include site-directed mutants and patient-derived isolates, he will examine whether differences in Nef function affect the ability of a cell to establish or maintain latency.

It is anticipated that the results will help identify critical Nef motifs, evaluate interactions between Nef and host cell proteins, and elucidate viral and cellular mechanisms of HIV latency. With increased understanding of the mechanisms of HIV latency, this research has the potential to improve the health of those infected with HIV.