Can you provide a brief overview of your lab’s current research focus?
Our joint lab groups at Simon Fraser University and the BC Center for Excellence in HIV/AIDS investigate HIV pathogenesis and the human immune response to viral infection. We use molecular, cell biology and genetics approaches to examine host/pathogen interactions that may inform the development of vaccines, therapeutics and potentially a cure for HIV.
What is the significance of the findings in this publication?
Our study explores how natural sequence diversity in the HIV Nef protein affects its ability to counteract two cell surface proteins, Serine incorporator (SERINC) 3 and 5. Human cells encode a variety of restriction factor proteins that protect them from viral infection. SERINC proteins integrate into the membrane of viral particles and impair their ability to infect new cells. The HIV Nef protein removes SERINC proteins from the infected cell’s surface, thereby restoring viral infectivity. HIV is genetically diverse and globally distributed viral subtypes display variable pathogenicity, but the impact of Nef-mediated SERINC antagonism on clinical outcome is unknown. In collaboration with our African partners, we isolated hundreds of Nef clones representing four major HIV subtypes and tested their ability to counteract SERINC3 and SERINC5. We observed that Nef isolates differed markedly in SERINC antagonism activity, but overall, each viral subtype’s ability to counteract the more potent restriction factor (SERINC5) correlated with its pathogenic potential, indicating that this Nef function likely contributes to disease. In addition, many Nef isolates from Canada displayed poor ability to counteract SERINC3 compared to those from African sites, suggesting unexpected differences in pathogenesis between viral subtypes. Finally, we identified naturally occurring Nef mutations that selectively impaired SERINC3 or SERINC5 antagonism, providing the first evidence that these functions are genetically separable.
What are the next steps for this research?
Our results indicate that HIV Nef uses somewhat distinct mechanisms to counteract SERINC3 and SERINC5, but precise details are not known. To explore this, we are using confocal microscopy to examine the intracellular localization of selected Nef mutants as well as their ability to co-localize with SERINC proteins and other components of the protein trafficking machinery. We hope this work will uncover critical interactions between Nef and cellular proteins that can be targeted by therapeutics.