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FHS scholars advance HIV pathogenesis research
Faculty of Health Sciences (FHS) postdoctoral fellow Dr. Francis Mwimanzi and MSc graduate Steven Jin worked together to study the interaction between HIV and its human host, revealing insights that deepen our understanding of HIV pathogenesis.
Human cells are equipped with proteins called "restriction factors" that help protect them from viral infection. Viruses in turn encode proteins that counteract these restriction factors, leading to an evolutionary "arms race" of sorts between host and pathogen. In the case of HIV, several viral proteins are known to counteract cellular restriction factors. HIV’s Nef protein was recently discovered to antagonize two restriction factors, called Serine incorporator (SERINC) protein 3 and SERINC 5.
These SERINC proteins are expressed on human cells and become integrated into new viral particles, where they dampen HIV’s ability to infect new cells and attenuate pathogenesis. The Nef protein removes SERINC3 and SERINC5 from the infected cell surface, thereby enhancing HIV’s ability to spread and cause disease.
HIV is a very genetically diverse virus, with many different strains circulating worldwide. Mwimanzi and Jin were interested to understand the impact of HIV genetic diversity on this critical Nef function. To address this, they isolated hundreds of HIV Nef variants from people living with HIV worldwide and tested the ability of each variant to counteract the human SERINC3 and SERINC5 proteins in the laboratory.
They discovered that Nef isolates from circulating viral strains that differed noticeably in their ability to antagonize SERINC3 and SERINC5, and they were able to pinpoint specific naturally occurring mutations in Nef that affected these functions.
“Our findings add another piece to the puzzle as to why some HIV subtypes may be more pathogenic than others and suggest that the interplay between HIV Nef and the human SERINC3/5 proteins may be important in mediating these differences,” Jin explains.
As for the next steps, Mwimanzi further explains that they hope to uncover the precise mechanisms through which Nef counteracts SERINC3 and SERINC5.
“We are using sophisticated microscopy techniques to study whether HIV Nef proteins interact with SERINC proteins inside human cells, and if so, how,” Mwimanzi explains. “This may reveal critical interactions between Nef and cellular proteins that can be targeted by therapeutics.”
Their work, recently published in the scientific journal PLoS Pathogens, uncovers viral features that may contribute to global differences in HIV pathogenesis and could potentially pave the way for new therapeutic strategies.