This week we profile a recent publication in Cell Reports from the laboratory of Dr. Mark Brockman (pictured) at Simon Fraser University and the British Columbia Centre for Excellence in HIV/AIDS.
Can you provide a brief overview of your lab’s current research focus?
Our laboratory uses molecular and cell biology methods to investigate questions at the intersection of virology, pathogenesis, and the human immune response to HIV. We are particularly interested to understand aspects of host innate and adaptive immunity that can control infection and mechanisms used by the virus to evade these responses, which will inform the development of vaccines and novel therapies. HIV is one the most diverse human pathogens known, with the global pandemic dominated by nine genetically distinct subtypes and numerous inter-subtype recombinant forms. HIV is also highly mutable, allowing it to evolve and adapt to the environment present within a specific host. As such, every HIV-infected individual represents a unique host/virus interaction that is complex and constantly changing in the absence of antiretroviral therapy. Ongoing studies in our group aim to better understand the impact of HIV sequence polymorphisms on viral protein function; to assess the role of HIV accessory proteins in establishment and maintenance of viral latency; and to employ new assays to identify patient-derived T cells (and T cell receptors) that display enhanced ability to recognize virus-infected cells.
What is the significance of the findings in this publication?
The cellular multipass transmembrane protein serine incorporator 5 (SERINC5) was recently identified to be a novel antiviral protein that restricts HIV infectivity. SERINC5 activity can be counteracted by the viral Nef protein, which internalizes SERINC5 from the plasma membrane of infected cells and prevents it from being loaded onto the surface of newly formed virions. To date, very few studies have examined the ability of circulating HIV Nef variants to antagonize SERINC5, thus our understanding of natural variation in this Nef function is limited.
In this paper, we compared the ability of HIV Nef clones isolated from 45 elite controllers (who maintain very low plasma viremia in the absence of therapy) and 46 untreated progressors (who display high plasma viremia and CD4 T cell decline) to antagonize SERINC5. Our results demonstrate that Nef clones from elite controllers were impaired in their ability to internalize SERINC5 compared to those from progressors. Furthermore, we identified several Nef polymorphisms that contributed to the reduced function seen in natural isolates. Notably, two of these Nef polymorphisms are known to be selected in individuals who express particular HLA class I alleles, suggesting that viral adaptation to CD8 T cell responses in these cases may lead to attenuation of Nef’s ability to counteract SERINC5.
This study is significant because it provides the largest analysis to date of SERINC5 antagonism activity in circulating HIV Nef variants. Attenuation of this function in Nef clones isolated from elite controllers suggests that natural variation in this activity may contribute to differences in viral pathogenesis, particularly in cases where the host adaptive immune response targets viral epitopes in regions of Nef that are also important for SERINC5 internalization function.
What are the next steps for this research?
We are currently extending this work by examining the SERINC5 antagonism activity of Nef clones isolated from diverse populations that represent several major HIV subtypes. Our results indicate that subtype-associated differences in SERINC5 antagonism are apparent, further suggesting that differences in this Nef function may contribute to clinical outcome.
This work was funded by:
This study was supported by research grants from the CIHR and the NIH (USA). The lead author, Steven Jin, received the Fredrick Banting and Charles Best Graduate Scholarship from the CIHR. Mark Brockman was supported by the Canada Research Chairs Program.
