Graduate Research Prize Winners 2009
After completing an undergraduate degree in basic science at the University of Manitoba in 2002, I had an opportunity to do a PhD in HIV immunology. However, I temporarily postponed this path as I started medical school at McGill University that same year. In my second year of medical studies, I was awarded the Rhodes Scholarship which allowed me to carry out research at Oxford University. Under the supervision of Prof. Sarah Rowland-Jones, Dr. Tao Dong, and Prof. Andrew McMichael, starting in2004, I conducted research in the very field I had always wanted to explore.
My DPhil research focused on HIV-2 immunology in West Africa. Similar to HIV-1, HIV-2 is a retrovirus responsible for causing immunodeficiency. However, unlike HIV-1, disease progression is much less frequent, with only approximately 20% of patients developing AIDS. Approximately 1 million people worldwide are infected with this virus, most of whom live in West Africa. The project’s aim was to determine how the cellular immune system in HIV-2 infected subjects prevents disease progression in the majority of the patients. This was accomplished by studying a community cohort in a remote village in Guinea Bissau, West Africa. The cohort offered the unique opportunity to study individuals in a community versus a clinical setting, the latter of which skews results to the proportion of patients with progressive disease.
The first phase of the study screened for anti-HIV-2 cellular immune responses using a 3-dimensional matrix of HIV-2 peptides spanning the entire proteome, allowing the mapping of immunodominant regions of the virus. The results identified a highly conserved region of the HIV-2 p26 capsid protein that was recognized more frequently by patients who demonstrated control of virus replication. The study for the first time identified an association between antigen-specific immune responses and virus replication control at a single epitope level.
Subsequent analysis involved determining the function of antigen-specific CD8 T cells. This was accomplished both ex vivo using tetramer staining, and in vitro using CD8 T cell clones. The results showed that immunodominant HIV-2 –specific T cells demonstrate high avidity, have an oligoclonal T cell receptor repertoire, and secrete multiple pro-inflammatory cytokines. Furthermore, viruses isolated from individuals making such strong immunodominant responses lack evidence of immune escape by sequence mutation in the region of the epitope. The study identifies the regions of the virus that induce strong immune responses and are resistant to immune escape by sequence evolution. These regions will be good targets for future vaccine design.
- Leligdowicz A, Yindom LM, Onyango C, Sarge-Njie R, Alabi A, Cotten M, Vincent T, da Costa C, Aaby P, Jaye A, Dong T, McMichael A, Whittle H, Rowland-Jones S. (2007) Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection. J Clin Invest. 117:3067-74.