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1. Understanding how to generate effective antiviral CD8 T cells specific for SIV/HIV
Even though designing an effective CD8 T cell based preventative HIV vaccine may be extremely challenging, there is reason to believe that a therapeutic CD8 T cell based HIV vaccine may be possible. However, eliciting the most potent CD8 T cells in someone who is HIV+ is key. We are currently testing the hypothesis that an IL-15 superagonist can boost the function of CD8 T cells in prophylactically or therapeutically vaccinated animals by increasing their number, altering their localization, and improving their antiviral capacity. We think that this type of intervention may be able to harness the host immune response to destroy SIV-infected cells, in the absence of antiretroviral treatment. We think that the information we learn from this study over the next five years will influence the development of therapeutic HIV interventions.
2. Determining how a pre-existing SIV-infection disrupts host immunity to M. tuberculosis
The most common cause of morbidity and mortality in HIV+ individuals is Tuberculosis (TB). Unfortunately, we do not fully understand why HIV+ individuals, even those on HAART, are at such a greater risk for developing active TB disease. We have been working with Drs. Charles Scanga and JoAnne Flynn at the University of Pittsburgh to study T cell responses to M. tuberculosis in Mauritian cynomolgus macaques. We have mapped epitopes in M. tuberculosis that are restricted by common MHC molecules in these animals to create specific MHC:peptide tetramers. We also find that SIV infection specifically disrupts the ability to mount an effective immune response to M. tuberculosis, leading to more active TB disease. We are now trying to understand the immunological mechanism responsible for the SIV-dependent defects in host immunity to M. tuberculosis in both adult and juvenile macaques. We hope our studies will help define how SIV (as a model for HIV) disrupts host immunity to M. tuberculosis so that interventions can be developed to preserve effective anti-M. tuberculosis immune responses in those infected with immunodeficiency virus.
3. Understanding the dynamics of virus and bacterial pathogens with molecularly barcoded strains
The development of the tools to molecularly barcode pathogens and then characterize them by deep sequencing has greatly facilitated our ability to study virus and bacterial dynamics upon infection. We are using molecular barcodes for different purposes. We are using barcoded SIV to track the number of infecting viruses in an animal, the selection of escape mutations, and the establishment of the viral reservoir. We are also using a barcoded strain of M. tuberculosis to track dissemination of Mtb in macaques. We have also used a barcoded strain of Zika to track the persistence of individual virus templates in different macaques. These tools are used to ask biologically interesting questions, but it requires a specific interest in sequencing pathogens and then the patience and skill to work through bioinformatic analyses to interpret the data.
4. Pathogen fee-for-service sequencing
Within our lab, we have a Pathogen fee-for-service sequencing unit that is a component of Research Services at the Wisconsin National Primate Research Center. This unit is devoted to sequencing pathogens for clients both at UW and outside of UW. We have sequenced strains of SIV, HIV, Zika, SARS-CoV-2, and other viruses for numerous clients. We sequenced several SARS-CoV-2 stocks that are being used in animal studies at other institutions over the past year. This service unit helps our lab’s sequencing skills continue to grow, lets us collaborate with other researchers, and provide a service to help other investigators.