Basic Science of Mucosal Immunity and Viral Persistence
Understanding HIV tissue reservoirs and the immunology and microbiome of mucosal sites
HIV persistence in mucosal sites may provide a significant reservoir for the virus, even in patients undergoing antiretroviral therapy (ART). This reservoir may be a substantial barrier to curing HIV. Dr. Bull studies factors that promote persistence and replenishment of the HIV reservoir. Her research includes defining the immunological environment within mucosal sites, assessing viral dynamics and shedding, and determining the contribution of the local microbiome and virome to the maintenance of HIV reservoirs. Much of Dr. Bull’s work focuses on HIV in the female genital tract, where she is defining immune T cell populations, characterizing inflammation related to the microbiome and chronic virus infections, and identifying factors that affect viral shedding and reservoir maintenance. This research addresses health disparities, as a majority of new US diagnoses of HIV infection are among non-Hispanic Black women.
In all individuals with HIV, co-infection with other chronic viruses is common, particularly herpes simplex viruses including HSV-1 and HSV-2; cytomegalovirus (CMV); and Epstein-Barr virus (EBV). Dr. Bull found that subclinical reactivation of HSV is associated with higher HIV DNA during ART. She is continuing to investigate the role of other viruses in HIV reservoir persistence, testing the hypothesis that the immune response to co-infecting viruses stimulates proliferation of CD4+ T cells with integrated HIV, which expands the HIV reservoir. This proliferation could select for an HIV population with greater diversity and enhanced survival. Dr. Bull is studying the relationship between subclinical herpes shedding and HIV DNA concentration, cytokine production, and HIV envelope diversity to gain a better understanding of the role of co-infections in promoting HIV persistence. Potential applications of her results include therapeutically controlling other chronic viruses or regulating inflammation as part of HIV therapy and cure strategies.
Dr. Bull’s is also evaluating CD4+ regulatory T cells in individuals infected with HIV in the context of vaccines. She is interested in determining if vaccines shift the T cell profile of people infected with HIV toward a more suppressive state, potentially making the vaccines less effective. Given Dr. Bull’s expertise in mucosal tissues and the immunologic environment in mucosal sites, she would be interested in industry collaborations focused on gaining a better understanding of the impact of and interplay among the environment of mucosal and tissue sites including the local microbiome and virome, vaccination, and the persistence of HIV reservoirs.
Stage of Development
- Human blood and tissue pre-clinical trials
- Human blood and tissue clinical trials
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Stinn T, Kuntz S, Varon D, Huang ML, Selke S, Njikan S…Bull ME. Subclinical genital herpes shedding in HIV/herpes simplex virus 2-coinfected women during antiretroviral therapy is associated with an increase in HIV tissue reservoirs and potentially promotes HIV evolution. J Virol. 2020;95(1):e01606-20.
- Bull ME, McKernan JL, Styrchak S, Kraft K, Hitti J, Cohn SE, et al. Phylogenetic analyses comparing HIV sequences from plasma at virologic failure to cervix versus blood sequences from antecedent antiretroviral therapy suppression. AIDS Res Hum Retroviruses. 2019;35(6):557-566.
- Bull ME, Mitchell C, Soria J, Styrchak S, Williams-Wietzikoski C, Legard J, et al. Monotypic low-level HIV viremias during antiretroviral therapy are associated with disproportionate production of X4 virions and systemic immune activation. AIDS. 2018; 32:1389-1401.
- Ticona E, Bull M, Soria J, Legard J, Styrchak S, Williams C, et al. Biomarkers of inflammation in HIV-infected Peruvian men and women before and during suppressive antiretroviral therapy. AIDS. 2015;29(13):1617-1622.
- Bull M, Legard J, Tapia K, Sorensen B, Cohn S, Garcia R, et al. HIV-1 Shedding From the Female Genital Tract is Associated With Increased Th1 Cytokines/Chemokines That Maintain Tissue Homeostasis and Proportions of CD8+FOXP3+ T Cells. JAIDS Journal of Acquired Immune Deficiency Syndromes. 2014;67(4):357-364.
- Bull M, Heath L, McKernan-Mullin J, Kraft K, Acevedo L, Hitti J, et al. Human Immunodeficiency Viruses Appear Compartmentalized to the Female Genital Tract in Cross-Sectional Analyses but Genital Lineages Do Not Persist Over Time. Journal of Infectious Diseases. 2013;207(8):1206-1215.
- Bull M, Learn G, Genowati I, Mckernan J, Hitti J, Lockhart D, et al. Compartmentalization of HIV-1 within the Female Genital Tract Is Due to Monotypic and Low-Diversity Variants Not Distinct Viral Populations. PLoS ONE. 2009;4(9):e7122.