HIV therapy now counts more than 30 anti-retroviral antiretroviral drugs that largely improved life conditions and prolonged AIDS-free survival. Nevertheless, no definitive cure is yet available for the life-long condition. One of the major problems related to obtaining a definitive cure, is the establishment of the so-called reservoirs o infection, where HIV can remains for decades in a latent state. New approaches are seeking to re-activate viral replication so that immune cells can while ART blocks infection of new cells. Moreover, some cancers are more frequent in HIV-infected patients, in some instances even when they are receiving antiretroviral therapy. Furthermore, antiretroviral therapy is available to less then half of the people living with HIV. Our proposal aims at exploring the effects of HIV on an immune cell type characterized by location in tissues and prompt response to a second encounter with the antigen. For their rapid response and location such cells, named resident memory T cells, might be perfect candidates eliminate latently infected cells upon re-activation of viral replication. We also propose to explore the role that these cells, or their lack, have in limiting neoplastic transformation in two different cancer model, cervical cancer and Kaposi sarcoma, both AIDS-defining cancers. Based on our preliminary results, we expect that HIV affect migration of CD8+ TRM cells. We think that this reduction in cell number, perhaps accompanied by modification of function, might facilitate the maintenance of the HIV reservoir as well as the neoplastic transformation linked to viral infection. To our knowledge, this will be the first project exploring the effects and modification of TRM in HIV infection as well as the possible consequences of such impairment. The project is built on a solid methodology: immunofluorescent staining of tissues in order to identify CD4 and CD8 TRM has been established in our Lab and will allow us to determine not only the number, but as well the location of such cells. Further immunofluorescent staining as well as in vitro assays will allow exploring a path we repute as being cause for the reduced number of TRM, a decrease in number of regulatory T cells, therefore of TGF-beta, a cytokine described to be important in overexpression of CD69. The results of the study will allow to clarify whether TRM numbers are altered by HIV and if their re- instauration can help reducing the latently infected cells as well s HIV-related cancers.
These exploratory studies are relevant to public health and for HIV therapy. They explore the effect of HIV on resident memory T cells, and the possible consequences that their HIV-mediated impairment could have on these cells in depleting reservoirs of infection and restraining tumor development.