- American Federation for Clinical Research
The Greene laboratory seeks to better understand the interface between human retroviruses (HIV and HTLV-I) and their cellular hosts. The progressive loss of CD4 T cells in HIV-infected individuals underlies clinical development of the Acquired Immune Deficiency Syndrome (AIDS). Greene’s team has shown that most CD4 T cells actually die as a result of their own innate immune response launched against viral DNA generated during abortive infection of non-permissive, resting CD4 T cells. Proinflammatory signals released by these abortively infected cells, which succumb by caspase-1 -dependent pyroptosis, attract more cells into the infected tissue to die. These events link the two signature events in HIV-disease, progressive CD4 T cell loss and chronic inflammation, within a single pathway. Chemical inhibition of the pyroptotic cell death pathway could reduce chronic inflammation and preserve CD4 T cell numbers, complementing the effects of anti-retroviral therapy.
Other studies in the laboratory focus on understanding how the latent HIV reservoir is formed and maintained. The latent reservoir is comprised of cells containing defective and intact proviruses. It is the infrequent production of infectious virus within this latent reservoir that necessitates lifelong antiretroviral therapy. The Greene Lab is exploring the molecular mechanisms that promote HIV reservoir formation and control maintenance of latency. This group is also exploring therapeutic approaches to “reduce and control” the reservoir allowing discontinuation of antiretroviral therapy in the absence of full viral eradication (functional cure). Other approaches are seeking ways to permanently silence latent retroviruses using CRISPRi to introduce sequence-specific combinations of repressive epigenetic marks.