Dr. Collins earned her M.D. and Ph.D. degrees from The Johns Hopkins University School of Medicine in the Medical Scientist Training Program. She received clinical training in Internal Medicine at Harvard University’s affiliated Brigham and Women’s Hospital. Thereafter, she was trained as an infectious disease fellow in a combined Harvard affiliated program and did postdoctoral training at Massachusetts Institute of Technology in the laboratory of the Nobel laureate, David Baltimore. She was recruited to the University of Michigan in 1998. Her research laboratory focuses on the molecular mechanisms underlying human immunodeficiency virus (HIV) persistence.
The Collins lab focuses on understanding the molecular mechanisms by which virally infected cells establish a persistent infection; we use patient samples to determine which cells form clinically significant reservoirs and to develop strategies to eradicate them. A major focus of the Collins laboratory has been on understanding the role of hematopoietic progenitors as reservoirs for HIV persistence. In addition, the Collins Lab uses basic cell biological and biochemical techniques to understand the fundamental biological processes that occur in infected cells as a necessary step to develop strategies to provide new therapeutic approaches to eradicate cells that cause disease. To this end, the Collins Lab has uncovered mechanisms by which viral proteins evade the innate and adaptive immune response to viral infection. By better understanding these mechanisms, we will identify potential pathways to target for development of novel drugs that will help arm the immune system against the pathogen.
- HIV-1 infects CD4+ hematopoietic stem and progenitor cells. The Collins Lab determined that HIV can infect hematopoietic progenitor and stem cells (HPSCs) in vitro, and demonstrated how infection of these cells contributes to the development of the acquired immunodeficiency syndrome in vivo. Moreover, they determined that HIV can achieve a latent state in HSPCs both in vitro and in vivo. In unpublished studies, the Collins Lab has confirmed these results in a larg cohort of 50 HIV-infected people. Moreover, in a number of optimally treated donors, a subset of plasma viral sequence was identical to provirus from HSPCs. Strategies to eliminate latently infected HSPCs will need to be developed to eradicate all potential viral reservoirs and cure disease.
- The role of Vpr in NK cell recognition and viral spread in T cells and macrophages. Downmodulation of MHC-I potentially sensities infected primary T cells to natural killer cell recognition. Thus, the Collins Lab examined natural killer cell recognition of primary T cells infected with wild type HIV-1 and HIV-1s harboring mutant accessory proteins. These studies revealed novel immunoevasive roles of HIV Vif-dependent APOBEC degradation. Moreover, these studies provided evidence that Vpr affects the extent to which the HIV-1 genome is uracilated in HIV-1 infected primary T cells. While Vpr does not affect the infection rate of HIV-infected primary T lymphocytes, subsequent studies in macrophages demonstrated a requirement for Vpr to evade a cellular intrinsic antiviral responses that targets Env and inhibits spread amongst macrophages and spread from macrophages to primary T lymphocytes. These studies underline the importance of the highly conserved lentiviral Vpr protein and highlight the need to better understand the molecular mechanism through which it functions.
- Mechanisms by which HIV-1 evades cytotoxic T lymphocyte recognition. Over the past 20 years Kathleen Collins and her laboratory have used molecular approaches to define ways in which HIV-1 evades the immune response and establishes a persistent infection. As a postdoctoral fellow and as a faculty member, Dr. Collins’ work uncovered mechanisms through which CTL recognition of infected cells is limited by viral factors. She showed that the HIV Nef protein reduces cell surface expression of MHC-I and protects infected primary T cells from CTL recognition. The effect of Nef on CTL recognition has been confirmed in a variety of systems including patient samples and SIV-infected macaques. In a collaboration with Dr. Sherman's laboratory at the LSI, her laboratory has made progress towards the development of inhibitors against Nef that reverses MHC-I downmodulation. Nef inhibitors may provide a way to enhance CTL recognition and clearance of infected cells.