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Faculty
Research InterestsThe human immunodeficiency virus (HIV) causes a lethal syndrome (acquired immunodeficiency syndrome) characterized by CD4+ T cell depletion and resultant immunodeficiency. HIV has caused a worldwide epidemic that has killed millions of people and continues to infect about 40,000 people each year in this country. The long-term goal of our research program is to provide improved treatments for people with HIV/AIDS. Existing therapies are highly effective at rendering viral particles non-infectious and thus reducing viral loads. However none of the current drugs are capable of destroying infected cells. Many infected cells have short half-lives and die within days or months. Others, however, remain in a state that is resistant to the immune system and can persist for years. To provide better therapies, our focus has been on understanding the molecular mechanisms of viral persistence within cellular reservoirs. The development of drugs that will inhibit these pathways will bring us closer to a cure. To this end, our research program focuses on major viral mechanisms of resistance to the cell mediated immune (CMI) response, which normally eradicates infected cells by direct lysis. To maintain a chronic infection HIV must evade lysis by both cytotoxic T lymphocytes (CTLs), and natural killer (NK) cells. CTLs recognize infected cells with receptors that detect foreign peptide antigens presented in association with host major histocompatibility class I protein (MHC-I). NK cells recognize cells with abnormally low MHC-I levels and/or those that have upregulated NK activating ligands. Our goals are to better understand viral mechanisms of immune evasion and to ultimately inhibit these processes. Education5/85 B.A. Wellesley College, Wellesley, MA. 5/93 M.D., Ph.D. Johns Hopkins University School of Medicine, Postgraduate Training7/93-6/94 Intern, Internal Medicine 7/94-6/95 Resident, Internal Medicine 7/96-7/98 Research Fellow, Medicine 7/96-7/98 Postdoctoral Fellow, laboratory of Dr. David Baltimore Honors and Awards1984 Phi Beta Kappa 1985 B.A., Summa cum laude with departmental honors in Molecular Biology; Thesis: "Characterization of the Interleukin-1 Gene." 1985 M.A. Cartland Shackford Medical Fellowship 1985 Wellesley College Trustee Scholar Award for Study in Medicine 1985 Wellesley College Durant Scholar 1986 Medical Scientist Training Program Award, Johns Hopkins University 1998 Biomedical Scholars Program Award, University of Michigan 1998 Massachusetts Infectious Disease Society Maxwell Finland Young Investigator Award for Excellence in Research 1999 Pew Scholars Award 2003 Padykula Lecturer, Wellesley College, Wellesley, MA 2004 Elizabeth C. Crosby Award 2005 Elected to The American Society for Clinical Investigation 2005 Elizabeth C. Crosby Award 2006 Member, NIH AIP study section 2008 Burroughs Wellcome Fund Clinical Scientist Award in Translational Research 2010 State-of-the-Art Speaker, 29th Annual Meeting of the American Society of Virology 2011 League of Research Excellence, U-M Medical School Recent PublicationsBobbitt, K.R., Addo, M.M, Altfeld, M., Filzen, T., Onafuwa, A.A., Walker, B.D. and Collins, K.L., (2003) Rev activity determines sensitivity of HIV-infected primary T cells to anti-Gag CTL killing, Immunity 18 (2) 289-299. (highlighted in Nature Reviews Immunology 3, (2003;266). Roeth, J.F., Kasper, M.R., Williams, M., Filzen, T.F., and Collins, K. L., (2004) HIV-1 Nef re-directs MHC-I from the TGN to lysosomes by stabilizing an interaction between MHC-I and AP-1. J Cell Biol 167(5); 903-913. Wonderlich, E., Williams, M., Collins, K.L. (2008) The tyrosine-binding pocket in the AP-1 mu 1 subunit is necessary for Nef to recruit AP-1 to the MHC-I cytoplasmic tail. J Biol Chem. 283 (6): 3011-3022. Epub 2007 Dec 11; PMID: 18073204. Schaefer, M., Williams, M., Gonzalez, P., Collins, K.L., (2008) The HLA-C cytoplasmic tail contains trafficking signals that allow regulated expression with differentiation of macrophages. J. Immunol. 180(12):7804-17. Schaefer, M., Roeth, J.F., Wonderlich, E., Leonard, H., Collins, K.L., (2008) HIV-1 Nef targets MHC-I and CD4 for degradation via a common beta-COP-dependent pathway in T lymphocytes. PLoS Pathogens 4(8): e1000131 doi:10.1371/journal. ppat.1000131. Carter, C.C., Onafuwa-Nuga, A., Riddell, J., Bixby, D., Savona, M.R. and Collins, K.L., (2010) HIV-1 Infects Multipotent Progenitor Cells Causing Cell Death and Establishing Latent Cellular Reservoirs, Nature Medicine, Apr;16(4):446-51. Epub 2010 Mar 7, PubMed PMID: 20208541. (Highlighted in Nature, Cell, Science and Nature Reviews Microbiology) Garcia-Perez, J.L., Morell, M., Scheys, J.O., Kulpa, D.A., Morell, S., Carter, C.C., Kim, J.K., Hammer, G.D., Collins, K.L., Andrews, P.W., O’Shea, K.S., Menendez, P., and Moran, J.V., (2010) Epigenetic silencing of LINE-1 retrotransposition events in human embryonic carcinoma cell lines, Nature, Aug 5;466(7307):769-73. Carter, C.C., McNamara, L.A., Onafuwa-Nuga, A., Shackleton, M., Riddell, J., Bixby, D., Morrison, S.J., and Collins, K.L., (2011) HIV-1 utilizes the CXCR4 chemokine receptor to infect multi-potent hematopoietic stem cells, Cell Host & Microbe, Mar 17;9(3):223-34. (Highlighted in Cell Host and Microbe, Nature Reviews Microbiology and Cell podcast). Leonard, J.A., Filzen, T., Carter, C.C., Schaefer, M., Collins, K.L., (2011) The HIV-1 Nef protein disrupts intracellular trafficking of MHC-I, CD4, CD8 and CD28 by distinct pathways that share common elements, J. Virol. Jul 85(14):6867-81. Epub 2011 May 4. PubMed PMID: 21543478, PubMed Central PMCID:PMC3126561. Norman, J.M., McNamara, L.A., Onafuwa-Nuga, Mashiba, M., Chiari, E. and Collins K.L., (2011) The antiviral factor APOBEC3G enhances the recognition of HIV-infected primary T cells by natural killer cells, Nature Immunology, Aug 28;12(10):975-83. doi: 10.1038/ni.2087. [Epub ahead of print] PubMed PMID: 21874023. (Highlighted with News and Views in Nature Immunology; selected as Nature Immunology article of the month). Wonderlich, E.R. Kulpa, D.A., Leonard, J.A., Leopold, K. and Collins, K.L., (2011) ARF-1activity is required to recruit AP-1 to the MHC-I cytoplasmic tail and disrupt MHC-I trafficking in HIV-1 infected primary T cells, J. Virol Sep 14. [Epub ahead of print] PubMed PMID: 21917951. Lab Projects Our future goals are to define the molecular mechanisms through which HIV establishes a persistent infection. Thus, we will uncover basic information about the innate and adaptive immune responses to viral pathogens, which will in turn contribute to the development of novel anti-viral therapeutics. Additional Lab LinksDepartment of Microbiology and Immunology Cellular and Molecular Biology Program Graduate Program in Immunology
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