Text Image: UM Medical School: Graduate Program in Immunology
Text Image: Faculty

Kathleen Collins, M.D., Ph.D.
Professor, Department of Internal Medicine
Division of Infectious Diseases
and Department of Microbiology and Immunology

klcollin@umich.edu


The 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.


Representative Publications

Collins, K.L., Chen, B.K., Kalams , S.A. , Walker , B.D., Baltimore, D. (1998). The HIV-1 Nef protein protects infected primary human cells from CTLs. Nature, 391:397-401.

Williams, M., Roethe, J., Kasper, M.R., Fleis, R., Przybycin, C.G., Collins, K.L., (2002) Direct binding of HIV-1 Nef to the MHC-I cytoplasmic tail disrupts MHC-I trafficking, J. Virol., 76 (23); 12173-12184.

Kasper, M.R., and Collins, K.L., (2003) Nef-mediated disruption of MHC-I transport to the cell surface in T cells, J. Virol., 77 (5) 3041-3049.

Bobbitt, 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;266-267).

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.

Williams, M., Roeth, J.F., and Collins, K.L., (2005) HIV-1 Nef domains required for disruption of MHC-I trafficking are also necessary for co-precipitation of Nef with HLA-A2. J Virol. 79(1);632-636.

Kasper, M.R., Williams, M., Xie, D., Fleis, R. and Collins, K.L., (2005) HIV-1 Nef disrupts viral antigen presentation early in the secretory pathway by preferentially binding hypo-phosphorylated MHC-I cytoplasmic tails. J Biol Chem. 280(13): 12840-12848.

Wonderlich ER, Williams M, Collins KL. The tyrosine binding pocket in the adaptor protein 1 (AP-1) mu1 subunit is necessary for Nef to recruit AP-1 to the major histocompatibility complex class I cytoplasmic tail. J Biol Chem. 2008 Feb 8;283(6):3011-22.

Schaefer MR, Williams M, Kulpa DA, Blakely PK, Yaffee AQ, Collins KL.
A Novel Trafficking Signal within the HLA-C Cytoplasmic Tail Allows Regulated Expression upon Differentiation of Macrophages.
J Immunol. 2008 Jun 15;180(12):7804-1.


Schaefer MR, Wonderlich ER, Roeth JF, Leonard JA, Collins KL. HIV-1 Nef
targets MHC-I and CD4 for degradation via a final common beta-COP-dependent
pathway in T cells.
PLoS Pathog. 2008 Aug 22;4(8):e1000131. PubMed PMID:
18725938; PubMed Central PMCID: PMC2515349.


Carter CC, Onafuwa-Nuga A, McNamara LA, Riddell J 4th, Bixby D, Savona MR, Collins KL. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010 Apr;16(4):446-51. Epub 2010 Mar 7. PubMed PMID: 20208541; PubMed Central PMCID: PMC2892382.

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 Hostand 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.

Norman, J.M., McNamara, L.A., Onafuwa-Nuga, Mashiba, M., Chiari,E. and Collins K.L., (2011) HIV-1 Vif and Nef limit natural killer cell recognition of infected primary T cells by restricting Vpr-dependent NKG2D upregulation, Nature Immunology, In Press.

 

 



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