Description of Research: Kathleen Collins

HIV Disease Pathogenesis

HIV establishes a chronic infection, and leads inexorably to the development of AIDS despite the acquisition of an anti-HIV immune response. My laboratory is interested in understanding the factors that allow HIV to thwart the immune system. Thus far, we have found that HIV evades the cytotoxic T lymphocyte (CTL) arm of the immune response by limiting presentation of viral antigens. This is accomplished by downmodulating MHC-I protein, which is required for immune recognition. Downmodulation of MHC-I occurs through the action of the HIV Nef protein. Work from our laboratory has indicated that the HIV Nef protein downmodulates MHC-I by physically interacting with specific amino acid sequences located in the MHC-I cytoplasmic tail. The specificity of this interaction allows Nef to selectively downmodulate MHC-I allotypes important for CTL recognition, while maintaining the expression of MHC-I allotypes that protect cells from natural killer cell recognition. Once bound, Nef allows the transport of MHC-I molecules into the Golgi apparatus, but then prevents their expression on the cell surface by recruiting a cellular adaptor protein, AP-1, which targets the complex to lysosomes for degradation. We have also learned that the effects of Nef are cell-type-specific in that Nef is much more active in T cells, a natural target for HIV infection. We have discovered that this results from the fact that The Nef-MHC-I complex recruits AP-1 much more efficiently in T cells. This observation is important because current models derived from non-T cell systems, have led to the incorrect conclusion that Nef functions exclusively by accelerating MHC-I enodocytosis. Thus, our studies have uncovered a key, previously overlooked mechanism for MHC-I downmodulation and immune evasion by HIV.

In addition, we have found that HIV limits antigen expression through the action of HIV Rev. The Rev protein normally functions by allowing late gene product mRNAs to exit the nucleus. Thus, the amount of Rev activity in the cell determines the relative amount of late gene product expression, the main source of CTL antigens. We have found that naturally occurring Rev alleles vary in their activity level and that those with less activity result in infected cells that are resistant to CTL lysis. These alleles are selected early in disease when the immune system is more active. Later on in disease, more active alleles emerge once the immune system has been destroyed and selective pressure wanes. In sum, the combined effects of Nef and Rev dramatically limit antigen presentation early in HIV disease when HIV must combat a highly active anti-HIV immune response.

Honors and Awards
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
2000 Center For AIDS Research Development Award
2001 Plenary speaker, American Association of Immunology Symposium on Microbial Invasion
2003 Padykula Lecturer, Wellesley College, Wellesley, MA
2003 Plenary speaker, 2004 Keystone Symposia on Molecular Mechanisms of HIV Pathogenesis
2004 Chair of the plenary session, Nef Function, 2004 Keystone Symposia on Molecular Mechanisms of HIV Pathogenesis
2004 Elizabeth C. Crosby Award
2005 Plenary speaker, 2005 ASM Symposia on Viral Immune Evasion
2005 Chair of the plenary session, Viral Regulation of Antigen Presentation, 2005 ASM Symposia on Viral Immune Evasion
2005 Plenary speaker, 91st International Titisee Conference "Cell biology meets the immune system: molecular aspects of host pathogen interactions"
2005 Elizabeth C. Crosby Award

Professional and University Service Contributions
Associate Director, Cellular and Molecular Biology Graduate Program
Member, CMB, MMMP, TTI, Experimental Immunology and Genetics training grants
Member, CMB and Immunology graduate training programs
Member, Editorial board of Journal of Virology and Current HIV Research
Ad Hoc Referee, Immunity, Journal of Virology, Journal of Clinical Investigation, Journal of Experimental medicine, Virology, EMBO, PLoS
Member, NIH AIP Study Section
Member, American Society for Microbiology
Member, American Society for Clinical Investigation

Recent Publications

Collins, K.L. Resistance of HIV-infected cells to cytotoxic T lymphocytes. Microbes Infect 5; 494-500, 2004.

Roeth, J.F., Kasper, M.R., Williams, M., Filzen, T.F., and Collins, K. L. 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, 2004.

Williams, M., Roeth, J.F., and Collins, K.L. 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, 2005.

Kasper, M.R., Williams, M., Xie, D., Fleis, R. and Collins, K.L. 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, 2005.

Roeth JF, Collins KL. Human immunodeficiency virus type 1 Nef: Adapting to intracellular trafficking pathways. Microbiol Molec Biol Rev 70: 548, 2006.

Thammavongsa V, Raghuraman G, Filzen TM, Collins KL, Raghavan M. HLA-B44 polymorphisms at position 116 of the heavy chain influence TAP complex minding via an effect on peptide occupancy. J Immunol 177 (5): 3150-3161, 2006.

Wonderlich ER, Williams M, Collins KL. The tyrosine binding pocket in the adaptor protein 1 (AP-1) mu 1 subunit is necessary for nef to recruit AP-1 to the major histocompatibility complex class I cytoplasmic tail. J Biol Chem 283 (6): 3011-3022, 2008.