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.

Recent Publications

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.

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 - art. no. e1000131. PLOS Path 4 (8): 131-131, 2008.

Collins KL. This Bud's for Vpu. Cell Host Microbe 5 (3): 217-219, 2009.