Michael Mashiba
e-mail address: mmashiba@umich.edu

Mentor: Kathleen Collins, MD, PhD

Research Description

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. As a result, MHC-I accumulates in the trans-Golgi network of Nef-expressing cells. 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. 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.

Publications

The adenoviral E1B 55-kilodalton protein controls expression of immune response genes but not p53-dependent transcription. Miller DL, Rickards B, Mashiba M, Huang W, Flint SJ. J Virol. 2009 Apr;83(8):3591-603. Epub 2009 Feb 11.

EGF-mediated regulation of IGFBP-3 determines esophageal epithelial cellular response to IGF-I. Takaoka M, Smith CE, Mashiba MK, Okawa T, Andl CD, El-Deiry WS, Nakagawa H. Am J Physiol Gastrointest Liver Physiol. 2006 Feb;290(2):G404-16. Epub 2005 Oct 6.

Honors and Awards