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

Mentor: Kathleen Collins, MD, PhD

Research Description

APOBEC3G dependent NK cell lysis of HIV infected cells

The innate immune system is a crucial component of host defense against the progression of disease associated with the Human immunodeficiency virus (HIV).  Natural Killer (NK) cells recognize and eliminate infected cells which upregulate ligands characteristic of infection, and which exhibit a “missing-self” surface phenotype.  It has been shown that the HIV protein, VPR, increases the expression of ligands recognized by the NK cell-activating, NKG2D receptor, by a mechanism involving derepression of the host DNA damage pathway. 

APOBEC3G (A3G) is a host antiviral factor that is best known for its deaminase-domain-dependent ability to introduce loss-of-function hypermutations in the viral genome.   It was discovered by flow cytometric analysis of HIV-infected primary CD4+ T lymphocytes from healthy donors that levels of NKG2D ligands and markers of DNA damage such as the phospho-histone H2AX correlate with A3G expression.  If A3G functions to enhance NK cell recognition of infected cells by way of the DNA damage pathway, this novel role has yet to be rationalized in the context of infection and immune defense.  Our current work hypothesizes that A3G expression is sufficient to activate the DNA damage pathway, in a mechanism dependent on the carboxy terminal cytidine deaminase domain. 

Publications

Norman JM, Mashiba M, McNamara LA, Onafuwa-Nuga A, Chiari-Fort E, Shen W, Collins KL. The antiviral factor APOBEC3G enhances the recognition of HIV-infected primary T cells by natural killer cells. Nat Immunol. 2011 Aug 28.

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

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

Abstracts

M. Mashiba and K. Collins.  “HIV-1 accessory proteins Vif and Vpr limit restriction by the innate immune response.”  Michigan Medical Scientist Training Program Retreat, Ralph A MacMullen Conference Center, Roscommon, MI.  July 29-31, 2011.

Awards