- Antigen Presentation
- Exanthema Subitum
- Genes, MHC Class I
- Herpesvirus 6, Human
- Herpesvirus 7, Human
- human CD45
- insulin-responsive glucose transport
- membrane trafficking
- synaptic vesicle recycling
- viral immune evasion
We are interested in how viruses escape detection by the immune system.
As a response to selective pressures exerted by the host immune system, many viruses have developed an equally complex set of immunoevasive strategies. Perhaps most interesting is the array of unique strategies that viruses employ to interfere with the presentation of viral antigens on the surface of host cells for recognition by cytotoxic T lymphocytes.
Many viruses, including all known members of the Herpesvirus family, target antigen presentation by class I MHC molecules as a means of undermining the anti-viral immune response. We focus on two recently discovered human herpesviruses, HHV-6 and -7. Little is known about the immunobiology of these two beta-herpesviruses. They are most closely related to human cytomegalovirus (HCMV), and like all other herpesviruses, HHV-6 and -7 remain latent or establish persistent infections. Thus, it seemed likely that HHV-6 and -7 would also encode unique mechanisms of immune evasion. Because so many of the viral immunoevasins affect trafficking or stability of class I MHC molecules, we took a biochemical approach to examine the maturation and stability of class I molecules in HHV-7-infected T cells.
We found that class I MHC stability was indeed decreased in HHV-7-infected T cells, and that a 55 kDa viral glycoprotein co-immunoprecipitated with class I MHC molecules. We identified this associated protein as the product of the HHV-7 U21 open reading frame. U21 binds to newly-synthesized, properly-folded MHC class I molecules in the ER, shortly after synthesis. Expression of U21 in cultured cells results in a reduction of class I molecules on the plasma membrane and a dramatic redistribution of class I molecules to lysosomes.
Targeting of a protein to the lysosomal compartment is generally accomplished through association of cellular sorting machinery with a sorting motif contained within its cytoplasmic tail. Surprisingly, however, even expression of a tailless U21 can divert class I MHC molecules to lysosomes. Thus it is the lumenal domain of U21 that is responsible for diverting class I molecules to lysosomes.
How does the lumenal domain of U21 divert class I MHC molecules, and what is the cellular mechanism for lysosomal sorting that U21 harnesses for its benefit? We focus on characterizing this novel immunoevasive strategy as a means of dissecting the underlying cell biology behind this lysosomal sorting mechanism.
(Dirck AT, Whyte ML, Hudson AW.) Mol Biol Cell. 2019 Dec 18:mbcE19070363 PMID: 31851583 12/19/2019
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(Sturgill ER, Malouli D, Hansen SG, Burwitz BJ, Seo S, Schneider CL, Womack JL, Verweij MC, Ventura AB, Bhusari A, Jeffries KM, Legasse AW, Axthelm MK, Hudson AW, Sacha JB, Picker LJ, Früh K.) PLoS Pathog. 2016 08;12(8):e1005868 PMID: 27580123 PMCID: PMC5006984 SCOPUS ID: 2-s2.0-84984830187 09/01/2016
(Hudson AW.) Curr Opin Virol. 2014 Dec;9:178-87 PMID: 25462451 SCOPUS ID: 2-s2.0-84915759618 12/03/2014
(May NA, Wang Q, Balbo A, Konrad SL, Buchli R, Hildebrand WH, Schuck P, Hudson AW.) J Virol. 2014 Mar;88(6):3298-308 PMID: 24390327 PMCID: PMC3957921 SCOPUS ID: 2-s2.0-84894543495 01/07/2014
(Kimpler LA, Glosson NL, Downs D, Gonyo P, May NA, Hudson AW.) PLoS One. 2014;9(6):e99139 PMID: 24901711 PMCID: PMC4047081 SCOPUS ID: 2-s2.0-84902477273 06/06/2014
(Fox LM, Miksanek J, May NA, Scharf L, Lockridge JL, Veerapen N, Besra GS, Adams EJ, Hudson AW, Gumperz JE.) Cancer Immun. 2013;13:9 PMID: 23885215 PMCID: PMC3721260 SCOPUS ID: 2-s2.0-84879033899 07/26/2013
(Schneider CL, Hudson AW.) PLoS Pathog. 2011 Nov;7(11):e1002362 PMID: 22102813 PMCID: PMC3213103 SCOPUS ID: 2-s2.0-81755166703 11/22/2011
(Glosson NL, Gonyo P, May NA, Schneider CL, Ristow LC, Wang Q, Hudson AW.) J Biol Chem. 2010 Nov 19;285(47):37016-29 PMID: 20833720 PMCID: PMC2978630 SCOPUS ID: 2-s2.0-78449233108 09/14/2010
(May NA, Glosson NL, Hudson AW.) J Virol. 2010 Apr;84(8):3738-51 PMID: 20106916 PMCID: PMC2849505 SCOPUS ID: 2-s2.0-77950482035 01/29/2010
(Glosson NL, Hudson AW.) Virology. 2007 Aug 15;365(1):125-35 PMID: 17467766 SCOPUS ID: 2-s2.0-34250165758 05/01/2007
(Cooper EM, Hudson AW, Amos J, Wagstaff J, Howley PM.) J Biol Chem. 2004 Sep 24;279(39):41208-17 PMID: 15263005 SCOPUS ID: 2-s2.0-4644295494 07/21/2004