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John Wills

TitleProfessor
InstitutionCollege of Medicine
DepartmentMicrobiology and Immunology
Address500 University Drive Hershey PA 17033
Mailbox: H107
Phone7175313528

 Overview 
 overview
TITLE:

Distinguished Professor of Microbiology and Immunology

GRADUATE PROGRAM AFFILIATIONS:

1) Biomedical Sciences, 2) Cell and Molecular Biology, 3) Genetics, 4) MD/PhD, 5) Microbiology and Immunology

EDUCATION:

B.S. in Biology, Grinnell College, Grinnell, Iowa, 1976
Ph.D. in Microbiology, University of Tennessee, Knoxville, 1982
Postdoctoral Training in Retrovirology, University of Alabama at Birmingham, 1982-1984

RESEARCH OVERVIEW:

The Wills lab is investigating several proteins of herpes simplex virus (HSV), all of which interact to form complexes within the infected cell and within the virion. The functions of these complexes are poorly understood. The following questions and answers provide some background.

WHAT IS HSV?
It is one of eight human herpesviruses, all of which cause lifelong infections. Most people are infected with more than one. It is fortunate that these infections are usually kept under control by the immune systems of healthy individuals; however, in the immunosuppressed, these large DNA viruses are often lethal. With our population aging and organ transplants increasing, herpesviruses are going to cause even greater incidence of disease. Thus, it is important to learn more about these ubiquitous viruses so that new ways can be found to fight them.

WHAT IS THE NATURE OF THE VIRION?
The structural proteins of herpesviruses are highly interconnected in the virion, but they are often classified according to their location within: 1) the nucleocapsid, 2) the surrounding but poorly-defined tegument layer, or 3) the outer, glycoprotein-containing lipid envelope. In the case of HSV, more than 40 different viral proteins have to be assembled, and understanding how they come together is a daunting task that is certain to require the continuing efforts of many investigators for decades to come. Nevertheless, the overall morphogenesis of the process is known. In brief, capsids are assembled and packaged with DNA in the nucleus, and some tegument proteins are attached soon afterwards. Nucleocapsids enter the cytoplasm by budding into the inner nuclear membrane and then fusing with the outer nuclear membrane. Additional tegument proteins are added before the capsid reaches the site of budding at Golgi-derived membranes, where yet more components of the tegument await in association with the cytoplasmic tails of the viral glycoproteins. Interactions between arriving capsid-tegument structures and tegument-glycoprotein complexes on the membrane result in envelopment and completed virions within vesicles. Finally, these vesicles move to the plasma membrane where they fuse, and the mature viruses are released. This is a very simple description of an extraordinarily complicated molecular process. But, because of its complexity, virus assembly events offer a large landscape for the discovery of novel antiviral targets as the molecular mechanisms emerge.

WHICH VIRAL PROTEINS ARE WE INVESTIGATING?
We began investigating tegument protein UL11, which is peripherally associated with membranes and needed for cytoplasmic budding. We later discovered that UL11 interacts with tegument protein UL16, which is bound in some manner to the capsid. UL16 is also a binding partner of UL21, which is also capsid associated. More recently, we discovered that UL11 and UL16 bind to the portion of glycoprotein E (gE) that extends from the membrane into the cytoplasm and the virion. gE has long been known to be important for the spread of HSV in a manner that does not involve cell-free virions.

WHAT DO THESE INTERACTING PROTEINS DO?
That is the big question. Homologs of UL11, UL16, and UL21 are found in all the herpesviruses, but their roles are largely unknown. Our studies have revealed that these tegument proteins are organized into an efficient molecular machine whose mechanism is triggered when the virus binds to its attachment receptors (heparan sulfate) on the host cell surface. In particular, we found that binding causes tegument protein UL16 to be released from the capsid as the tegument rearranges. This occurs prior to fusion of viral and host membranes; indeed, it occurs even when the virus binds to immobilized receptors on agarose beads. This is first example of an external signal being transmitted into any enveloped virus. We are still trying to identify all the parts of this machine. We want to know how are they assembled? How do they move? However, our studies also indicate that UL16 and its binding partners are involved in: a) virion budding in the cytoplasm, b) lateral spread of the virus in a cell-to-cell manner, and c) some sort of a function in the nucleus where most of UL16 accumulates during an infection.



 Bibliographic 
 selected publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Starkey JL, Han J, Chadha P, Marsh JA, Wills JW. Elucidation of the block to herpes simplex virus egress in the absence of tegument protein UL16 reveals a novel interaction with VP22. J Virol. 2014 Jan; 88(1):110-9.
    View in: PubMed
  2. Han J, Chadha P, Starkey JL, Wills JW. Function of glycoprotein E of herpes simplex virus requires coordinated assembly of three tegument proteins on its cytoplasmic tail. Proc Natl Acad Sci U S A. 2012 Nov 27; 109(48):19798-803.
    View in: PubMed
  3. Chadha P, Han J, Starkey JL, Wills JW. Regulated interaction of tegument proteins UL16 and UL11 from herpes simplex virus. J Virol. 2012 Nov; 86(21):11886-98.
    View in: PubMed
  4. Yeh PC, Han J, Chadha P, Meckes DG, Ward MD, Semmes OJ, Wills JW. Direct and specific binding of the UL16 tegument protein of herpes simplex virus to the cytoplasmic tail of glycoprotein E. J Virol. 2011 Sep; 85(18):9425-36.
    View in: PubMed
  5. Han J, Chadha P, Meckes DG, Baird NL, Wills JW. Interaction and interdependent packaging of tegument protein UL11 and glycoprotein e of herpes simplex virus. J Virol. 2011 Sep; 85(18):9437-46.
    View in: PubMed
  6. Meckes DG, Marsh JA, Wills JW. Complex mechanisms for the packaging of the UL16 tegument protein into herpes simplex virus. Virology. 2010 Mar 15; 398(2):208-13.
    View in: PubMed
  7. Harper AL, Meckes DG, Marsh JA, Ward MD, Yeh PC, Baird NL, Wilson CB, Semmes OJ, Wills JW. Interaction domains of the UL16 and UL21 tegument proteins of herpes simplex virus. J Virol. 2010 Mar; 84(6):2963-71.
    View in: PubMed
  8. Baird NL, Starkey JL, Hughes DJ, Wills JW. Myristylation and palmitylation of HSV-1 UL11 are not essential for its function. Virology. 2010 Feb 5; 397(1):80-8.
    View in: PubMed
  9. Meckes DG, Wills JW. Structural rearrangement within an enveloped virus upon binding to the host cell. J Virol. 2008 Nov; 82(21):10429-35.
    View in: PubMed
  10. Yeh PC, Meckes DG, Wills JW. Analysis of the interaction between the UL11 and UL16 tegument proteins of herpes simplex virus. J Virol. 2008 Nov; 82(21):10693-700.
    View in: PubMed
  11. Baird NL, Yeh PC, Courtney RJ, Wills JW. Sequences in the UL11 tegument protein of herpes simplex virus that control association with detergent-resistant membranes. Virology. 2008 May 10; 374(2):315-21.
    View in: PubMed
  12. O'Regan KJ, Murphy MA, Bucks MA, Wills JW, Courtney RJ. Incorporation of the herpes simplex virus type 1 tegument protein VP22 into the virus particle is independent of interaction with VP16. Virology. 2007 Dec 20; 369(2):263-80.
    View in: PubMed
  13. Meckes DG, Wills JW. Dynamic interactions of the UL16 tegument protein with the capsid of herpes simplex virus. J Virol. 2007 Dec; 81(23):13028-36.
    View in: PubMed
  14. Bucks MA, O'Regan KJ, Murphy MA, Wills JW, Courtney RJ. Herpes simplex virus type 1 tegument proteins VP1/2 and UL37 are associated with intranuclear capsids. Virology. 2007 May 10; 361(2):316-24.
    View in: PubMed
  15. Spidel JL, Wilson CB, Craven RC, Wills JW. Genetic Studies of the beta-hairpin loop of Rous sarcoma virus capsid protein. J Virol. 2007 Feb; 81(3):1288-96.
    View in: PubMed
  16. O'Regan KJ, Bucks MA, Murphy MA, Wills JW, Courtney RJ. A conserved region of the herpes simplex virus type 1 tegument protein VP22 facilitates interaction with the cytoplasmic tail of glycoprotein E (gE). Virology. 2007 Feb 5; 358(1):192-200.
    View in: PubMed
  17. Loomis JS, Courtney RJ, Wills JW. Packaging determinants in the UL11 tegument protein of herpes simplex virus type 1. J Virol. 2006 Nov; 80(21):10534-41.
    View in: PubMed
  18. Johnson MC, Spidel JL, Ako-Adjei D, Wills JW, Vogt VM. The C-terminal half of TSG101 blocks Rous sarcoma virus budding and sequesters Gag into unique nonendosomal structures. J Virol. 2005 Mar; 79(6):3775-86.
    View in: PubMed
  19. Spidel JL, Craven RC, Wilson CB, Patnaik A, Wang H, Mansky LM, Wills JW. Lysines close to the Rous sarcoma virus late domain critical for budding. J Virol. 2004 Oct; 78(19):10606-16.
    View in: PubMed
  20. Loomis JS, Courtney RJ, Wills JW. Binding partners for the UL11 tegument protein of herpes simplex virus type 1. J Virol. 2003 Nov; 77(21):11417-24.
    View in: PubMed
  21. Callahan EM, Wills JW. Link between genome packaging and rate of budding for Rous sarcoma virus. J Virol. 2003 Sep; 77(17):9388-98.
    View in: PubMed
  22. Brignati MJ, Loomis JS, Wills JW, Courtney RJ. Membrane association of VP22, a herpes simplex virus type 1 tegument protein. J Virol. 2003 Apr; 77(8):4888-98.
    View in: PubMed
  23. Patnaik A, Chau V, Li F, Montelaro RC, Wills JW. Budding of equine infectious anemia virus is insensitive to proteasome inhibitors. J Virol. 2002 Mar; 76(6):2641-7.
    View in: PubMed
  24. Patnaik A, Wills JW. In vivo interference of Rous sarcoma virus budding by cis expression of a WW domain. J Virol. 2002 Mar; 76(6):2789-95.
    View in: PubMed
  25. Loomis JS, Bowzard JB, Courtney RJ, Wills JW. Intracellular trafficking of the UL11 tegument protein of herpes simplex virus type 1. J Virol. 2001 Dec; 75(24):12209-19.
    View in: PubMed
  26. Bowzard JB, Wills JW, Craven RC. Second-site suppressors of Rous sarcoma virus Ca mutations: evidence for interdomain interactions. J Virol. 2001 Aug; 75(15):6850-6.
    View in: PubMed
  27. Krishna NK, Wills JW. Insertion of capsid proteins from nonenveloped viruses into the retroviral budding pathway. J Virol. 2001 Jul; 75(14):6527-36.
    View in: PubMed
  28. Callahan EM, Wills JW. Repositioning basic residues in the M domain of the Rous sarcoma virus gag protein. J Virol. 2000 Dec; 74(23):11222-9.
    View in: PubMed
  29. Oda Y, Sanders J, Evans M, Kiddie A, Munkley A, James C, Richards T, Wills J, Furmaniak J, Smith BR. Epitope analysis of the human thyrotropin (TSH) receptor using monoclonal antibodies. Thyroid. 2000 Dec; 10(12):1051-9.
    View in: PubMed
  30. Patnaik A, Chau V, Wills JW. Ubiquitin is part of the retrovirus budding machinery. Proc Natl Acad Sci U S A. 2000 Nov 21; 97(24):13069-74.
    View in: PubMed
  31. Bowzard JB, Visalli RJ, Wilson CB, Loomis JS, Callahan EM, Courtney RJ, Wills JW. Membrane targeting properties of a herpesvirus tegument protein-retrovirus Gag chimera. J Virol. 2000 Sep; 74(18):8692-9.
    View in: PubMed
  32. Parent LJ, Cairns TM, Albert JA, Wilson CB, Wills JW, Craven RC. RNA dimerization defect in a Rous sarcoma virus matrix mutant. J Virol. 2000 Jan; 74(1):164-72.
    View in: PubMed
  33. Craven RC, Harty RN, Paragas J, Palese P, Wills JW. Late domain function identified in the vesicular stomatitis virus M protein by use of rhabdovirus-retrovirus chimeras. J Virol. 1999 Apr; 73(4):3359-65.
    View in: PubMed
  34. Garnier L, Parent LJ, Rovinski B, Cao SX, Wills JW. Identification of retroviral late domains as determinants of particle size. J Virol. 1999 Mar; 73(3):2309-20.
    View in: PubMed
  35. Bennett RP, Wills JW. Conditions for copackaging rous sarcoma virus and murine leukemia virus Gag proteins during retroviral budding. J Virol. 1999 Mar; 73(3):2045-51.
    View in: PubMed
  36. Bowzard JB, Bennett RP, Krishna NK, Ernst SM, Rein A, Wills JW. Importance of basic residues in the nucleocapsid sequence for retrovirus Gag assembly and complementation rescue. J Virol. 1998 Nov; 72(11):9034-44.
    View in: PubMed
  37. McDonnell JM, Fushman D, Cahill SM, Zhou W, Wolven A, Wilson CB, Nelle TD, Resh MD, Wills J, Cowburn D. Solution structure and dynamics of the bioactive retroviral M domain from Rous sarcoma virus. J Mol Biol. 1998 Jun 19; 279(4):921-8.
    View in: PubMed
  38. Garnier L, Ratner L, Rovinski B, Cao SX, Wills JW. Particle size determinants in the human immunodeficiency virus type 1 Gag protein. J Virol. 1998 Jun; 72(6):4667-77.
    View in: PubMed
  39. Nelle TD, Verderame MF, Leis J, Wills JW. The major site of phosphorylation within the Rous sarcoma virus MA protein is not required for replication. J Virol. 1998 Feb; 72(2):1103-7.
    View in: PubMed
  40. Garnier L, Bowzard JB, Wills JW. Recent advances and remaining problems in HIV assembly. AIDS. 1998; 12 Suppl A:S5-16.
    View in: PubMed
  41. Krishna NK, Campbell S, Vogt VM, Wills JW. Genetic determinants of Rous sarcoma virus particle size. J Virol. 1998 Jan; 72(1):564-77.
    View in: PubMed
  42. Puffer BA, Parent LJ, Wills JW, Montelaro RC. Equine infectious anemia virus utilizes a YXXL motif within the late assembly domain of the Gag p9 protein. J Virol. 1997 Sep; 71(9):6541-6.
    View in: PubMed
  43. Xiang Y, Cameron CE, Wills JW, Leis J. Fine mapping and characterization of the Rous sarcoma virus Pr76gag late assembly domain. J Virol. 1996 Aug; 70(8):5695-700.
    View in: PubMed
  44. Garnier L, Wills JW, Verderame MF, Sudol M. WW domains and retrovirus budding. Nature. 1996 Jun 27; 381(6585):744-5.
    View in: PubMed
  45. Nelle TD, Wills JW. A large region within the Rous sarcoma virus matrix protein is dispensable for budding and infectivity. J Virol. 1996 Apr; 70(4):2269-76.
    View in: PubMed
  46. Verderame MF, Nelle TD, Wills JW. The membrane-binding domain of the Rous sarcoma virus Gag protein. J Virol. 1996 Apr; 70(4):2664-8.
    View in: PubMed
  47. Krishna NK, Weldon RA, Wills JW. Transport and processing of the Rous sarcoma virus Gag protein in the endoplasmic reticulum. J Virol. 1996 Mar; 70(3):1570-9.
    View in: PubMed
  48. Parent LJ, Wilson CB, Resh MD, Wills JW. Evidence for a second function of the MA sequence in the Rous sarcoma virus Gag protein. J Virol. 1996 Feb; 70(2):1016-26.
    View in: PubMed
  49. Pan W, Craven RC, Qiu Q, Wilson CB, Wills JW, Golovine S, Wang JF. Isolation of virus-neutralizing RNAs from a large pool of random sequences. Proc Natl Acad Sci U S A. 1995 Dec 5; 92(25):11509-13.
    View in: PubMed
  50. Lu YL, Bennett RP, Wills JW, Gorelick R, Ratner L. A leucine triplet repeat sequence (LXX)4 in p6gag is important for Vpr incorporation into human immunodeficiency virus type 1 particles. J Virol. 1995 Nov; 69(11):6873-9.
    View in: PubMed
  51. Parent LJ, Bennett RP, Craven RC, Nelle TD, Krishna NK, Bowzard JB, Wilson CB, Puffer BA, Montelaro RC, Wills JW. Positionally independent and exchangeable late budding functions of the Rous sarcoma virus and human immunodeficiency virus Gag proteins. J Virol. 1995 Sep; 69(9):5455-60.
    View in: PubMed
  52. Craven RC, Leure-duPree AE, Weldon RA, Wills JW. Genetic analysis of the major homology region of the Rous sarcoma virus Gag protein. J Virol. 1995 Jul; 69(7):4213-27.
    View in: PubMed
  53. Wills JW, Cameron CE, Wilson CB, Xiang Y, Bennett RP, Leis J. An assembly domain of the Rous sarcoma virus Gag protein required late in budding. J Virol. 1994 Oct; 68(10):6605-18.
    View in: PubMed
  54. Sakalian M, Wills JW, Vogt VM. Efficiency and selectivity of RNA packaging by Rous sarcoma virus Gag deletion mutants. J Virol. 1994 Sep; 68(9):5969-81.
    View in: PubMed
  55. Zhou W, Parent LJ, Wills JW, Resh MD. Identification of a membrane-binding domain within the amino-terminal region of human immunodeficiency virus type 1 Gag protein which interacts with acidic phospholipids. J Virol. 1994 Apr; 68(4):2556-69.
    View in: PubMed
  56. Bennett RP, Nelle TD, Wills JW. Functional chimeras of the Rous sarcoma virus and human immunodeficiency virus gag proteins. J Virol. 1993 Nov; 67(11):6487-98.
    View in: PubMed
  57. Craven RC, Leure-duPree AE, Erdie CR, Wilson CB, Wills JW. Necessity of the spacer peptide between CA and NC in the Rous sarcoma virus gag protein. J Virol. 1993 Oct; 67(10):6246-52.
    View in: PubMed
  58. Weldon RA, Wills JW. Characterization of a small (25-kilodalton) derivative of the Rous sarcoma virus Gag protein competent for particle release. J Virol. 1993 Sep; 67(9):5550-61.
    View in: PubMed
  59. Craven RC, Bennett RP, Wills JW. Role of the avian retroviral protease in the activation of reverse transcriptase during virion assembly. J Virol. 1991 Nov; 65(11):6205-17.
    View in: PubMed
  60. Wills JW, Craven RC, Weldon RA, Nelle TD, Erdie CR. Suppression of retroviral MA deletions by the amino-terminal membrane-binding domain of p60src. J Virol. 1991 Jul; 65(7):3804-12.
    View in: PubMed
  61. Wills JW, Craven RC. Form, function, and use of retroviral gag proteins. AIDS. 1991 Jun; 5(6):639-54.
    View in: PubMed
  62. Bennett RP, Rhee S, Craven RC, Hunter E, Wills JW. Amino acids encoded downstream of gag are not required by Rous sarcoma virus protease during gag-mediated assembly. J Virol. 1991 Jan; 65(1):272-80.
    View in: PubMed
  63. Erdie CR, Wills JW. Myristylation of Rous sarcoma virus Gag protein does not prevent replication in avian cells. J Virol. 1990 Oct; 64(10):5204-8.
    View in: PubMed
  64. Weldon RA, Erdie CR, Oliver MG, Wills JW. Incorporation of chimeric gag protein into retroviral particles. J Virol. 1990 Sep; 64(9):4169-79.
    View in: PubMed
  65. Wills JW, Craven RC, Achacoso JA. Creation and expression of myristylated forms of Rous sarcoma virus gag protein in mammalian cells. J Virol. 1989 Oct; 63(10):4331-43.
    View in: PubMed
  66. Wills JW. Retro-secretion of recombinant proteins. Nature. 1989 Jul 27; 340(6231):323-4.
    View in: PubMed
  67. Perez L, Wills JW, Hunter E. Expression of the Rous sarcoma virus env gene from a simian virus 40 late-region replacement vector: effects of upstream initiation codons. J Virol. 1987 Apr; 61(4):1276-81.
    View in: PubMed
  68. Hardwick JM, Shaw KE, Wills JW, Hunter E. Amino-terminal deletion mutants of the Rous sarcoma virus glycoprotein do not block signal peptide cleavage but can block intracellular transport. J Cell Biol. 1986 Sep; 103(3):829-38.
    View in: PubMed
  69. Barker CS, Wills JW, Bradac JA, Hunter E. Molecular cloning of the Mason-Pfizer monkey virus genome: characterization and cloning of subgenomic fragments. Virology. 1985 Apr 30; 142(2):223-40.
    View in: PubMed
  70. Wills JW, Srinivas RV, Hunter E. Mutations of the Rous sarcoma virus env gene that affect the transport and subcellular location of the glycoprotein products. J Cell Biol. 1984 Dec; 99(6):2011-23.
    View in: PubMed
  71. Wills JW, Hardwick JM, Shaw K, Hunter E. Alterations in the transport and processing of Rous sarcoma virus envelope glycoproteins mutated in the signal and anchor regions. J Cell Biochem. 1983; 23(1-4):81-94.
    View in: PubMed
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