Immunology Graduate Group

James Hoxie, M.D.
Professor of Medicine
Medicine, Hematology-Oncology Division

Address: Rm 356 BRB II/III, 421 Curie Blvd
Office Phone: 215-898-0261
Lab Phone: 215-898-0263
Fax: 215-573-7356
Email:  hoxie@mail.med.upenn.edu

Education:
M.D., University of Pennsylvania
B.S., Wesleyan University

Research Interests

HIV and SIV envelope glycoproteins; viral entry; immune evasion; neutralizing antibodies; vaccines

Research Summary

Research in Dr. Hoxie's lab focuses on identifying viral and cellular determinants that are relevant to the ability of HIV and SIV to infect cells and induce cytopathic effects. Main goals are to understand the molecular basis for differences in viral tropism among CD4 positive and negative cell types. Particular areas of interest include studies of the interactions of the viral envelope glycoprotein with chemokine receptors and the cytoskeleton. Efforts are in progress to understand the structural determinants and mechanisms involved in the binding and entry of viruses into target cells and in the expression and processing of viral glycoproteins.

In recent studies, isolates of CD4-independent isolates of HIV-1 and HIV-2 have been derived that infect cells using chemokine receptors as primary receptors rather than coreceptors. The genetic basis for this phenotype has been mapped to the envelope gene, and results have indicated that the mechanism for this effect results from mutations in env that expose the chemokine receptor binding site. Efforts are in progress to identify the structural basis for this effect and the potential for using CD4-independent envelope glycoproteins as vaccine candidates.

In other areas, Dr. Hoxie's group has identified endocytosis signals in the cytoplasmic tails of HIV, SIV and FIV env proteins that function to reduce the level of envelope glycoproteins on the surface of infected cells. Dr. Hoxie has proposed that this motif could be relevant in pathogenesis by enabling virus-producing cells to survive a host anti-viral immune response. Preliminary studies in an SIV model have shown that viruses that contain mutations in this site are markedly attenuated in vivo. Ongoing studies are addressing the mechanism for this attenuation as well as the structural basis for the interaction of the virus envelope protein with the cellular endocytic machinery.

Additional research areas include studies of the humoral immune response to the viral envelope where efforts are in progress to develop strategies to augment the immunogenicity of this protein for vaccine studies in animal models.

Recent Publications

Nolan KM, Jordan AP, and Hoxie JA.  Effects of partial deletions within the HIV-1 V3 loop on coreceptor tropism and sensitivity to entry inhibitors.  J. Virology, Jan;82(2): 664-73, 2008.

Lin G, Bertolotti-Ciarlet A, Haggarty B, Romano J, Nolan KM, Leslie GJ, Jordan AP, Huang CC, Kwong PD, Doms RW, Hoxie J. Replication-competent variants of human immunodeficiency virus type 2 lacking the V3 loop exhibit resistance to chemokine receptor antagonists. J. Virology, Sep;81(18):9956-66, 2007.

Laakso MM, Lee FH, Haggarty B, Agrawal C, Nolan KM, Biscone M, Romano J, Jordan AP, Leslie GJ, Meissner EG, Su L, Hoxie JA, Doms RW.  V3 loop truncations in HIV-1 envelope impart resistance to coreceptor inhibitors and enhanced sensitivity to neutralizing antibodies. PLoS Pathogens, Aug 24;3(8):e117, 2007.

Fernando K, Hu H, Ni H, Hoxie JA, Weissman D. Vaccine-delivered HIV envelope inhibits CD4(+) T-cell activation, a mechanism for poor HIV vaccine responses. Blood, Mar 15; 09(6):2538-44, 2007.

Byland R, Vance PJ, Hoxie JA, Marsh M.  A conserved dileucine motif mediates clathrin and AP-2-dependent endocytosis of the HIV-1 envelope protein.  Mol. Biol Cell, Feb;18(2):414-25, 2007.

Chaipan C, Soilleux EJ, Simpson P, Hofmann H, Gramberg T, Marzi A, Geier M, Stewart EA, Eisemann J, Steinkasserer A, Suzuki-Inoue K, Fuller GL, Pearce AC, Watson SP, Hoxie JA, Baribaud F, Pohlmann S. DC-SIGN and CLEC-2 mediate human immunodeficiency virus type 1 capture by platelets. J. Virology, Sep;80(18):8951-60, 2006.

Wei Q, Stallworth JW, Vance PJ, Hoxie JA, Fultz PN. Simian immunodeficiency virus (SIV)/immunoglobulin G immune complexes in SIV-infected macaques block detection of CD16 but not cytolytic activity of natural killer cells. Clin. Vaccine Immunology, Jul;13(7):768-78, 2006.

 

Lab personnel:

    Research Specialists:

    Beth Haggarty

    Josephine Romano

    Andrea Polacchini-Oliveira Jordan

Students:

    George J. Leslie

    Gregory Q. Del Prete

 

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