James A. Hoxie
Professor, Dept of Medicine
Director, Penn Center for AIDS Research

Microbiology, Virology and Parasitology Program

Address

356 Biomedical Rsch Bldg (BRB) II/III
421 Curie Boulevard
Philadelphia, PA 19104

Office tel.: 215 898-0261
Lab tel.: 215 898-0263
Fax: 215 573-7356
E-mail: hoxie@mail.med.upenn.edu

Research Interests

• Viral and cellular aspects of HIV (human immunodeficiency virus) and SIV (simian immunodeficiency virus) entry into cells; mechanisms of viral resistance to the host immune response; neutralizing antibodies.

Key words: AIDS, CD4, chemokine receptors, HIV, SIV, envelope glycoproteins, viral entry, neutralization, vaccine.

Description of Research

Research in Dr. Hoxie's lab is focused on identifying viral and cellular determinants that are relevant to the ability of HIV and SIV to infect cells and to evade host immune responses. Three specific areas of work include:

1. Producing modified HIV envelope glycoproteins for vaccine studies. This work is directed towards deriving HIV envelope glycoproteins that can elicit broadly neutralizing antibodies. Current approaches are deriving viruses lacking structures that are believed to shield the envelope from humoral immune responses.
2. Studies of CD4-independent isolates of HIV. Dr. Hoxie has described CD4-independent isolates of HIV-1 and HIV-2 that can infect cells using chemokine receptors without CD4. His lab has shown that the genetic basis for this phenotype results from mutations that expose the chemokine receptor binding site on gp120. Efforts are in progress to identify the structural basis for this effect and to use CD4-independent envelope glycoproteins as HIV vaccine candidates.
3. The role of the HIV/SIV cytoplasmic tail in pathogenesis. Dr. Hoxie's group has identified endocytosis signals in the cytoplasmic tails of HIV, SIV and FIV Env proteins that reduce Env expression on the surface of infected cells. Dr. Hoxie has proposed that these signals could be relevant in pathogenesis by enabling virus-producing cells to survive host anti-viral immune responses. He has shown in an SIV model that viruses with mutations in this domain are markedly attenuated in vivo and controllable by host immune responses. Ongoing studies are addressing the mechanism for this attenuation, the components of the host immune response that are involved, and defects in viral assembly that are believed to underlie this effect.

Selected 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.

Search PubMed for more articles

Lab

Rotation Projects

• Structure function studies of envelope glycoproteins focusing on mechanisms of CD4 and chemokine receptor engagement.
• Modulation of Envelope glycoproteins for the design of immunogens that can elicit broadly neutralizing antibodies.
• The role of the HIV/SIV cytoplasmic tail in pathogenesis.
• Studies evaluating mechanisms of neutralization sensitivity and resistance to antibodies.

Lab personnel:

Research Specialists:
Beth Haggarty
Josephine Romano
Andrea Polacchini-Oliveira Jordan

Students:
George J. Leslie
Gregory Q. Del Prete