356 BRB II/III
421 Curie Blvd.
Philadelphia, PA 19104

215-898-0261
215-573-7356 fax

Research interests:
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 evade host immune responses. Main goals are to understand the molecular basis for differences in viral tropism on 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 infected cells.

In recent studies, isolates of CD4-independent isolates of HIV-1 and HIV-2 have been derived that infect cells using chemokine receptors in the absence of CD4. It has shown that this phenotype results from mutations in the viral envelope that increase the expoure and/or affinity of the chemokine receptor binding site. Research goals are to understand the underlying mechanisms for this effect and to explore 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 env protein with the cellular endocytic machinery.

References

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 JA. 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.