Description of Research Expertise:
Viral and cellular aspects of HIV (human immunodeficiency virus) and SIV (simian immunodeficiency virus) entry into cells; HIV and SIV pathogenesis; mechanisms of viral resistance to the host immune response; neutralizing antibodies; gene therapy of HIV infection.
Key words: AIDS, CD4, chemokine receptors, HIV, SIV, envelope glycoproteins, viral entry, neutralization, vaccine, vaccines, pathogenesis
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. Four specific areas of work include:
1. 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. Additional studies are focusing on translating this project to SHIV viruses containing an HIV-1 envelope to determine if analogous mutations in their cytoplasmic tails can also lead to broadly protective immunity.
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. In addition, novel simian immunodeficiency viruses have been generated that lack a CD4 binding site to explore the consequences of CD4 tropism on pathogenesis and host immune responses. Additional studies are focusing on translating this project to novel SHIV viruses containing an HIV-1 envelope for evaluation in nonhuman primates.
3. 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.
4. Gene therapy approaches using a fusion inhibitory peptide from the HIV-1 gp41 envelope molecule conjugated to the human chemokine receptor CXCR4. Published studies have shown that this molecule is potent and broad inhibitor of HIV-1 entry. Studies in the Hoxie lab are focusing on understanding the mechanism for this effect and exploring ways in which viral resistance to this inhibitor can occur. The modified CXCR4 inhibitory protein (termed C34-CXCR4) is currently being evaluated in human trials and the Hoxie lab is currently assessing whether subjects receiving autologous T cells that express this protein, produce antibodies to the C34-CXCR4 protein).
-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.
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 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 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 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 9 (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 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 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 13 (7): 768-78,2006.
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