Scientific Overview

The aim of our research is the development of effective HIV-1 vaccines, with the potential to prevent infection or assist in controlling already established infection. We are focusing on three areas of HIV-1 vaccine development:

Enhancement of DNA vaccine immunogenicity
Our research in recent years has focused on the design and development of a multigenic subtype C-based DNA vaccine as a priming component of DNA prime and recombinant MVA boost vaccine. This effort culminated in a recent Phase I clinical trial of the ADVAX DNA vaccine. Although DNA immunization is a promising vaccine strategy, inoculation with antigen-encoding DNA has generally provided limited immunogenicity in non-human primate models and in human clinical trials. As a result, we are currently pursuing strategies to augment the magnitude and enhance the quality of the immune response to DNA vaccines. Our approach centers on novel DNA constructs that facilitate antigen (Ag) cross-presentation by dendritic cells (DC) in conjunction with the use of cutting edge delivery technologies.

Induction of HIV-1 neutralizing antibodies (Nabs) with envelope-based immunogens
Our efforts to induce NAbs focus on the V3 loop of gp120. V3 loop based immunogens have historically been potent inducers of strain-specific NAbs, yet have been incapable of eliciting NAbs to heterologous primary isolates. This failure is in part explained by the vast sequence diversity among different primary isolates and the potential inaccessibility to Nabs. Focusing on V3 alone is therefore not a viable global vaccine strategy. Targeting the V3 loop may however be a pragmatic strategy to develop a prophylactic vaccine for HIV-1 in a geographically restricted area with limited sequence diversity. We are testing the hypothesis that coupling selected V3 immunogens to DC targeting vaccine platforms will enhance B cell maturation and yield high titer, high affinity NAbs against primary isolates of limited sequence divergence.

Novel IgG Fc and TLR5 ligand based vaccine platforms
We believe that a recombinant fusion vaccine incorporating both the Ag of interest and a APC/DC targeting moiety would have distinct advantages, including i) capability to target the Ag to DC, ii) coupling stimulation of DC maturation with Ag uptake, and iii) enhanced processing and ultimately presentation and co-stimulation. To this end, we are pursuing promising APC/DC targeting and activation strategies that focus on two pivotal immunologic interactions: Fc-Fc receptor and flagellin-TLR5. We are testing the hypothesis that novel Fc-based and flagellin-based platforms will engender robust and long-lasting immunity.

The aim of our research is the development of an effective HIV-1 vaccine, which could be used to prevent infection or assist in controlling already established infection. Thus far, our efforts have culminated in a Phase I clinical trial of our DNA vaccine candidate (ADVAX). Although DNA immunization is a promising vaccine strategy, by itself, inoculation with HIV-1 protein-encoding DNA is unlikely to elicit adequate immune responses. We are therefore intently focusing on three areas of HIV-1 vaccine development: 1) enhancing the quality and augmenting the magnitude of immune responses generated by DNA vaccines, 2) designing vaccines that elicit HIV-1 envelope protein-specific antibodies capable of neutralizing the virus and 3) designing vaccines that leverage fundamental immunologic interactions: a) the relationship between the Fc regions of antibodies and their associated receptors, and b) the interplay between “danger sensing” receptors and the “danger signals” presented by certain pathogens, particularly bacterial flagellin proteins.

NAME: Yaoxing Huang

TITLE: Assistant Professor/Staff Investigator

EDUCATION

1988	B.Med.   Shanghai Medical University, China
1994	M.S.   New York University, NY
1997	Ph.D.   New York University, NY

INTERNSHIP AND RESIDENCY

1997-2001	Postdoctoral Research Fellow, Aaron Diamond AIDS Research Center
2001-2003	Research Scientist, Aaron Diamond AIDS Research Center
2003-Present	Staff Investigator, Aaron Diamond AIDS Research Center Assistant Professor, Rockefeller University

BIBLIOGRAPHY

• Moore JP, JA McKeating, Y Huang, A Ashkenazi and Ho DD. 1992. Virions of primary human immunodeficiency virus type 1 isolates resistant to soluble CD4 (sCD4) neutralization differ in sCD4 binding and glycoprotein gp120 retention from sCD4-sensitive isolates. J Virol. 66: 235-43.
• Huang Y, L Zhang and Ho DD. 1995. Characterization of nef sequences in long-term survivors of human immunodeficiency virus type 1 infection. J Virol. 69: 93-100.
• Huang Y, L Zhang and Ho DD. 1995. Biological characterization of nef in long-term survivors of human immunodeficiency virus type 1 infection. J Virol. 69: 8142-6.
• Dragic T, V Litwin, GP Allaway, SR Martin, Y Huang, KA Nagashima, C Cayanan, PL Maddon, RA Koup, JP Moore and Paxton WA. 1996. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR5. Nature. 381: 667-73.
• Zhang L, Y Huang, T He, Y Cao and Ho DD. 1996. HIV-1 subtype and second-receptor use. Nature 383: 768.
• Huang Y, WA Paxton, SM Wolinsky, AU Neumann, L Zhang, T He, S Kang, D Ceradini, X Jin, K Yazdanbakhsh, K Kunstman, D Erickson, E Dragon, NR Landau, J Phair, DD Ho and Koup RA. 1996. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nature Med. 2: 1240-3.
• Zhang L, Y Huang, H Yuan, S Tuttleton and Ho DD. 1997. Genetic characterization of vif, vpr, and vpu sequences from long-term survivors of human immunodeficiency virus type 1 infection. Virology 228: 340-9.
• Zhang L, Y Huang, H Yuan, BK Chen, J Ip and Ho DD. 1997. Identification of replication-competent pathogenic human immunodeficiency virus type 1 with a duplication in the TCF-1 alpha region but lacking NF-kappaB binding sites. J Virol. 71: 1651-6.
• Zhang L, Y Huang, BK Chen, J Ip and Ho DD. 1997. Genotypic and phenotypic characterization of long terminal repeat sequences from long-term survivors of human immunodeficiency virus type 1 infection. J Virol. 71: 5608-13.
• Zhang L, CD Carruthers, T He, Y Huang, Y Cao, G Wang, B Hahn and Ho DD. 1997. HIV type 1 subtypes, coreceptor usage, and CCR5 polymorphism. AIDS Res Human Retroviruses 13: 1357-65.
• Huang Y, L Zhang and Ho DD. 1998. Characterization of gag, and pol sequences from long-term survivors of human immunodeficiency virus type 1 infection. Virology 240: 36-49.
• Kostrikis LG, Y Huang, JP Moore, SM Wolinsky, L Zhang, Y Guo, L Deutsch, J Phair, AU Neumann and Ho DD. 1998. A chemokine receptor CCR2 allele delays HIV-1 disease progression and is associated with a CCR5 promoter mutation. Nature Med. 4: 350-353.
• Zhang L, T He, Y Huang, Z Chen, Y Guo, S Wu, KJ Kunstman, RC Brown, JP Phair, AU Neumann, DD Ho and Wolinsky SM. 1998. Chemokine coreceptor usage by diverse primary isolates of human immunodeficiency virus type 1. J Virol. 72: 9307-12.
• Binley JM, X Jin, Y Huang, L Zhang, Y Cao, DD Ho and Moore JP. 1998. Persistent antibody responses but declining cytotoxic T-lymphocyte responses to multiple human immunodeficiency virus type 1 antigens in a long-term nonprogressing individual with a defective p17 proviral sequence and no detectable viral RNA expression. J Virol. 72: 3472-4.
• Kostrikis LG, AU Neumann, B Thomson, BT Korber, P McHardy, R Karanicolas, L Deutsch, Y Huang, JF Lew, K McIntosh, H Pollack, W Borkowsky, HM Spiegel, P Palumbo, J Oleske, A Bardeguez, K Luzuriaga, J Sullivan, SM Wolinsky, RA Koup, DD Ho and Moore JP. 1999. A polymorphism in the regulatory region of the CC-chemokine receptor 5 gene influences perinatal transmission of human immunodeficiency virus type 1 to African American infants. J Virol. 73: 10264-71.
• Jin X, C Robert, D Nixon, J Safrit, L Zhang, Y Huang, B Bhardwaj, A DeGroot and Koup RA. 2001. Identification of subdominant cytotoxic T lymphocyte epitopes encoded by autologous HIV type 1 sequences, using dendritic cell stimulation and computer-driven algorithm. AIDS Res Hum Retroviruses, 16: 67-76.
• Chen Z, Y Huang, X Zhao, E Skulsky, S Lewin, D Lin, J Ip, A Gettie and Ho DD. 2000. Enhanced infectivity of an R5-tropic SHIVCHN19 carrying HIV-1 subtype C envelope after passages in pig-tailed macaques (Macaca nemestrina). J Virol. 74: 6501-10.
• Foster JL, RP Molina, T Luo, VK Arora, Y Huang, DD Ho and Garcia JV. 2001. Genetic and functional diversity of human immunodeficiency virus type 1 subtype B Nef primary isolates. J Virol. 75: 1672-80.
• Chen Z, X Zhao, Y Huang, A Gettie, L Ba, J Blanchard and Ho DD. 2002. CD4+ lymphocytopenia in acute infection of Asian macaques by a vaginally transmissible subtype-C, CCR5-tropic Simian/Human Immunodeficiency Virus (SHIV). J Acquir. Immune. Defic. Syndr. 30: 133-45.
• Ho DD and Huang Y. 2002. The HIV-1 Vaccine Race. Cell (review). 110: 135-8.
• Simon V, Zennou V, Murray D, Huang Y, Ho DD and Bieniasz PD. 2005. Natural variation in Vif: differential impact on APOBEC3G/3F and a potential role in HIV-1 diversification. PLoS Pathogens. 1: 1-9.
• Gardiner D, Huang Y, Basu S, Leung L, Song Y, Chen Z and Ho DD. 2006. Multiple-site DNA vaccination enhances immune responses in mice. Vaccine 24: 287-292.
• Trumpfheller C, Finke JS, Lopez CB, Moran TM, Moltedo B, Soares H, Huang Y, Schlesinger SJ, Park CG, Nussenzweig MC, Granelli-Piperno A and Steinman RM. 2006. Intensified and protective CD4+ T cell immunity in mice with anti-dendritic cell HIV gag fusion antibody vaccine. J Exp Med 203:607-17.
• Trumpfheller C, Caskey M, Nchinda G, Longhi MP, Mizenina O, Huang Y, Schlesinger SJ, Colonna M, Steinman RM. 2008. The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci U S A. 105(7): 2574-9.
• Huang Y, Chen A, Li X, Chen Z, Zhang W, Song Y, Gurner D, Gardiner D, Basu S, Ho DD, Tsuji M. 2008. Enhancement of HIV DNA vaccine immunogenicity by the NKT cell ligand, alpha-galactosylceramide. Vaccine. 26(15): 1807-16.
• Nchinda G, Kuroiwa J, Oks M, Trumpfheller C, Park CG, Huang Y, Hannaman D, Schlesinger SJ, Mizenina O, Nussenzweig MC, Uberla K, Steinman RM. 2008. The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells. J Clin Invest. 2008 Mar 6; [Epub ahead of print]
• Huang Y, Chen Z, Zhang W, Gurner D, Song Y, Gardiner DF, Ho DD. 2008. Design, Construction, and Characterization of a Dual-Promoter Multigenic DNA Vaccine Directed Against an HIV-1 Subtype C/B' Recombinant. J Acquir Immune Defic Syndr. 47(4): 403-11.
• Chen Z, Huang Y, Zhao X, Ba L, Zhang W, Ho DD. 2008. Design, construction, and characterization of a multigenic modified vaccinia ankara candidate vaccine against human immunodeficiency virus type 1 subtype c/b'. J Acquir Immune Defic Syndr. 47(4):412-21.
• Bozzacco L, Trumpfheller C, Huang Y, Longhi MP, Shimeliovich I, Schauer JD, Park CG, Steinman RM. 2009. HIV gag protein is efficiently cross-presented when targeted with an antibody towards the DEC-205 receptor in Flt3 ligand-mobilized murine dendritic cells. Eur J Immunol. 2009 Oct 14. [view]

• Ho DD and Huang Y. 2002. The HIV-1 Vaccine Race. Cell (review) 110: 135-8. [view]
• Huang Y, Chen A, Li X, Chen Z, Zhang W, Song Y, Gurner D, Gardiner D, Basu S, Ho DD, Tsuji M. 2008. Enhancement of HIV DNA Vaccine Immunogenicity by the NKT Cell Ligand, alpha-galactosylceramide. Vaccine 26(15): 1807-16. [view]
• Huang Y, Chen Z, Zhang W, Gurner D, Song Y, Gardiner DF, Ho DD. 2008. Design, Construction, and Characterization of a Dual-Promoter Multigenic DNA Vaccine Directed Against an HIV-1 Subtype C/B' Recombinant. J Acquir Immune Defic Syndr. 47(4): 403-11. [view]
• Bozzacco L, Trumpfheller C, Huang Y, Longhi MP, Shimeliovich I, Schauer JD, Park CG, Steinman RM. 2009. HIV gag protein is efficiently cross-presented when targeted with an antibody towards the DEC-205 receptor in Flt3 ligand-mobilized murine dendritic cells. Eur J Immunol. 2009 Oct 14. [view]

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Yaoxing Huang	Assistant Professor
Faye Yu	Research Associate