Despite considerable success in the treatment of AIDS, its global impact heightens the need for the development of an efficacious vaccine against human immunodeficiency virus. In this regard, recent advances in our understanding of the virus-cell interactions that mediate entry into target cells, as well as the structural features of the HIV-1 envelope gp120 provided critical insights into the mechanism(s) by which the virus escapes immune recognition. Together with studies aimed at identifying antibody responses to the HIV-1 envelope that are involved in controlling or limiting viral replication, it may be possible to rationally design and evaluate immunogens that will elicit the type and nature of immune responses capable of conferring broadly cross- reactive protection. Towards this end, we propose to: 1. Continue immunochemical probing of oligomeric gp140 to identify the form of antigen most likely to evoke broadly reactive neutralizing antibodies. In addition to gp140 from the primary R5 isolate HIV-1SF162, we will examine the structures of gp140 prepared from neutralization resistant and sensitive X4 viruses to assess the impact of differing envelope strains and phenotypes on immune efficacy. 2. Define and assess, quantitatively and qualitatively, the rhesus macaque antibody responses directed against envelopes of X4 neutralization sensitive and resistant viruses, and of R5 viruses. The titers, conformation dependence, and neutralization potency, both in terms of breath and depth, of antibodies in sera obtained from rhesus macaques immunized with X4 or R5 SHIVs will be determined. 3. Compare the antigenicity and immunogenicity of HIV envelope glycoproteins in humans and macaques. With the use of envelope mutants, epitopes recognized by HIV-1 polyclonal and SHIV antisera will be examined and compared. This should allow us to assess whether the antigenicity of the HIV envelope is similar in the context of the HIV and SIV genome, and whether the immune responses directed against HIV envelope in infected macaques are comparable to that found in infected humans. 4. Compare the qualitative and quantitative aspects of the immune responses in intravenously (IV) and intravaginally (IVAG) inoculated animals. Since the outcome of SHIV infection via the mucosal route appears to be attenuated, it is possible that the type or extent of immune responses elicited by these two routes of immunization may differ.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072822-16
Application #
6712796
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Howcroft, Thomas K
Project Start
1990-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2006-03-31
Support Year
16
Fiscal Year
2004
Total Cost
$311,500
Indirect Cost
Name
Aaron Diamond AIDS Research Center
Department
Type
DUNS #
786658872
City
New York
State
NY
Country
United States
Zip Code
10016
Ho, Siu-Hong; Martin, Francine; Higginbottom, Adrian et al. (2006) Recombinant extracellular domains of tetraspanin proteins are potent inhibitors of the infection of macrophages by human immunodeficiency virus type 1. J Virol 80:6487-96
Ho, Siu-hong; Shek, Lili; Gettie, Agegnehu et al. (2005) V3 loop-determined coreceptor preference dictates the dynamics of CD4+-T-cell loss in simian-human immunodeficiency virus-infected macaques. J Virol 79:12296-303
Hsu, Mayla; Ho, Siu-Hong; Balfe, Peter et al. (2005) A CCR5-tropic simian-HIV molecular clone capable of inducing AIDS in rhesus macaques. J Acquir Immune Defic Syndr 40:383-7
Balfe, Peter; Shapiro, Sarah; Hsu, Mayla et al. (2004) Expansion of quasispecies diversity but no evidence for adaptive evolution of SHIV during rapid serial transfers among seronegative macaques. Virology 318:267-79
Hsu, Mayla; Zhang, Jie; Flint, Mike et al. (2003) Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc Natl Acad Sci U S A 100:7271-6
Hsu, M; Buckner, C; Harouse, J et al. (2003) Antigenic variations in the CD4 induced sites of the CCR5-tropic, pathogenic SHIVsf162p3 gp120 variants. J Med Primatol 32:211-7
Hsu, Mayla; Harouse, Janet M; Gettie, Agegnehu et al. (2003) Increased mucosal transmission but not enhanced pathogenicity of the CCR5-tropic, simian AIDS-inducing simian/human immunodeficiency virus SHIV(SF162P3) maps to envelope gp120. J Virol 77:989-98
Chakrabarti, Lisa A; Ivanovic, Tijana; Cheng-Mayer, Cecilia (2002) Properties of the surface envelope glycoprotein associated with virulence of simian-human immunodeficiency virus SHIV(SF33A) molecular clones. J Virol 76:1588-99
Lue, James; Hsu, Mayla; Yang, David et al. (2002) Addition of a single gp120 glycan confers increased binding to dendritic cell-specific ICAM-3-grabbing nonintegrin and neutralization escape to human immunodeficiency virus type 1. J Virol 76:10299-306
Malenbaum, S E; Yang, D; Cheng-Mayer, C (2001) Evidence for similar recognition of the conserved neutralization epitopes of human immunodeficiency virus type 1 envelope gp120 in humans and macaques. J Virol 75:9287-96

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