Our studies aim at developing vaccine strategies that will prevent the establishment of HIV-infection. Vaccination strategies that only elicit cellular antiviral responses are not capable of sterilizing immunity, but can reduce the plasma viral load during the chronic phase of infection; prevent the rapid elimination of CD4+ T lymphocytes; and delay the development of disease. Vaccination methodologies that principally elicit neutralizing antibodies also offer protection (and in certain cases sterilizing immunity), but only against the homologous virus. This is due to the inability of currently used envelope immunogens to elicit cross-reactive neutralizing antibodies. The proposed studies are based on our observation that the partial elimination of the V2 loop from the SF162 envelope increases the exposure of conserved neutralization epitopes. Macaques immunized with this modified envelope, termed SF162 V2, but not with the unmodified SF162 envelope, generate antibodies that neutralize several heterologous primary HIV-1 isolates. We propose that the antibodies elicited by the SF162 V2 envelope immunogen will offer protection from heterologous viral challenge, while those elicited by the unmodified SF162 envelope immunogen will offer protection only from the homologous viral challenge. To test this hypothesis macaques will first be immunized with DNA vectors expressing the SIVmac239 Gag and Pol and either the SF162 or SF162 V2 envelope proteins, to elicit cellular responses against multiple antigens and subsequently immunized with the corresponding purified envelope protein to increase the titer of neutralizing antibodies. The animals will then be challenged with the homologous SHIVSF162P4 or the heterologous SHIV89.6P viruses. Specifically we wish to: (1) Demonstrate that while both envelope-immunogens elicit protective antibodies against the homologous viral challenge, only the SF162 V2 immunogen elicits antibodies against heterologous viral challenges; (2) Examine whether the rate of progression to disease differs when only cellular anti-viral responses or only neutralizing antibody responses (not potent enough to offer sterilizing immunity) are present at the time of viral challenge; and (3) demonstrate that although infection will be initiated in the presence of vaccine-induced cellular anti-viral responses and neutralizing antibodies, at titers that are insufficient to offer sterilizing immunity, the infection process will be aborted.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI051217-01
Application #
6450983
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Warren, Jon T
Project Start
2002-01-01
Project End
2006-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
1
Fiscal Year
2002
Total Cost
$571,171
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
Kraft, Zane; Derby, Nina R; McCaffrey, Ruth A et al. (2007) Macaques infected with a CCR5-tropic simian/human immunodeficiency virus (SHIV) develop broadly reactive anti-HIV neutralizing antibodies. J Virol 81:6402-11
Xu, Rong; Srivastava, Indresh K; Kuller, Larene et al. (2006) Immunization with HIV-1 SF162-derived Envelope gp140 proteins does not protect macaques from heterologous simian-human immunodeficiency virus SHIV89.6P infection. Virology 349:276-89
Xu, Rong; Srivastava, Indresh K; Greer, Catherine E et al. (2006) Characterization of immune responses elicited in macaques immunized sequentially with chimeric VEE/SIN alphavirus replicon particles expressing SIVGag and/or HIVEnv and with recombinant HIVgp140Env protein. AIDS Res Hum Retroviruses 22:1022-30
Burke, Brian; Derby, Nina R; Kraft, Zane et al. (2006) Viral evolution in macaques coinfected with CCR5- and CXCR4-tropic SHIVs in the presence or absence of vaccine-elicited anti-CCR5 SHIV neutralizing antibodies. Virology 355:138-51
Bolesta, Elizabeth; Kowalczyk, Aleksandra; Wierzbicki, Andrzej et al. (2006) Increased level and longevity of protective immune responses induced by DNA vaccine expressing the HIV-1 Env glycoprotein when combined with IL-21 and IL-15 gene delivery. J Immunol 177:177-91
Derby, Nina R; Kraft, Zane; Kan, Elaine et al. (2006) Antibody responses elicited in macaques immunized with human immunodeficiency virus type 1 (HIV-1) SF162-derived gp140 envelope immunogens: comparison with those elicited during homologous simian/human immunodeficiency virus SHIVSF162P4 and heterologous H J Virol 80:8745-62
McCaffrey, Ruth A; Saunders, Cheryl; Hensel, Mike et al. (2004) N-linked glycosylation of the V3 loop and the immunologically silent face of gp120 protects human immunodeficiency virus type 1 SF162 from neutralization by anti-gp120 and anti-gp41 antibodies. J Virol 78:3279-95