We recently described novel serological assays that revealed for the first time a complex and lengthy maturation of envelope-specific antibody responses to HIV-1 and animal lentivirus (SIV, SHIV, EIAV, FIV) infections, Using these novel serological parameters to characterize antibody responses elicited by a diverse panel of experiments SIV)and EIAV) vaccines , we further demonstrated a close association between protective efficacy and the extent of immune maturation achieved by a particular vaccine. Based on this model of immature/non-protective and mature/protective antibody responses, we hypothesize that a more detailed definition of the maturation of envelope-specific antibody responses to experimental SIV and SHIV vaccines can provide fundamental new insights into the nature of protective immunity and provide new parameters that can be used as predictive immune correlates of experimental vaccine SIV and HIV-1 envelope proteins, i.e., """"""""domain- specific serology"""""""", can provide a higher resolution definition of the antibody responses to vaccines compared to the use of complete envelope protein antigens in serological assays. Therefore, we propose the following specific aims to develop and evaluate domain-specific serology in the SIV and SHIV monkey vaccine models: (1) To map and characterize conformationally dependent epitopes of SIV envelope proteins using complementary techniques of HIV-1/ SIV chimeric antigens and antibody protected proteolysis. (2) To develop deep novel domain-specific serological assays to characterize the maturation of antibody responses to attenuated SIV vaccines and its association with the development of protective immunity, (3) To evaluate domain-specific serology as a correlate of SIV vaccine efficacy in experimental trials of subunit, DNA, live attenuated and vector expression-based vaccine trials. (4) To develop domain-specific serological assays to map HIV-1 envelope antigenic determinants, to characterize the maturation of antibody responses to SHIV infection, and to identify immune correlates of SHIV vaccine efficacy. It is anticipated that the information gained from the proposed domain- specific serological studies in the SIV and SHIV vaccine models will provide importance guidance for the design of human AIDS vaccine strategies and validate the new serological methods as potential correlates of HIV-1 vaccine efficacy in human clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047758-03
Application #
6532820
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
D'Souza, Patricia D
Project Start
2000-09-30
Project End
2005-05-31
Budget Start
2002-08-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$240,697
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kalia, Vandana; Sarkar, Surojit; Gupta, Phalguni et al. (2005) Antibody neutralization escape mediated by point mutations in the intracytoplasmic tail of human immunodeficiency virus type 1 gp41. J Virol 79:2097-107
Abdel-Motal, Ussama M; Gillis, Jacqueline; Manson, Kelledy et al. (2005) Kinetics of expansion of SIV Gag-specific CD8+ T lymphocytes following challenge of vaccinated macaques. Virology 333:226-38
Cole, Kelly Stefano; Steckbeck, Jonathan D; Rowles, Jennifer L et al. (2004) Removal of N-linked glycosylation sites in the V1 region of simian immunodeficiency virus gp120 results in redirection of B-cell responses to V3. J Virol 78:1525-39
Sarkar, Surojit; Kalia, Vandana; Montelaro, Ronald C (2003) Caspase-mediated apoptosis and cell death of rhesus macaque CD4+ T-cells due to cryopreservation of peripheral blood mononuclear cells can be rescued by cytokine treatment after thawing. Cryobiology 47:44-58
Van Rompay, Koen K A; Greenier, Jennifer L; Cole, Kelly Stefano et al. (2003) Immunization of newborn rhesus macaques with simian immunodeficiency virus (SIV) vaccines prolongs survival after oral challenge with virulent SIVmac251. J Virol 77:179-90
Sarkar, Surojit; Kalia, Vandana; Murphey-Corb, Michael et al. (2002) Detailed analysis of CD4+ Th responses to envelope and Gag proteins of simian immunodeficiency virus reveals an exclusion of broadly reactive Th epitopes from the glycosylated regions of envelope. J Immunol 168:4001-11
Sarkar, S; Kalia, V; Murphey-Corb, M et al. (2002) Characterization of CD4+ T helper cell fine specificity to the envelope glycoproteins of simian immunodeficiency virus. J Med Primatol 31:194-204