During the past 30 years we have developed a comprehensive multidisciplinary research program using the equine infectious anemia virus (EIAV) system to examine the fundamental mechanisms by which lentiviruses persist despite robust host immune responses and to evaluate experimental immunization strategies as models for HIV-1 infection and vaccine development. In the previous grant period, we demonstrated for the first time that Env variation is indeed a primary determinant of lentivirus vaccine efficacy that will need to be addressed in the effort to develop broadly protective vaccines. In the current competitive renewal application we propose to extend these studies to test our central hypothesis that EIAV Env is the primary determinant of vaccine efficacy and that effective vaccines must elicit appropriate broadly reactive immunity against diverse virus strains. Moreover, we suggest that Env antigen and its method of presentation need to be optimized to elicit enduring broadly protective immunity. Thus, the following complementary specific aims are proposed: (i) to define the Env determinants of vaccine protection and to characterize the specificity of vaccine immunity to these critical determinants, (ii) to characterize the maturation of immune responses to attenuated EIAV vaccines that is associated with the development of enduring protective vaccine immunity, and (iii) to develop and evaluate novel immunization procedures using multivalent and consensus Env immunogens for their ability to elicit broadly protective immunity to diverse EIAV strains. In the first specific aim, we will use selected chimeric Env viruses derived from two defined variant Env species that differ markedly in vaccine protection to map specific Env determinants of protection based on experimental challenge of ponies immunized with a reference attenuated EIAV vaccine. In the second specific aim, we will perform a complementary study to define the immune correlates of vaccine efficacy by characterizing the Env-specific antibody and cellular immune reponses that distinguish nonprotective and protective vaccine immunity. In the third specific aim, we will evaluate a series of vaccine modalities (attenuated virus, virus like particles, and adenovirus vectors) expressing either a mixture of variant Env species or a consensus Env for their ability to produce broadly reactive vaccine immunity and to protect against diverse Env strains of EIAV in experimentally immunized ponies. It is anticiapated that the results of these studies will provide novel insights into the fundamental mechanisms by which Env variation can circumvent protective vaccine immunity and determine the potential of alternative vaccine strategies to overcome the challenge of Env diversity in vaccine development. Thus, these EIAV studies address critical issues in AIDS vaccine research and can provide important information relevant to the design of candidate human AIDS vaccines.

Public Health Relevance

Development of an effective and practical AIDS vaccine represents a critical need in the effort to control the worldwide AIDS epidemic. Recent advances in multiple drug therapy for HIV-1 infected patients have certainly improved the length and quality of life for patients in economically developed countries, but have had little impact on the predominant AIDS epidemic centered in developing countries in Africa and Asia with severely limited health care resources. In fact, the explosion of new HIV-1 infections being experienced in countries such as India, China, Russia, and South Africa and the failure to substantially reduce HIV-1 infections in targeted developing countries highlight the urgency of increasing AIDS vaccine efforts. We have developed a comprehensive multidisciplinary research program using the equine infectious anemia virus (EIAV) system to examine the fundamental mechanisms by which lentiviruses persist despite robust host immune responses and to evaluate experimental immunization strategies as models for HIV-1 infection and vaccine development. We recently demonstrated for the first time that Env variation is indeed a primary determinant of lentivirus vaccine efficacy that will need to be addressed in the effort to develop broadly protective vaccines. Thus, these EIAV studies address critical issues in AIDS vaccine research and can provide important information relevant to the design of candidate human AIDS vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025850-25
Application #
8448624
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Miller, Nancy R
Project Start
1987-09-30
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
25
Fiscal Year
2013
Total Cost
$632,994
Indirect Cost
$106,111
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Craigo, Jodi K; Ezzelarab, Corin; Cook, Sheila J et al. (2015) Protective efficacy of centralized and polyvalent envelope immunogens in an attenuated equine lentivirus vaccine. PLoS Pathog 11:e1004610
Liu, Chong; Cook, Sheila J; Craigo, Jodi K et al. (2014) Epitope shifting of gp90-specific cellular immune responses in EIAV-infected ponies. Vet Immunol Immunopathol 161:161-9
Craigo, Jodi K; Ezzelarab, Corin; Cook, Sheila J et al. (2013) Envelope determinants of equine lentiviral vaccine protection. PLoS One 8:e66093
Craigo, Jodi K; Montelaro, Ronald C (2013) Lessons in AIDS vaccine development learned from studies of equine infectious, anemia virus infection and immunity. Viruses 5:2963-76
Craigo, Jodi K; Ezzelarab, Corin; Montelaro, Ronald C (2012) Development of a high throughput, semi-automated, infectious center cell-based ELISA for equine infectious anemia virus. J Virol Methods 185:221-7
Liu, Chong; Cook, Frank R; Cook, Sheila J et al. (2012) The determination of in vivo envelope-specific cell-mediated immune responses in equine infectious anemia virus-infected ponies. Vet Immunol Immunopathol 148:302-10
Craigo, Jodi K; Montelaro, Ronald C (2011) EQUINE INFECTIOUS ANEMIA VIRUS INFECTION AND IMMUNITY: LESSONS FOR AIDS VACCINE DEVELOPMENT. Future Virol 6:139-142
Craigo, Jodi K; Montelaro, Ronald C (2010) EIAV envelope diversity: shaping viral persistence and encumbering vaccine efficacy. Curr HIV Res 8:81-6
Craigo, Jodi K; Barnes, Shannon; Cook, Sheila J et al. (2010) Divergence, not diversity of an attenuated equine lentivirus vaccine strain correlates with protection from disease. Vaccine 28:8095-104
Craigo, Jodi K; Barnes, Shannon; Zhang, Baoshan et al. (2009) An EIAV field isolate reveals much higher levels of subtype variability than currently reported for the equine lentivirus family. Retrovirology 6:95

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