Live, attenuated virus strains are the most effective AIDS vaccines identified to date. The protective immune responses elicited by attenuated vaccines are unknown. We recently developed a monkey model in which immune cells can transferred between animals, allowing us to explore the immunological requirements for vaccine-mediated protection. Similar adoptive transfer experiments in mice have revolutionized our understanding of pathogen immunity but have been impossible to perform in monkeys. In this proposal, we test the hypothesis that lymphocytes from animals vaccinated with attenuated viruses are responsible for the success of attenuated vaccines. We will test this hypothesis by transferring variable numbers of lymphocytes from monkeys vaccinated with live, attenuated virus into vaccine naive recipients who will subsequently be infected with pathogenic virus. We anticipate that a dose-dependent relationship exists between the number of transferred lymphocytes and protection from pathogenic disease. If we find that a high dose (1 x 1010) total lymphocytes are protective, we will test progressively lower lymphocyte doses to determine the protective threshold. If high doses of transferred lymphocytes are not protective, we will attempt to augment protection by combining lymphocyte transfer with transfer of antibodies purified from attenuated vaccinees. Successful completion of these experiments will determine which immune responses are responsible attenuated-vaccine mediated protection, one of the most important questions in contemporary AIDS vaccine research. Moreover, demonstration that adoptive transfer studies are feasible in macaques will potentiate future studies examining the minimal immunological prerequisites for vaccine-mediated protection.

Public Health Relevance

With the number of new infections rising faster than ever, a prophylactic vaccine for HIV is urgently needed. Live strains of virus, genetically modified to grow poorly, elicit the most effective immune responses ever witnessed in more than 20 years of testing. For the first time, we will attempt to transfer this immunity between animals in order to understand which arms of the immune response are involved in protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077376-02
Application #
7560022
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Warren, Jon T
Project Start
2008-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
2
Fiscal Year
2009
Total Cost
$749,799
Indirect Cost
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Buechler, Connor R; Bailey, Adam L; Lauck, Michael et al. (2017) Genome Sequence of a Novel Kunsagivirus (Picornaviridae: Kunsagivirus) from a Wild Baboon (Papio cynocephalus). Genome Announc 5:
Moncla, Louise H; Weiler, Andrea M; Barry, Gabrielle et al. (2017) Within-Host Evolution of Simian Arteriviruses in Crab-Eating Macaques. J Virol 91:
Szafir, Danielle Albers; Sarikaya, Alper; Gleicher, Michael (2016) Lightness Constancy in Surface Visualization. IEEE Trans Vis Comput Graph 22:2107-21
Gleicher, Michael (2016) A Framework for Considering Comprehensibility in Modeling. Big Data 4:75-88
Kuhn, Jens H; Lauck, Michael; Bailey, Adam L et al. (2016) Reorganization and expansion of the nidoviral family Arteriviridae. Arch Virol 161:755-68
Bailey, Adam L; Lauck, Michael; Ghai, Ria R et al. (2016) Arteriviruses, Pegiviruses, and Lentiviruses Are Common among Wild African Monkeys. J Virol 90:6724-6737
Moncla, Louise H; Zhong, Gongxun; Nelson, Chase W et al. (2016) Selective Bottlenecks Shape Evolutionary Pathways Taken during Mammalian Adaptation of a 1918-like Avian Influenza Virus. Cell Host Microbe 19:169-80
Bailey, Adam L; Lauck, Michael; Sibley, Samuel D et al. (2016) Zoonotic Potential of Simian Arteriviruses. J Virol 90:630-5
Bailey, Adam L; Lauck, Michael; Mohns, Mariel et al. (2015) Durable sequence stability and bone marrow tropism in a macaque model of human pegivirus infection. Sci Transl Med 7:305ra144
Mohns, Mariel S; Greene, Justin M; Cain, Brian T et al. (2015) Expansion of Simian Immunodeficiency Virus (SIV)-Specific CD8 T Cell Lines from SIV-Naive Mauritian Cynomolgus Macaques for Adoptive Transfer. J Virol 89:9748-57

Showing the most recent 10 out of 45 publications