Many T cell based vaccines against human immunodeficiency virus (HIV) are in clinical trials. One promising study was canceled in 2007 after showing no evidence of protection, underscoring how little is known about the nature of protective T cell responses against HIV. We have discovered that Mauritian cynomolgus macaques (MCM) infected with simian immunodeficiency virus (SIV), a virus that causes the same disease as HIV causes in humans, offer unprecedented opportunities for understanding protective T cell responses. The distinguishing feature of MCM is their very simple genetics. This allows investigators to identify groups of animals who will mount predictable T cell responses against SIV and use these animals to advance our understanding of T cell immunity to HIV and SIV. We hypothesize that the HIV vaccines tested so far have not been successful at least partially due to their failure to elicit a broad repertoire of T cell specificities. It is difficult to test this hypothesis in humans, so we will test this hypothesis in SIV+ MCM, taking advantage of their simple genetics. These experiments rely on groups of MCM that are either homozygous or heterozygous for major histocompatibility complex (MHC) class I genes that present SIV-derived peptides to T cells. We predict that MHC heterozygous MCM have the capacity to present twice as many peptides to T cells as MHC homozygous MCM when challenged with pathogenic strains of SIV, and therefore are more likely to control infection with this AIDS virus. First, we will infect MHC homozygous and heterozygous MCM with pathogenic SIV and monitor SIV disease progression, the number of recognized T cell epitopes, and virus evolution. We anticipate that MHC homozygous animals will recognize fewer SIV CD8+ T cell peptides than MHC heterozygous MCM, and that this will result in higher viral burdens in the homozygous animals. Next, we will produce a strain of SIV where the T cell epitopes that are normally recognized during SIV infection are "knocked out" and ask whether this virus can be effectively controlled by the immune systems of MCM. Lastly, we will immunize MCM with a weakened vaccine strain of SIV that elicits potent immune responses. The MCM will be challenged with the "knockout" strain of SIV that does not contain specific T cell epitopes. Since the vaccine and challenge viruses will differ primarily within defined T cell epitopes, this experiment will determine how important broadly directed T cell responses are to the impressive control afforded by attenuated SIV. Taken together, these experiments will fundamentally advance our understanding of the importance of T cell breadth in control of HIV and SIV, and help determine whether eliciting a broad CD8+ T cell "repertoire" should be a major goal for HIV vaccines. Researchers still do not know what sorts of immune responses might protect people against AIDS. In this work, we will use a unique animal model to determine whether the ability to mount diverse cellular immune responses against multiple targets within the AIDS virus influences the ability of infected individuals to control virus replication.

Public Health Relevance

Researchers still do not know what sorts of immune responses might protect people against AIDS. In this work, we will use a unique animal model to determine whether the ability to mount diverse cellular immune responses against multiple targets within the AIDS virus influences the ability of infected individuals to control virus replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI084787-04
Application #
8314110
Study Section
Special Emphasis Panel (ZAI1-SV-A (M2))
Program Officer
Warren, Jon T
Project Start
2009-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$696,003
Indirect Cost
$227,314
Name
University of Wisconsin Madison
Department
None
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Greene, Justin M; Weiler, Andrea M; Reynolds, Matthew R et al. (2014) Rapid, repeated, low-dose challenges with SIVmac239 infect animals in a condensed challenge window. Retrovirology 11:66
Goldberg, Tony L; Gendron-Fitzpatrick, Annette; Deering, Kathleen M et al. (2014) Fatal metacestode infection in Bornean orangutan caused by unknown Versteria species. Emerg Infect Dis 20:109-13
Sibley, Samuel D; Lauck, Michael; Bailey, Adam L et al. (2014) Discovery and characterization of distinct simian pegiviruses in three wild African Old World monkey species. PLoS One 9:e98569
Lauck, Michael; Switzer, William M; Sibley, Samuel D et al. (2014) Discovery and full genome characterization of a new SIV lineage infecting red-tailed guenons (Cercopithecus ascanius schmidti) in Kibale National Park, Uganda. Retrovirology 11:55
Albers, Danielle; Correll, Michael; Gleicher, Michael (2014) Task-Driven Evaluation of Aggregation in Time Series Visualization. Proc SIGCHI Conf Hum Factor Comput Syst 2014:551-560
Greene, Justin M; Lhost, Jennifer J; Hines, Paul J et al. (2013) Adoptive transfer of lymphocytes isolated from simian immunodeficiency virus SIVmac239?nef-vaccinated macaques does not affect acute-phase viral loads but may reduce chronic-phase viral loads in major histocompatibility complex-matched recipients. J Virol 87:7382-92
Wilker, Peter R; Dinis, Jorge M; Starrett, Gabriel et al. (2013) Selection on haemagglutinin imposes a bottleneck during mammalian transmission of reassortant H5N1 influenza viruses. Nat Commun 4:2636
Harris, Max; Burns, Charles M; Becker, Ericka A et al. (2013) Acute-phase CD8 T cell responses that select for escape variants are needed to control live attenuated simian immunodeficiency virus. J Virol 87:9353-64
O'Connor, Shelby L; Becker, Ericka A; Weinfurter, Jason T et al. (2012) Conditional CD8+ T cell escape during acute simian immunodeficiency virus infection. J Virol 86:605-9
Burwitz, Benjamin J; Sacha, Jonah B; Reed, Jason S et al. (2011) Pyrosequencing reveals restricted patterns of CD8+ T cell escape-associated compensatory mutations in simian immunodeficiency virus. J Virol 85:13088-96

Showing the most recent 10 out of 12 publications