Abstract

In the previous funding period, we have used the SIV infection/rhesus macaque animal model to investigate factors contributing to CMV pathogenesis in AIDS. In the next grant period, we propose to examine mechanisms of loss of CMV-specific immunity in AIDS. We hypothesize that SIV-mediated loss of CMV-specific CD4 v T cell help is necessary for loss or dysfunction of CMV-specific CD8 v T lymphocytes and memory B lymphocytes in rhesus macaques that develop AIDS. The SIV-induced loss of immune control of latent CMV infection may be due to a combination of destruction, impaired differentiation or effector function, and impaired homing of CMV-specific lymphocytes to tissue sites of CMV reactivation. Insight into mechanisms by which SIV infection affects CMV-specific immune responses will be valuable for understanding how immunological memory is disrupted in HIV-infected humans.
Our specific aims are as follows:
Specific Aim #1 : To investigate whether SIV infection of CMV-specific CD4 + T lymphocytes is a predictor of their decline in rhesus macaques with AIDS.
Specific Aim #2 : To determine whether the SIV-related decline in CMV-specific CD8 +T lymphocyte responses is secondary to depletion and/or functional anergy associated with loss of CD4 + T cell help.
Specific Aim #3 : To examine mechanisms of restoration of CMV-specific immunity in SIV-infected macaques treated with HAART.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI043890-05A1
Application #
6696422
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Young, Janet M
Project Start
1998-07-01
Project End
2007-12-31
Budget Start
2003-07-01
Budget End
2003-12-31
Support Year
5
Fiscal Year
2003
Total Cost
$224,620
Indirect Cost

  Institution

Name
Harvard University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Assaf, Basel T; Mansfield, Keith G; Strelow, Lisa et al. (2014) Limited dissemination and shedding of the UL128 complex-intact, UL/b'-defective rhesus cytomegalovirus strain 180.92. J Virol 88:9310-20
Schmitz, Jörn E; Zahn, Roland C; Brown, Charles R et al. (2009) Inhibition of adaptive immune responses leads to a fatal clinical outcome in SIV-infected pigtailed macaques but not vervet African green monkeys. PLoS Pathog 5:e1000691
Chan, Kenneth S; Kaur, Amitinder (2007) Flow cytometric detection of degranulation reveals phenotypic heterogeneity of degranulating CMV-specific CD8+ T lymphocytes in rhesus macaques. J Immunol Methods 325:20-34
Gauduin, Marie-Claire; Yu, Yi; Barabasz, Amy et al. (2006) Induction of a virus-specific effector-memory CD4+ T cell response by attenuated SIV infection. J Exp Med 203:2661-72
Rivailler, Pierre; Kaur, Amitinder; Johnson, R Paul et al. (2006) Genomic sequence of rhesus cytomegalovirus 180.92: insights into the coding potential of rhesus cytomegalovirus. J Virol 80:4179-82
Macchia, Iole; Gauduin, Marie-Claire; Kaur, Amitinder et al. (2006) Expression of CD8alpha identifies a distinct subset of effector memory CD4+ T lymphocytes. Immunology 119:232-42
Cohen, George B; Kaur, Amitinder; Johnson, R Paul (2005) Isolation of viable antigen-specific CD4 T cells by CD40L surface trapping. J Immunol Methods 302:103-15
Gauduin, Marie-Claire; Kaur, Amitinder; Ahmad, Shabbir et al. (2004) Optimization of intracellular cytokine staining for the quantitation of antigen-specific CD4+ T cell responses in rhesus macaques. J Immunol Methods 288:61-79
Mueller, Nicolas J; Livingston, Christine; Knosalla, Christoph et al. (2004) Activation of porcine cytomegalovirus, but not porcine lymphotropic herpesvirus, in pig-to-baboon xenotransplantation. J Infect Dis 189:1628-33
Mueller, Nicolas J; Sulling, Kristen; Gollackner, Bernd et al. (2003) Reduced efficacy of ganciclovir against porcine and baboon cytomegalovirus in pig-to-baboon xenotransplantation. Am J Transplant 3:1057-64

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