The objective of this project is to examine T regulatory cells (Tregs) in Rhesus macaques (Rh) and African green monkeys (AGMs). Tregs, initially defined as CD4+CD25+, suppress T-cell activation and proliferation in mice and humans. As chronic immune activation and rapid turnover of T cells are hallmarks of pathogenic HIV/SIVmac infections in humans and Rh, these cells may play an important role in HIV/SIV pathogenesis. Rh and AGMs, the best models for the study of SIV pathogenesis, differ in one fundamental aspect: Rh infected SIVmac develop AIDS, while AGMs infected with SIVagm typically remain healthy. Our preliminary studies showed a loss of CD4+CD25+ T cells in SIVmac-infected Rh that may explain the aberrant chronic T cell hyperactivation described in this pathogenic infection. In contrast, we have found an increase in the number of Tregs during very early stages of SIVagm infection and a better preservation of CD4+CD25+ T cells in chronically SIVagm-infected AGMs. The pattern of CD4+CD25+ T cell dynamics in SIVagm-infected AGMs corroborates the lack of immune activation and turnover during SIV infection in natural hosts. We therefore hypothesize that fully functional Tregs are present in non-human primates and may play a protective role in SIV infection. To clearly define the role of Tregs in pathogenic and non- pathogenic SIV infections, we designed experiments in this proposal for normal and SIV-infected Rh and AGMs, to confirm the existence of functional Tregs and to verify our ability to manipulate this T cell subset. We propose the following Specific Aims (SA): SA1: To characterize Tregs in normal and SIV-infected Rh and AGMs. CD25 is not a specific marker for Tregs; it is also upregulated upon conventional T cell activation. Our proposal will therefore focus on identification of specific markers for Tregs such as FOXP3, GITR, CD223 and neuropilin-1 in association with previously studied CD4+CD25+ T cells and also on determining the in vitro suppressive functions of T cell subsets identified with these markers, that have never been studied in non-human primates (NHP). SA2: To determine the distribution of Tregs in tissues of normal and SIV-infected Rh and AGMs. CD4+CD25+ cells from peripheral blood might represent only a small portion of the total Tregs. In order to focus our future SIV studies, we intend to determine the density and function of Tregs in lymph nodes (LNs), lung and intestine in both Rh and AGMs. SA3: To verify the ability of available anti-CD25 blocking/depleting drugs to eliminate Tregs in Rh and AGMs. Elimination of Tregs or Treg function in SIV-infected Rh and AGMs will enhance our knowledge about the role of this T cell subset in pathogenic and non-pathogenic SIV infections. If this specific aim will establish that this experiment is possible in normal NHPs, we will further assess the impact of Treg depletion on viral replication in chronically SIVagm-infected AGMs. Combined, these aims are designed to characterize and manipulate simian Tregs. This data will be critical for future studies examining the role of these cells in AIDS pathogenesis and may also open numerous avenues for the study of Tregs in other infectious or immune diseases for which Rh and AGMs are used as models. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI069935-02
Application #
7244050
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Finzi, Diana
Project Start
2006-06-01
Project End
2008-11-30
Budget Start
2007-06-01
Budget End
2008-11-30
Support Year
2
Fiscal Year
2007
Total Cost
$200,269
Indirect Cost
Name
Tulane University
Department
Type
Other Domestic Higher Education
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Raehtz, Kevin; Pandrea, Ivona; Apetrei, Cristian (2016) The well-tempered SIV infection: Pathogenesis of SIV infection in natural hosts in the wild, with emphasis on virus transmission and early events post-infection that may contribute to protection from disease progression. Infect Genet Evol 46:308-323
He, Tianyu; Brocca-Cofano, Egidio; Gillespie, Delbert G et al. (2015) Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues. J Virol 89:9616-30
Pandrea, Ivona; Gaufin, Thaidra; Gautam, Rajeev et al. (2011) Functional cure of SIVagm infection in rhesus macaques results in complete recovery of CD4+ T cells and is reverted by CD8+ cell depletion. PLoS Pathog 7:e1002170
Apetrei, Cristian; Gaufin, Thaidra; Gautam, Rajeev et al. (2010) Pattern of SIVagm infection in patas monkeys suggests that host adaptation to simian immunodeficiency virus infection may result in resistance to infection and virus extinction. J Infect Dis 202 Suppl 3:S371-6
Pandrea, Ivona; Apetrei, Cristian (2010) Where the wild things are: pathogenesis of SIV infection in African nonhuman primate hosts. Curr HIV/AIDS Rep 7:28-36
Gaufin, Thaidra; Ribeiro, Ruy M; Gautam, Rajeev et al. (2010) Experimental depletion of CD8+ cells in acutely SIVagm-infected African Green Monkeys results in increased viral replication. Retrovirology 7:42
Pandrea, Ivona; Silvestri, Guido; Apetrei, Cristian (2009) AIDS in african nonhuman primate hosts of SIVs: a new paradigm of SIV infection. Curr HIV Res 7:57-72
Souquiere, Sandrine; Onanga, Richard; Makuwa, Maria et al. (2009) Simian immunodeficiency virus types 1 and 2 (SIV mnd 1 and 2) have different pathogenic potentials in rhesus macaques upon experimental cross-species transmission. J Gen Virol 90:488-99
Gaufin, Thaidra; Gautam, Rajeev; Kasheta, Melissa et al. (2009) Limited ability of humoral immune responses in control of viremia during infection with SIVsmmD215 strain. Blood 113:4250-61
Gaufin, Thaidra; Pattison, Melissa; Gautam, Rajeev et al. (2009) Effect of B-cell depletion on viral replication and clinical outcome of simian immunodeficiency virus infection in a natural host. J Virol 83:10347-57

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