This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The efficacy of antiretroviral therapy (ART) in HIV-1 infected individuals is determined by restoration of peripheral blood CD4+ T cell numbers and viral suppression. However, peripheral blood represents only 2% of the total lymphocytes in the body. In contrast, gut associated lymphoid tissue (GALT) harbors 80% of the lymphocytes in the body. Our previous studies showed that severe CD4+ T cell depletion occurs in GALT during primary HIV infection and that CD4+ T cell restoration in GALT is modest and slow compared to peripheral blood during ART. These changes in GALT are not adequately reflected in peripheral blood analysis. The kinetics and mechanisms of CD4+ T cell restoration and function in GALT following ART have not been fully determined. Simian immunodeficiency virus (SIV) infected rhesus macaques provide an excellent animal model to study the gut mucosal immune system in comparison to peripheral blood compartment. The overall objective of this research proposal is to examine the suppression of viral replication and kinetics and mechanisms of restoration of gut mucosal immune system and function in comparison to mucosal and peripheral lymph nodes and peripheral blood in rhesus macaques starting ART (combination of PMPA and FTC) during primary or chronic SIV infection. Our hypothesis is that slow restoration of CD4+ T cells in GALT during therapy can be attributed to the disruption of the functional organization of the gut mucosal tissue occurring very early in SIV infection and this may not adequately support survival and maintenance of the CD4+ T cells homing to gut mucosa. Longitudinal evaluation in the SIV model will lead to characterization of the mechanisms and relationship between CD4+ T cell restoration in GALT, peripheral blood, and lymph node compartments (peripheral, and those draining mucosal sites). There are 3 specific aims. In rhesus macaques initiating ART during primary or chronic SIV infection, (1) to determine suppression of SIV replication and genomic diversity, and the kinetics of CD4+ T cell restoration in GALT in comparison to peripheral blood and lymph nodes;(2) to determine the homing and survival of CD4+ T cells in the GALT microenvironment and (3) to investigate the molecular processes involved in the restoration of gut mucosal immune system. The proposal capitalizes on our experience in enteropathogenic studies in the SIV model, expertise in multi-color flow cytometry, in vivo molecular imaging, autologous T cell transfer and gene expression methodologies. The proposed studies promise to provide valuable insights into the impact of impaired gut microenvironment on the viral suppression and restoration of gut mucosal immune system compared to mucosal and peripheral lymph node compartments, and molecular basis of pathophysiologic processes in GALT.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000169-50
Application #
8357341
Study Section
Special Emphasis Panel (ZRR1-CM-5 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
50
Fiscal Year
2011
Total Cost
$95,666
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Comrie, Alison E; Gray, Daniel T; Smith, Anne C et al. (2018) Different macaque models of cognitive aging exhibit task-dependent behavioral disparities. Behav Brain Res 344:110-119
Day, George Q; Ng, Jillian; Oldt, Robert F et al. (2018) DNA-based Determination of Ancestry in Cynomolgus Macaques (Macaca fascicularis). J Am Assoc Lab Anim Sci 57:432-442
Carroll, Timothy D; Jegaskanda, Sinthujan; Matzinger, Shannon R et al. (2018) A Lipid/DNA Adjuvant-Inactivated Influenza Virus Vaccine Protects Rhesus Macaques From Uncontrolled Virus Replication After Heterosubtypic Influenza A Virus Challenge. J Infect Dis 218:856-867
Midic, Uros; VandeVoort, Catherine A; Latham, Keith E (2018) Determination of single embryo sex in Macaca mulatta and Mus musculus RNA-Seq transcriptome profiles. Physiol Genomics 50:628-635
Almodovar, Sharilyn; Swanson, Jessica; Giavedoni, Luis D et al. (2018) Lung Vascular Remodeling, Cardiac Hypertrophy, and Inflammatory Cytokines in SHIVnef-Infected Macaques. Viral Immunol 31:206-222
Ciupe, Stanca M; Miller, Christopher J; Forde, Jonathan E (2018) A Bistable Switch in Virus Dynamics Can Explain the Differences in Disease Outcome Following SIV Infections in Rhesus Macaques. Front Microbiol 9:1216
Kyle, Colin T; Stokes, Jared; Bennett, Jeffrey et al. (2017) Cytoarchitectonically-driven MRI atlas of nonhuman primate hippocampus: Preservation of subfield volumes in aging. Hippocampus :
Moadab, Gilda; Bliss-Moreau, Eliza; Bauman, Melissa D et al. (2017) Early amygdala or hippocampus damage influences adolescent female social behavior during group formation. Behav Neurosci 131:68-82
Seil, Shannon K; Hannibal, Darcy L; Beisner, Brianne A et al. (2017) Predictors of insubordinate aggression among captive female rhesus macaques. Am J Phys Anthropol 164:558-573
Zhang, Xinjun; Kanthaswamy, Sree; Trask, Jessica S et al. (2017) Genetic Characterization of a Captive Colony of Pigtailed Macaques (Macaca nemestrina). J Am Assoc Lab Anim Sci 56:390-395

Showing the most recent 10 out of 408 publications