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. Our work has provided compelling evidence that the onset of immune deficiency in pathogenic SIVmac239 infection of rhesus macaques (RM) is intimately linked with patterns of CD4+ memory T cell dynamics, and reflects a complex interplay of direct viral cytopathogenicity, and the indirect effects of persistent immune activation on CD4+ memory T cell proliferation, differentiation and survival. Our data have strongly implicated a decline in effector site, CD4+ effector memory (TEM) populations below a crucial threshold as a major proximate mechanism of overt immunodeficiency, but significantly, have also demonstrated that in CCR5-tropic SIV infection, even massive viral-mediated destruction of CD4+ TEM is rarely, if ever, sufficient for functional failure of this population. Instead, our data indicate that this failure is determined in large part by the ability of CD4+ central memory T cells (TCM) to produce new TEM, which in turn depends on the maintenance of the CD4+ TCM population itself. In chronic SIV infection, we found that a slow decline of the number and often, proliferative activity of CD4+ TCM underlies CD4+ TEM population failure, and """"""""sets the clock"""""""" for the onset of overt disease. Recent work has focused on the mechanisms responsible for CD4+ TCM homeostatic failure, in particular the role of IL-7 and IL-15 in maintaining CD4+ TCM homeostasis and the relative contribution of recruitment of new TCM from the na?ve compartment vs. regeneration of pre-existent TCM in the maintenance of the CD4+ TCM compartment during progressive SIV infection. By mAb-mediated depletion of CD4+ T cell in thymectomized monkeys, we have created """"""""CD4 naiveless"""""""" RM after memory cells regenerate in the absence of a thymus. Importantly, the lack of a na?ve CD4+ T cell compartment has little measureable effect on the maintenance of CD4+ memory T cells after SIV infection, suggesting that maintenance of this population depends predominantly on the regeneration of pre-existent memory cells as opposed to na?ve cell recruitment. Other work in this project has looked at B cell dynamics in SIV infection and mechanisms by which CD8+ T cells affect SIV replications and pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000163-52
Application #
8357743
Study Section
Special Emphasis Panel (ZRR1-CM-8 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
52
Fiscal Year
2011
Total Cost
$194,877
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Su, Weiping; Foster, Scott C; Xing, Rubing et al. (2017) CD44 Transmembrane Receptor and Hyaluronan Regulate Adult Hippocampal Neural Stem Cell Quiescence and Differentiation. J Biol Chem 292:4434-4445
Lima, Fernanda B; Leite, Cristiane M; Bethea, Cynthia L et al. (2017) Progesterone increased ?-endorphin innervation of the locus coeruleus, but ovarian steroids had no effect on noradrenergic neurodegeneration. Brain Res 1663:1-8
Slayden, Ov Daniel (2016) Translational In Vivo Models for Women's Health: The Nonhuman Primate Endometrium--A Predictive Model for Assessing Steroid Receptor Modulators. Handb Exp Pharmacol 232:191-202
Chadderdon, S M; Belcik, J T; Bader, L et al. (2016) Vasoconstrictor eicosanoids and impaired microvascular function in inactive and insulin-resistant primates. Int J Obes (Lond) 40:1600-1603
Dufour, Brett D; McBride, Jodi L (2016) Intravascular AAV9 Administration for Delivering RNA Silencing Constructs to the CNS and Periphery. Methods Mol Biol 1364:261-75
Meyer, Thomas J; Held, Ulrike; Nevonen, Kimberly A et al. (2016) The Flow of the Gibbon LAVA Element Is Facilitated by the LINE-1 Retrotransposition Machinery. Genome Biol Evol 8:3209-3225
Pleil, Kristen E; Helms, Christa M; Sobus, Jon R et al. (2016) Effects of chronic alcohol consumption on neuronal function in the non-human primate BNST. Addict Biol 21:1151-1167
Mohiuddin, Muhammad M; Singh, Avneesh K; Corcoran, Philip C et al. (2016) Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft. Nat Commun 7:11138
Sylwester, Andrew; Nambiar, Kate Z; Caserta, Stefano et al. (2016) A new perspective of the structural complexity of HCMV-specific T-cell responses. Mech Ageing Dev 158:14-22
Laws, L H; Parker, C E; Cherala, G et al. (2016) Inflammation Causes Resistance to Anti-CD20-Mediated B Cell Depletion. Am J Transplant 16:3139-3149

Showing the most recent 10 out of 481 publications