In the absence of treatment, infection of rhesus macaques with pathogenic SlV, like HIV infection of humans, is almost always progressive with deterioration of immune function, and ultimately death due to either direct consequences of SlV itself or opportunistic infection. The tempo of progression, however, varies considerably from host to host, even with cloned virus, suggesting that host factors play a role in supporting and/or mitigating the extent and consequences of viral replication. Recent documentation of massive, systemic depletion of SlV """"""""target"""""""" cells (CCR5+, CD4+ memory T cells) in early SlVmac239 infection, and a concomitant, profound increase in the production and turnover of this population suggests that target cell availability and mechanisms of target cell generation may significantly contribute to the outcome of infection. Indeed, our preliminary data suggest that plateau-phase viral replication may be largely supported by infection of """"""""new"""""""" T cell targets generated by this marked increase CD4+ memory T cell turnover. The overall goal of this project is therefore to characterize the nature and regulation of T cell turnover in various stages of SlV infection, and to ascertain the impact of this regulation on viral dynamics and disease progression. Specifically, we will: 1) characterize depletion of pre-existent CD4+ memory T cell """"""""targets"""""""", and the extent, kinetics, anatomic location, infection rate, and fate of newly generated """"""""targets"""""""" over the course of SlV infection, and determine the relationship of these dynamics to systemic viral replication, CD8+ T cell dynamics, and long-term maintenance of CD4+ memory T cell numbers, 2) examine the effect of anti-retroviral therapy (ART), ART interruption, and cycled structured treatment interruptions on CD4+ memory T cell population dynamics and """"""""target"""""""" cell availability, 3) determine the extent to which SIV-specific responses, other Ag-specific responses, or """"""""bystander"""""""" (cytokine-driven) proliferation contribute to CD4+ memory T cell dynamics and target generation, and 4) ascertain whether T cell selective anti-proliferative therapy can inhibit overall CD4+ memory T cell turnover, alter viral target availability, and thereby influence viral dynamics and disease progression in either acute- and/or plateau-phase SlV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054292-05
Application #
7162987
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (02))
Program Officer
Sharma, Opendra K
Project Start
2003-01-01
Project End
2008-06-30
Budget Start
2007-01-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$716,501
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Früh, Klaus; Picker, Louis (2017) CD8+ T cell programming by cytomegalovirus vectors: applications in prophylactic and therapeutic vaccination. Curr Opin Immunol 47:52-56
McMichael, Andrew J; Picker, Louis J (2017) Unusual antigen presentation offers new insight into HIV vaccine design. Curr Opin Immunol 46:75-81
Del Prete, Gregory Q; Park, Haesun; Fennessey, Christine M et al. (2014) Molecularly tagged simian immunodeficiency virus SIVmac239 synthetic swarm for tracking independent infection events. J Virol 88:8077-90
Masopust, David; Picker, Louis J (2012) Hidden memories: frontline memory T cells and early pathogen interception. J Immunol 188:5811-7
Klatt, Nichole R; Canary, Lauren A; Vanderford, Thomas H et al. (2012) Dynamics of simian immunodeficiency virus SIVmac239 infection in pigtail macaques. J Virol 86:1203-13
Kuhrt, David; Faith, Seth; Hattemer, Angela et al. (2011) Naïve and memory B cells in the rhesus macaque can be differentiated by surface expression of CD27 and have differential responses to CD40 ligation. J Immunol Methods 363:166-76
Murray, Shannon M; Picker, Louis J; Axthelm, Michael K et al. (2008) Replication in a superficial epithelial cell niche explains the lack of pathogenicity of primate foamy virus infections. J Virol 82:5981-5
Wilk, Jennifer; Lewis, Anne; Lukas, Victor (2008) Dermatitis in a rhesus macaque (Macaca mulatta) experimentally infected with simian immunodeficiency virus. J Med Primatol 37 Suppl 1:25-8
Okoye, Afam; Meier-Schellersheim, Martin; Brenchley, Jason M et al. (2007) Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection. J Exp Med 204:2171-85
Picker, Louis J; Reed-Inderbitzin, Edward F; Hagen, Shoko I et al. (2006) IL-15 induces CD4 effector memory T cell production and tissue emigration in nonhuman primates. J Clin Invest 116:1514-24

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