Elevation in the number of CD8+ cells is a consistent feature of HIV and FIV infections. In the case of HIV, this abnormal homeostasis is marked by a progressive loss of L-selectin (LS) positive naive CD8+ cells and a concomitant expansion of LS negative CD8+ effector cells, such that the CD8+ LSneg cells may represent 80-90 percent of the total circulating CD8+ cells in the late asymptomatic stage infection. FIV infection induces the progressive expansion of a CD8+ subset characterized by a marked reduction of the beta chain. This CD8+ betalo phenotype may comprise as much as 90 percent of total blood CD8+ cells at late-stage asymptomatic infection. We have taken advantage of beta chain down-regulation to FACStar sort highly enriched CD8+ betalo and CD8+ betahi phenotypes, and have shown that the CD8+ betalo phenotype synthesizes high levels of IL10 and IFNgamma mRNA, and has potent anti- FIV activity. In addition, we have shown by 2- and 3-color FACS that the CD8+ betalo cells is an effector phenotype (CD8+ betaloLSneg CD44hi) and the CD8+ betahi is a naive phenotype (CD8+ betahiLSneg CD44hi). This proposal will test the hypothesis that FIV induces a chronic expansion of a CD8+betaloLSneg CD44hi effector phenotype that not only has potent antiviral activity but exhibits abnormal tissue trafficking and immunosuppressive responses to secondary infections. Experiments will be designed to further characterize the phenotype of this CD8+betaloLSneg subset and its distribution in lymphoid and nonlymphoid tissues at different stages of FIV infection. Fluorescent dye labeling will be done to assess the trafficking potential of CD8+ betaloLSneg cells between blood and LN, and between blood and the lung in response to T. gondii infection. RT-qcPCR studies will be designed to determine if the CD8+betaloLSneg phenotype is regulated at the level of gene transcription and if it is related to virus load. Purified subsets of CD8+betaloLSneg (effector) and CD8+betahiLSpos (naive) will be assayed by RT-qcPCR assays for cytokine and chemokine mRNA to address the hypothesis that the CD8+ betaloLSneg has the cytokine/chemokine profile of a CTL and/or T suppressor cell. In vitro experiments will determine if CD8+ betaloSneg cells are CTL's or virus suppressor cells and whether they suppress mitogen and antigen-specific recall responses by PBMC. Studies will also address the hypothesis that CD8+betaloLSneg cells exert immunosuppressive effects on lung macrophages resulting in decreased cytokine responses and uncontrolled replication of T. gondii tachyzoites. These experiments will collectively test the hypothesis that FIV induces the chronic expansion of a novel CD8+betaloLSneg T- suppressor-like activation phenotype that not only mediates immunity to FIV, but because of its altered tissue trafficking (loss of L-selectin) and cytokine expression profile (e.g. IL10) is selectively recruited into inflammatory sites and suppresses immune responses to secondary pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043858-02
Application #
2887851
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Sarver, Nava
Project Start
1998-08-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
North Carolina State University Raleigh
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Tompkins, Mary B; Tompkins, Wayne A (2008) Lentivirus-induced immune dysregulation. Vet Immunol Immunopathol 123:45-55
Joshi, Anjali; Garg, Himanshu; Tompkins, Mary B et al. (2005) Different thresholds of T cell activation regulate FIV infection of CD4+CD25+ and CD4+CD25- cells. Virology 335:212-21
Vahlenkamp, Thomas W; Tompkins, Mary B; Tompkins, Wayne A F (2005) The role of CD4+CD25+ regulatory T cells in viral infections. Vet Immunol Immunopathol 108:219-25
Joshi, Anjali; Garg, Himanshu; Tompkins, Mary B et al. (2005) Preferential feline immunodeficiency virus (FIV) infection of CD4+ CD25+ T-regulatory cells correlates both with surface expression of CXCR4 and activation of FIV long terminal repeat binding cellular transcriptional factors. J Virol 79:4965-76
Garg, Himanshu; Joshi, Anjali; Tompkins, Wayne A (2004) Feline immunodeficiency virus envelope glycoprotein mediates apoptosis in activated PBMC by a mechanism dependent on gp41 function. Virology 330:424-36
Joshi, Anjali; Vahlenkamp, Thomas W; Garg, Himanshu et al. (2004) Preferential replication of FIV in activated CD4(+)CD25(+)T cells independent of cellular proliferation. Virology 321:307-22
Levy, Julie K; Liang, Yinghua; Ritchey, Jerry W et al. (2004) Failure of FIV-infected cats to control Toxoplasma gondii correlates with reduced IL2, IL6, and IL12 and elevated IL10 expression by lymph node T cells. Vet Immunol Immunopathol 98:101-11
Bull, Marta E; Vahlenkamp, Thomas W; Dow, Janet L et al. (2004) Spontaneous T cell apoptosis in feline immunodeficiency virus (FIV)-infected cats is inhibited by IL2 and anti-B7.1 antibodies. Vet Immunol Immunopathol 99:25-37
Vahlenkamp, Thomas W; Tompkins, Mary B; Tompkins, Wayne A F (2004) Feline immunodeficiency virus infection phenotypically and functionally activates immunosuppressive CD4+CD25+ T regulatory cells. J Immunol 172:4752-61
Vahlenkamp, Thomas W; Bull, Marta E; Dow, Janet L et al. (2004) B7+CTLA4+ T cells engage in T-T cell interactions that mediate apoptosis: a model for lentivirus-induced T cell depletion. Vet Immunol Immunopathol 98:203-14

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