Preferential Feline Immunodeficiency Virus (FIV) Infection of CD4<sup>+</sup>CD25<sup>+</sup>T-Regulatory Cells Correlates both with Surface Expression of CXCR4 and Activation of FIV Long Terminal Repeat Binding Cellular Transcriptional Factors

SUMMARY Over 40 nonhuman primate (NHP) species harbor species-specific simian immunodeficiency viruses (SIVs). Similarly, more than 20 species of nondomestic felids and African hyenids demonstrate seroreactivity against feline immunodeficiency virus (FIV) antigens. While it has been challenging to study the biological implications of nonfatal infections in natural populations, epidemiologic and clinical studies performed thus far have only rarely detected increased morbidity or impaired fecundity/survival of naturally infected SIV- or FIV-seropositive versus -seronegative animals. Cross-species transmissions of these agents are rare in nature but have been used to develop experimental systems to evaluate mechanisms of pathogenicity and to develop animal models of HIV/AIDS. Given that felids and primates are substantially evolutionarily removed yet demonstrate the same pattern of apparently nonpathogenic lentiviral infections, comparison of the biological behaviors of these viruses can yield important implications for host-lentiviral adaptation which are relevant to human HIV/AIDS infection. This review therefore evaluates similarities in epidemiology, lentiviral genotyping, pathogenicity, host immune responses, and cross-species transmission of FIVs and factors associated with the establishment of lentiviral infections in new species. This comparison of consistent patterns in lentivirus biology will expose new directions for scientific inquiry for understanding the basis for virulence versus avirulence.

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“…Terwee ϩ CD25 ϩ T cells in vitro and in vivo. This appears to be due to receptor expression as well as cell activation (197)(198)(199)380).…”

Section: Cytokine Induction and Immune Activation During Infection Fivmentioning

confidence: 99%

Going Wild: Lessons from Naturally Occurring T-Lymphotropic Lentiviruses

2006

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“…First, HIV-1, as well as FIV, preferential infection of Treg cells, to a certain extent, correlates with increased viral coreceptor expression on human and feline Treg cells, respectively [8,129]. Second, transcriptional regulation of the viral promoter is altered in Treg cells, namely the effect of Foxp3 on lentivirus gene expression.…”

Section: Hiv-1 Infection and Replication In Treg Cellsmentioning

confidence: 99%

“…Given that Foxp3 + Tregs cells are thought to be functionally anergic in vitro, characterized by the repression of the T-cell activation-dependent IL-2 gene, it was surprising to find Treg cells support higher levels of infection by HIV-1 or FIV compared to Foxp3-CD4 + T cells in vitro [8,129]. Recently, a precursor of Treg cells, naïve Tregs (CD4 + CD25 + CD45RA + ) capable of in vivo expansion and suppression, also support high levels of HIV infection and replication [130].…”

Section: Hiv-1 Infection and Replication In Treg Cellsmentioning

confidence: 99%

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

et al. 2008

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FoxP3 + CD4 + CD25 + regulatory T (Treg) cells are implicated in a number of pathologic processes including elevated levels in cancers and infectious diseases, and reduced levels in autoimmune diseases. Treg cells are activated to modulate immune responses to avoid over-reactive immunity. However, conflicting findings are reported regarding relative levels of Treg cells during HIV-1 infection and disease progression. The role of Treg cells in HIV-1 diseases (aberrant immune activation) is poorly understood due to lack of a robust model. We summarize here the regulation and function of Foxp3 in Treg cells and in modulating HIV-1 replication. Based on recent findings from SIV/monkey and HIV/humanized mouse models, a model of the dual role of Treg cells in HIV-1 infection and immuno-pathogenesis is discussed. KeywordsRegulatory T cells; AIDS; Chromatin; Epigenetic; Humanized mouse; DKO-hu; ONTAK Regulatory T cells play an important role in self immune tolerance and in balanced immune responsesThe regulation of immune tolerance is a critical aspect of immunology. The balance between recognition of self versus non-self is essential for maintenance of immune homeostasis. Regulatory T cells (CD4 + CD25 + ) are a crucial component for the control of deleterious effects from excessive immune responses as seen in autoimmune disease or allergic insult [1,2]. Treg cells have been implicated in a number of pathologic processes including elevated levels in cancers [3][4][5] and infectious diseases [6][7][8][9], and reduced levels in autoimmune diseases [1,[10][11][12][13]. It is apparent that Treg cells are induced (or recruited and expanded) by most infections to modulate host immune responses to avoid overreactive immunity (Fig. 1). As a result, Treg play a critical role in immune responses, vaccinations as well as in immunopathogenesis of pathogens. For example, Leishmania infection leads to induction of Treg that help to maintain the balance of immune response and pathogen persistence [18,19]. For the host, persistence of the pathogen is beneficial to maintain effective immunity against these pathogens [18]. In a number of chronic viral infections, Treg are induced to subdue the anti-viral immune responses and allow persistent infection. Mechanisms of CD4 T-cell differentiationT-cell lineage commitment and activation of T cells are usually accompanied by changes in patterns of gene expression. During T-cell responses, T helper (Th) progenitor cells will undergo Th1 or Th2 lineage commitments involving well-defined initiation cytokines, transcription factors, and effector cytokines. Expression of T-bet and GATA3 in Th1 and Th2 cells, respectively, is epigenetically regulated by histone modification and DNA methylation. As T lineage determinants, T-bet or GATA3 are also involved in epigenetically reprogramming the T-cell genome to silence the Th2 or Th1 effector cytokines, respectively, and to activate Th1 or Th2 cytokine genes for transcription (Fig. 2). Similarly, Th17 cell differentiation requires IL-6/TGF-β (mo...

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“…While Treg cell activation is associated with virus infection of the host, it is not known whether virus antigens or direct virus infection activates these cells. In support of the latter, we have demonstrated that feline CD4 ϩ CD25 ϩ cells support a productive, noncytopathic FIV infection in vitro that correlates with overexpression of the FIV coreceptor CXCR4 and constitutive activation of transcription factors such as AP1 and ATF that bind to and activate the FIV promoter (12,13). We have also reported that as early as 1 week post-FIV infection of cats, CD4 ϩ CD25 ϩ T cells support a productive virus infection and are phenotypically and functionally activated (5).…”

Section: D4mentioning

confidence: 95%

Infection with Feline Immunodeficiency Virus Directly Activates CD4 ⁺ CD25 ⁺ T Regulatory Cells

Miller

Fogle

Tompkins

2013

J Virol

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Lentivirus infection activates CD4؉ CD25 ؉ T regulatory (Treg) cells. Activation of Treg cells may be due to direct virus infection or chronic antigenic stimulation. Herein we demonstrate that in vitro feline immunodeficiency virus (FIV) infection, but not UV-inactivated virus, activates Treg cells as measured by immunosuppressive function and upregulation of GARP, FoxP3, and membrane-bound transforming growth factor ␤ (TGF-␤). These data demonstrate for the first time that AIDS lentiviruses infect and activate Treg cells, potentially contributing to immune dysfunction. C D4ϩ regulatory T cells (Treg cells), currently defined by constitutive expression of the high-affinity interleukin-2 (IL-2) receptor CD25 and the transcription factor Foxp3, play an important role in controlling autoimmune disease and shaping the pathogenesis of viral infections by regulating expansion of T and B effector subsets (1-7). Although Treg cells play an important role in preventing excessive inflammation associated with immune responses to infection, they may in the process prematurely abort protective T and B cell immune responses and allow chronic viremia and more severe pathogenesis. This negative effect of Treg cell activation has been demonstrated in herpesvirus, B and C hepatitis virus, and AIDS lentivirus infections (1, 2, 8-10), supporting the speculation that Treg cells may in part be responsible for the chronic nature of these infections. In the case of the lentiviruses human immunodeficiency virus (HIV) and feline immu- ϩ in vitro infection methods. Purified feline CD4 ϩ CD25 ϩ cells were infected with the NCSU 1 isolate of FIV at an MOI of 2.5. Cells and culture supernatant were harvested at 6 days postinfection and analyzed for virus copy by real-time RT-PCR (A) and p24 antigen (Ag) by ELISA (B). Each bar represents the mean Ϯ standard error of the mean (SEM) of 3 replicates. O.D., optical density. (C) UV inactivation of FIV was confirmed using the FIV-susceptible feline T cell line FCD4-E. Virus was exposed to 1 J of UV light for various times and then added to FCD4-E cells at an MOI of 2. Five cultures per UV inactivation time were observed daily up to 14 days for the formation of syncytia.

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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

Cited by 47 publications

References 55 publications

Going Wild: Lessons from Naturally Occurring T-Lymphotropic Lentiviruses

Going Wild: Lessons from Naturally Occurring T-Lymphotropic Lentiviruses

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

Infection with Feline Immunodeficiency Virus Directly Activates CD4 ⁺ CD25 ⁺ T Regulatory Cells

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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

Cited by 47 publications

References 55 publications

Going Wild: Lessons from Naturally Occurring T-Lymphotropic Lentiviruses

Going Wild: Lessons from Naturally Occurring T-Lymphotropic Lentiviruses

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

Infection with Feline Immunodeficiency Virus Directly Activates CD4 + CD25 + T Regulatory Cells

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Product

Resources

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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

Infection with Feline Immunodeficiency Virus Directly Activates CD4 ⁺ CD25 ⁺ T Regulatory Cells