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

Abstract

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.

Feline Immunodeficiency Virus Neuropathogenesis: A Model for HIV-Induced CNS Inflammation and Neurodegeneration

“…Among the many achievements, these efforts led to approval of an effective FIV vaccine in 2002. Recent studies have addressed important issues such as mechanisms of FIV transmission, replication and evolution [ 22 , 23 , 24 , 25 , 26 , 27 ], FIV vaccine efficacy [ 28 , 29 ], the role of neutralizing antibodies in disease progression [ 28 , 30 , 31 ], virus assembly and release [ 32 , 33 ], viral latency and eradication strategies [ 34 , 35 , 36 ], development of adjunctive therapies [ 37 , 38 , 39 , 40 ], immunology [ 41 , 42 , 43 , 44 , 45 ], interactions with the microbiome [ 46 , 47 ], development of antiretroviral compounds [ 48 , 49 , 50 ] and development of protocols for assessing feline cognitive function [ 51 , 52 , 53 , 54 ]. Many of these efforts are summarized in this volume and in a review by Bienzle [ 55 ].…”

Changes of CD4+CD25+ Cells Ratio in Immune Organs from Chickens Challenged with Infectious Bursal Disease Virus Strains with Varying Virulences

“…Previous reports have demonstrated that various viruses may take advantage of host immune mechanisms associated with immunosuppressive functions to aid viral expansion and contribute to viral pathophysiology [ 12 ]. Viral infection can induce CD25 expression in lymphocytes [ 13 ] or directly activate CD4+CD25+ cells, potentially contributing to immune dysfunction [ 14 ]. Expanded Treg populations have been detected in many virus-related diseases, such as those caused by hepatitis C virus [ 15 , 16 , 17 ], hepatitis B virus [ 18 , 19 ], Epstein-Barr virus [ 20 ], and porcine reproductive and respiratory syndrome virus [ 21 ], as well as upon secondary infection with a virus [ 22 ].…”

Micro-RNA 10a Is Increased in Feline T Regulatory Cells and Increases Foxp3 Protein Expression Following In Vitro Transfection

“…Foxp3 mRNA and protein are increased in lentivirus activated Treg cells when compared to Treg cells from uninfected cats [ 8 , 26 ]. To document increased Foxp3 expression in Treg cells for these studies, we harvested peripheral blood Treg cells from FIV − control cats and FIV + cats 1 week, 4 weeks, 8 weeks and 24 weeks post infection (p.i.)…”