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In vivo depletion of CD4(+)CD25(hi) regulatory T cells is associated with improved antiviral responses in cats chronically infected with feline immunodeficiency virus.

ABSTRACT: Regulatory T (Treg) cells are activated and suppress immune responses during infection, and are characterized as CD4(+)CD25(hi)FOXP3(+). Ex vivo studies demonstrate that Treg cells potentially suppress anti-HIV-1 T cell responses. Lentivirus-induced CD4(+)CD25(hi) Treg cells were first described in feline immunodeficiency virus (FIV)-infected cats. In the present study we demonstrate that anti-feline CD25 monoclonal antibody (mAb) therapy depletes Treg cells in FIV-infected cats for 4 weeks and does not exacerbate viral replication or proinflammatory cytokine production. Significant FIV-specific immune responses are revealed in Treg cell-depleted cats. These anti-FIV effector cells exist prior to Treg cell depletion and are not expanded while Treg cells are depleted. Importantly, cats receiving the Treg cell-depleting mAb are able to produce a robust humoral response to new antigen. We propose that short-term in vivo Treg cell depletion during chronic HIV-1 infection could provide a window of opportunity for therapeutic vaccination in individuals with controlled viral replication.

SUBMITTER: Mikkelsen SR

PROVIDER: S-EPMC2879469 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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In vivo depletion of CD4(+)CD25(hi) regulatory T cells is associated with improved antiviral responses in cats chronically infected with feline immunodeficiency virus.

Mikkelsen S Rochelle SR Reckling Stacie K SK Egan Erin A EA Dean Gregg A GA

Virology 20100514 2

Regulatory T (Treg) cells are activated and suppress immune responses during infection, and are characterized as CD4(+)CD25(hi)FOXP3(+). Ex vivo studies demonstrate that Treg cells potentially suppress anti-HIV-1 T cell responses. Lentivirus-induced CD4(+)CD25(hi) Treg cells were first described in feline immunodeficiency virus (FIV)-infected cats. In the present study we demonstrate that anti-feline CD25 monoclonal antibody (mAb) therapy depletes Treg cells in FIV-infected cats for 4 weeks and ...[more]

PMID: 20471053

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Project description:Approximately 5% of cats in animal shelters in the United States test positive for either feline leukemia virus (FeLV) or feline immunodeficiency virus (FIV), which translates to more than 100,000 positive cats managed by shelters each year. Little is known about the current status of retroviral management in animal shelters, particularly in regions burdened by chronic pet overpopulation and high shelter admissions, such as the southern United States. The purpose of this study was to describe feline retroviral management in Florida shelters. Shelters were surveyed on practices including selection of cats for testing, diagnostic techniques, and outcome options for cats with positive test results. Responses were received from 139 of 153 animal shelters known to admit cats, including 55 municipal shelters (40%), 70 private shelters (50%), and 14 private shelters with municipal contracts (10%). A total of 115 shelters (83%) performed at least some testing, most using combination point-of-care devices for simultaneous FeLV antigen and FIV antibody screening. Of shelters that performed any testing, 56 (49%) tested all cats for FeLV and 52 (45%) tested all cats for both FeLV and FIV. The most common reason for testing was screening adoptable cats (108 shelters; 94%) and cats available for transfer to other organizations (78; 68%). Testing cats in trap-neuter-return/return-to-field programs was least common (21; 18%). Most common outcome options for positive cats included adoption (74; 64%), transfer (62; 54%), and euthanasia (49; 43%). Euthanasia following a positive test result was more common for cats with FeLV (49; 43%) than for cats with FIV (29; 25%) and was more common in municipal shelters, rural shelters, shelters taking in <500 cats a year, and shelters with overall live outcome rates for cats <70%. Although Florida shelter compliance with national guidelines for identification and management of FeLV and FIV positive cats was variable, most had live outcome options for at least some of their cats with positive test results. Increased access to training and practical programmatic tools may help more shelters implement cost-effective testing protocols, reduce risk for transmission to other cats, and support the best outcomes for this vulnerable population of cats.

Project description:A full-length feline immunodeficiency virus NCSU1 (FIV-NCSU1) genome (JSY3) was cloned directly from FIV-NCSU1-infected feline CD4+ lymphocyte (FCD4E) genomic DNA and identified by PCR amplification with 5' long terminal repeat, gag, env, and 3' long terminal repeat primer sets. Supernatant from FCD4E cells cocultured with JSY3-transfected Crandell feline kidney (CrFK) cells was used as an inoculum. Cell-free JSY3 virus was cytopathogenic for FCD4E lymphocytes but did not infect CrFK cells in vitro. To determine in vivo infectivity and pathogenesis, six young adult specific-pathogen-free cats were inoculated with cell-free JSY3 virus. Provirus was detected at 2 weeks postinfection (p.i.) and was still detectable at 25 weeks p.i. as determined by gag region PCR-Southern blot analysis of peripheral blood mononuclear cell lysates. Infectious virus was recovered from peripheral blood mononuclear cells at 6 and 25 weeks p.i., and an antibody response to FIV was detected by 4 weeks. In the acute phase of infection, JSY3 provirus was found only in the CD4+ lymphocyte subset; however, by 14 weeks p.i., the greatest provirus burden was detected in B lymphocytes. All six cats were panlymphopenic at 2 weeks p.i., CD4+/CD8+ ratios were inverted by 6 weeks p.i., and five of the six cats developed lymphadenopathy by 10 weeks p.i. To determine if the JSY3 molecular clone caused immunodeficiency similar to that of the parental wild-type FIV-NCSU1, the cats were challenged with the low-virulence ME49 strain of Toxoplasma gondii at 29 weeks p.i. Five of six cats developed clinical signs consistent with generalized toxoplasmosis, and three of six cats developed acute respiratory distress and required euthanasia. Histopathologic examination of the severely affected cats revealed generalized inflammatory reactions and the presence of T. gondii tachyzoites in multiple tissues. None of the six age- and sex-matched specific-pathogen-free cats inoculated with only T. gondii developed clinical disease. Our results suggest that the pathogenesis of the molecularly cloned NCSU1 JSY3 is similar to that of wild-type FIV-NCSU1.

Project description:BACKGROUND:Recombination is a relatively common phenomenon in retroviruses. We investigated recombination in Feline Immunodeficiency Virus from naturally-infected New Zealand domestic cats (Felis catus) by sequencing regions of the gag, pol and env genes. RESULTS:The occurrence of intragenic recombination was highest in env, with evidence of recombination in 6.4% (n = 156) of all cats. A further recombinant was identified in each of the gag (n = 48) and pol (n = 91) genes. Comparisons of phylogenetic trees across genes identified cases of incongruence, indicating intergenic recombination. Three (7.7%, n = 39) of these incongruencies were found to be significantly different using the Shimodaira-Hasegawa test.Surprisingly, our phylogenies from the gag and pol genes showed that no New Zealand sequences group with reference subtype C sequences within intrasubtype pairwise distances. Indeed, we find one and two distinct unknown subtype groups in gag and pol, respectively. These observations cause us to speculate that these New Zealand FIV strains have undergone several recombination events between subtype A parent strains and undefined unknown subtype strains, similar to the evolutionary history hypothesised for HIV-1 "subtype E".Endpoint dilution sequencing was used to confirm the consensus sequences of the putative recombinants and unknown subtype groups, providing evidence for the authenticity of these sequences. Endpoint dilution sequencing also resulted in the identification of a dual infection event in the env gene. In addition, an intrahost recombination event between variants of the same subtype in the pol gene was established. This is the first known example of naturally-occurring recombination in a cat with infection of the parent strains. CONCLUSION:Evidence of intragenic recombination in the gag, pol and env regions, and complex intergenic recombination, of FIV from naturally-infected domestic cats in New Zealand was found. Strains of unknown subtype were identified in all three gene regions. These results have implications for the use of the current FIV vaccine in New Zealand.

Dataset Information

In vivo depletion of CD4(+)CD25(hi) regulatory T cells is associated with improved antiviral responses in cats chronically infected with feline immunodeficiency virus.

Publications

In vivo depletion of CD4(+)CD25(hi) regulatory T cells is associated with improved antiviral responses in cats chronically infected with feline immunodeficiency virus.

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