Cats naturally infected with feline immunodeficiency virus (FIV) develop an AIDS-like syndrome whereas experimentally infected cats do not. To investigate the role of cofactors in the development of this disease in cats, 7 specific pathogen-free (SPF) and 12 random-source (RS) cats were infected with FIV. Over 4 years, infected cats developed similar phenotypic and functional immune abnormalities characterized by early and chronic inversion of CD4+:CD8+ cell ratios and significantly decreased mitogen responses compared with controls. Beginning 18-24 months after infection, 10 RS cats developed chronic clinical disease typical of feline AIDS, including stomatitis and recurrent upper respiratory disease; 4 SPF cats also developed chronic clinical disease, 2 with neurologic disease and 2 with B cell lymphomas. Thus, immunologic background is important in the type of disease that develops in cats infected with FIV, and FIV represents a promising animal model for studying the immunopathogenesis of AIDS in humans.

Disease progression of feline immunodeficiency virus (FIV) infection is characterized by up-regulation of B7.1 and B7.2 costimulatory molecules and their ligand CTLA4 on CD4+ and CD8+ T cells. The CD4+CTLA4+B7+ phenotype described in FIV+ cats is reminiscent of CD4+CD25+CTLA4+ cells, a phenotype described for immunosuppressive T regulatory (Treg) cells. In the present study, we describe the phenotypic and functional characteristics of CD4+CD25+ T cells in PBMC and lymph nodes (LN) of FIV+ and control cats. Similar to Treg cells, feline CD4+CD25+ but not CD4+CD25− T cells directly isolated from LN of FIV+ cats do not produce IL-2 and fail to proliferate in response to mitogen stimulation. Unstimulated CD4+CD25+ T cells from FIV+ cats significantly suppress the proliferative response and the IL-2 production of Con A-stimulated autologous CD4+CD25− T cells compared with unstimulated CD4+CD25+ T cells from FIV− cats. Flow-cytometric analysis confirmed the apparent activation phenotype of the CD4+CD25+ cells in LN of chronically FIV+ cats, because these cells showed significant up-regulation of expression of costimulatory molecules B7.1, B7.2, and CTLA4. These FIV-activated, anergic, immunosuppressive CD25+CTLA4+B7+CD4+ Treg-like cells may contribute to the progressive loss of T cell immune function that is characteristic of FIV infection.

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HIV-induced AIDS may be mediated by the activation of immunosuppressive CD4+CD25+ T regulatory cells (Treg cells). Treg cells have been shown to regulate CD4+ and CD8+ immune responses to HIV and FIV antigens in vitro. We tested the hypothesis that Treg cells become infected and activated during the acute infection with FIV leading to the suppression of CD4+ T helper cell responses. Cats were experimentally infected with FIV-NCSU1 and blood and lymph node cells were collected at weekly intervals following inoculation. Real-Time RT-PCR was used to determine plasma viremia and the relative expression of FIV, FoxP3, TGF-β, and GAPDH mRNA copies in CD4+CD25+ and CD4+CD25− T cell subsets. Flow cytometry was used to assess the absolute numbers of each cell type and the expression of surface TGF-β and intracellular FoxP3 in CD4+CD25+ and CD4+CD25− T cells at each time point. Treg suppression of IL-2 production in CD4+ T helper cells was assessed by ELISPOT assays. Our results showed that peak viremia occurred at 2 weeks post infection and correlated with maximal infectivity in CD4+CD25+ T cell populations. FIV-gag-mRNA levels were higher in CD4+CD25+ T cells than CD4+CD25− T cells throughout the acute phase of infection. Induction of FoxP3 and TGF-β indicated activation of Treg cells during the acute stage infection, which was confirmed by Treg cell suppression of IL-2 production by CD4+ Th cells in an ELISPOT assay. Our findings support the hypothesis that early activation of Treg immunosuppressor function may limit an effective anti-FIV response, contributing to the establishment of chronic infection and the immunodeficiency caused by this virus.

It is now well accepted that type 1 interferons (IFNs), IFN-alpha and IFN-beta, in addition to being molecules with powerful antiviral activity, play a critical role in modulating immune responses to foreign and self-antigens. This review of the literature documents the immunomodulatory effects of IFN-alpha and discusses its position and importance in the cytokine cascade. In addition, this review attempts to organize the literature describing local and systemic immunomodulatory effects of orally administered low doses of IFN-alpha, and provide a physiological explanation for the mechanism of action. Evidence suggests that, early in the process of antigen presentation to T helper (Th) cells, IFN-alpha derived principally from the antigen-presenting cells (APC) provides an important signal for Th precursor differentiation in favor of a Th1 immune response. IFN-alpha, perhaps via upregulation of the high-alphaffinity interleukin-12beta1/beta2 (IL-12beta1/beta2) receptor, renders Th1 cells responsive to IL-12 resulting in production of high levels of IFN-gamma crucial to the development of Th1 immune responses. In addition to being instrumental in the development of Th1 immune responses, IFN-alpha appears to be the major cytokine responsible for the amplification of the CD8+ T cell response and resistance to viral infections. Orally administered IFN-alpha induces similar Th1 cytokine responses in buccal mucosal lymph nodes (LN), including upregulation of IFN-gamma expression and downregulation of IL-4. Moreover, reports of systemic immune effects such as decreased autoimmune responses, increased antiviral and antibacterial responses, and generalized immune function changes after oral IFN-alpha administration are consistent with the known immunomodulatory role of IFN-alpha in a physiological setting. Responses to orally administered low doses of IFN-alpha also adhere to the principle of low-dose priming and high-dose anergy that dictates the cellular and cytokine responses to exogenously added cytokines both in vivo and in vitro. These observations collectively suggest that IFN-alpha administered to mucosal-associated immune tissue replicates the known physiological role of IFN-alpha, including regulation of CD4+ Th1 immunomodulatory cells and activation of CD8+ effector cells, which are both crucial to development of protective immune responses. What remains to be determined is how local mucosal immune responses to IFN-alpha given orally are translated into systemic immune responses and resistance to disease. This important question, the answer to which will have profound implications for new immunotherapies for immune-based diseases, is the focus of current research.

By utilizing the kinetics of neutralization, it was found that an antibody response to type 1 (oral) and type 2 (genital) herpesvirus infection could be independently measured and correlated with type of virus isolated from the patient. The presence of antibodies to type 1 and type 2 herpesvirus was examined in patients with carcinoma of the cervix, in matched controls, random controls, and patients with other types of malignancy. Antibodies to type 2 were found with greater frequency in patients with carcinoma of the cervix (83 percent) than in the other groups tested (0 to 20 percent). The data suggest an association of genital herpesvirus and carcinoma of the cervix.

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CD8þ lymphocytes are critical to the control and elimination of viral pathogens. Impaired CD8 þ responses are well recognized in lentiviral infections; however, the mechanisms underlying CD8 þ impairment remain elusive. Using the feline immunodeficiency virus (FIV) model for human AIDS, we reported previously that CD4 þ CD25 þ Treg cells in both the acute and long-term, asymptomatic phase of infection are constitutively activated and suppress CD4 þ CD25-T cell responses. In the current study, we have demonstrated that CD4 þ CD25 þ Treg cells suppress CD8 þ responses to immune stimulation during both the acute and chronic, asymptomatic phase of FIV infection and that the mechanism of suppression may be mediated by membrane-þ lymphocytes from lymph node suspensions significantly enhanced production of IFN-g during the acute phase of infection and coculture of CD8 þ lymphocytes with CD4 þ CD25 þ lymphocytes resulted in suppression of CD8 þ IFN-g during both the acute and chronic stages of infection. FACS analysis indicated that there was TGF-bRII upregulation on CD8 CD25þ subset in chronically infected cats. In support of activation of the TGF-b signaling pathway, Western blotting showed Smad 2 phosphorylation in CD8coculture. These results demonstrate the suppressive effect CD4 þ CD25 þ Treg cells have on the CD8 þ immune response during the acute and chronic stages of FIV infection and suggest that the mechanism of suppression may be mediated by mTGF-b.