Anti-Feline Immunodeficiency Virus (FIV) Soluble Factor(s) Produced from Antigen-Stimulated Feline CD8+ T Lymphocytes Suppresses FIV Replication

Feline immunodeficiency virus (FIV) is a T-lymphotropic lentivirus in the family Retroviridae (35). Infection of cats with FIV causes transient fever, leukopenia, generalized lymphadenopathy, and finally an immunodeficiency-like syndrome, such as stomatitis, upper respiratory disease, neurological disease, or lymphoma (16, 35, 50). FIV infects both CD4+ and CD8+ T lymphocytes (9) and induces the characteristic inversion of CD4+/CD8+ T-cell ratios (1, 16, 31, 42). As with human immunodeficiency virus (HIV) infection in humans (7, 26, 46), following infection of cats with FIV, cytolytic and noncytolytic cellular immune mechanisms are suggested to participate in the control of virus replication in vivo (3, 10, 23, 40). Major histocompatibility complex-restricted FIV- and HIV-specific cytotoxic T lymphocytes (CTL) are predominantly composed of CD8+ T lymphocytes (7, 40). CTL-mediated cellular immunity has been suggested to control the initial viral infection prior to the production of virus-specific antibody (3, 26). It has also been suggested that CTL activity correlates with disease progression in HIV-infected patients (20, 37). HIV type 1-infected individuals exerting active CTL responses showed rapidly reduced plasma viremia and virus replication. In contrast, patients with low or undetectable CTL responses did not show control of virus replication and progressed to the AIDS state. FIV-infected cats or cats vaccinated with inactivated FIV have been shown to produce FIV-specific CTL responses (3, 18, 28, 41, 44). FIV-specific CTL also are suggested to participate in establishing protective immunity in cats (21, 45). CD8+ T lymphocytes from HIV-infected subjects have also been shown to inhibit viral replication without cytotoxicity in CD8+ T-cell-depleted peripheral blood mononuclear cells (PBMC) (46). Furthermore, this noncytolytic mechanism could be reconstituted following the addition of CD8+ T cells to infected CD4+ T lymphocytes (48). The soluble anti-HIV factor present in cell-free supernatants of CD8+ T cells was later designated CD8+ T-cell antiviral factor (29, 47). The presence of similar soluble antiviral factors was demonstrated for CD8+ T cells of simian immunodeficiency virus-infected African green monkeys and HIV type 2-infected baboons (5, 17). In addition to the uncharacterized T-cell antiviral factor, interleukin 16 (IL-16) and several chemokines have been identified as HIV-suppressive factors (2, 6, 13, 33). It appears that the antiviral activities derived from CD8+ cells consist of multiple independent factors (38, 39). Like the cytolytic antiviral activity of CTL, the noncytolytic antiviral activities of CD8+ T cells were associated with the clinical stages of HIV and FIV infections (4, 10). CD8+ T lymphocytes from HIV-infected long-term survivors very efficiently suppressed HIV replication, but CD8+ T cells from AIDS patients did not inhibit viral replication (4). Some infected cats, showing no evidence of seroconversion or FIV infection, had strong CD8+ T-cell-mediated activity that readily inhibited FIV replication (10). In the present study, we demonstrated that PBMC with consistent FIV-specific CTL activity produced an anti-FIV soluble factor(s) following stimulation with FIV-infected and irradiated antigen-presenting cells (APC). The anti-FIV factor(s) suppressed viral replication in PBMC by a noncytolytic mechanism.