Protective efficacy of nonpathogenic nef-deleted SHIV vaccination combined with recombinant IFN-gamma administration against a pathogenic SHIV challenge in rhesus monkeys.
ABSTRACT We previously reported that a nef-deleted SHIV (SHIV-NI) is nonpathogenic and gave macaques protection from challenge infection with pathogenic SHIV-C2/1. To investigate whether IFN-gamma augments the immune response induced by this vaccination, we examined the antiviral and adjuvant effect of recombinant human IFN-gamma (rIFN-gamma) in vaccinated and unvaccinated monkeys. Nine monkeys were vaccinated with nef-deleted nonpathogenic SHIV-NI. Four of them were administered with rIFN-gamma and the other five monkeys were administered with placebo. After the challenge with pathogenic SHIV-C2/1, CD4(+) T-cell counts were maintained similarly in monkeys of both groups, while those of the unvaccinated monkeys decreased dramatically at 2 weeks after challenge. However, the peaks of plasma viral load were reduced to 100-fold in SHIV-NI vaccinated monkeys combined with rIFN-gamma compared with those in SHIV-NI vaccinated monkeys without rIFN-gamma. The peaks of plasma viral load were inversely correlated with the number of SIV Gag-specific IFN-gamma-producing cells. In SHIV-NI-vaccinated monkeys with rIFN-gamma, the number of SIV Gag-specific IFN-gamma-producing cells of PBMCs increased 2-fold compared with those in SHIV-NI-vaccinated monkeys without rIFN-gamma, and the NK activity and MIP-1alpha production of PBMCs were also enhanced. Thus, vaccination of SHIV-NI in combination with rIFN-gamma was more effective in modulating the antiviral immune system into a Th1 type response than SHIV-NI vaccination alone. These results suggest that IFN-gamma augmented the anti-viral effect by enhancing innate immunity and shifting the immune response to Th1.
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ABSTRACT: That HTLV-I infects CD4(+) T cells and enhances their cell growth has been shown as successful long-term in vitro proliferation in the presence of IL-2. It is known that T cells isolated from HAM patients possess strong ability for cell proliferation in vitro and mRNA of various cytokines are abundantly expressed in CNS tissues of HAM patients. Hence, the cytokine-induced proliferation could have an important role in pathogenesis and immune responses of HAM. In this study, we examined the relationship between cell proliferation and ability of in vitro cytokine production of CD4(+) T cell clones isolated from HAM patients. We started a culture from a single cell to isolate cell clones immediately after drawing blood from the patients using limiting dilution method, which could allow the cell to avoid in vitro HTLV-I infection after initiation of culture. Many cell clones were obtained and the rate of proliferation efficiency from a single cell was as high as 80%, especially in the 4 weeks' culture cells from HAM patients. These cells were classified as mainly Th0 phenotype that produce both IFN-gamma and IL-4 after CD3-stimulation. However, the frequency of proviral DNA in these cloned cells was significantly low. Our results indicate that the ability of cell proliferation in HAM patients is not restricted in HTLV-I-infected T cells. HTLV-Iuninfected CD4(+) T cells, mainly Th0 cells, also have a strong ability to respond to IL-2-stimulation, showing that unusual immune activation on T cells has been observed in HAM patients.Microbiology and Immunology 02/2007; 51(2):235-42. · 1.55 Impact Factor