Protective Efficacy of Nonpathogenic Nef‐Deleted SHIV Vaccination Combined with Recombinant IFN‐γ 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‐γ augments the immune response induced by this vaccination, we examined the antiviral and adjuvant effect of recombinant human IFN‐γ (rIFN‐γ) in vaccinated and unvaccinated monkeys. Nine monkeys were vaccinated with nef‐deleted nonpathogenic SHIV‐NI. Four of them were administered with rIFN‐γ 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‐γ compared with those in SHIV‐NI vaccinated monkeys without rIFN‐γ. The peaks of plasma viral load were inversely correlated with the number of SIV Gag‐specific IFN‐γ‐producing cells. In SHIV‐NI‐vaccinated monkeys with rIFN‐γ, the number of SIV Gag‐specific IFN‐γ‐producing cells of PBMCs increased 2‐fold compared with those in SHIV‐NI‐vaccinated monkeys without rIFN‐γ, and the NK activity and MIP‐1α production of PBMCs were also enhanced. Thus, vaccination of SHIV‐NI in combination with rIFN‐γ was more effective in modulating the antiviral immune system into a Th1 type response than SHIV‐NI vaccination alone. These results suggest that IFN‐γ augmented the anti‐viral effect by enhancing innate immunity and shifting the immune response to Th1.