Journal of virology 2017 11 08() pii 10.1128/JVI.01748-17
Developing biological interventions to control HIV replication in the absence of antiretroviral therapy (ART) could contribute to the development of a functional cure. As a potential alternative to ART, the IL-15 superagonist ALT-803 has been shown to boost the number and function of HIV-specific CD8(+) T and NK cell populations, in vitro. Four SIV(+) rhesus macaques, three of whom possessed MHC alleles associated with control of SIV, and all of whom had received SIV vaccine vectors that had the potential to elicit CD8(+) T cell responses, were given ALT-803 in three treatment cycles. The first and second cycles of treatment were separated by two weeks, while the third cycle was administered after a 29-week break. ALT-803 transiently elevated the total CD8(+) effector and central memory T cell and NK cell populations in peripheral blood, while viral loads transiently decreased by ∼2 logs in all animals. Virus suppression was not sustained as T cells became less responsive to ALT-803 and waned in numbers. No effect on viral loads was observed in the second cycle of ALT-803, concurrent with downregulation of the IL-2/15 common γ-C and β chain receptors on both CD8(+) T cells and NK cells. Furthermore, populations of immunosuppressive T cells increased during the second cycle of ALT-803. During the third treatment cycle, responsiveness to ALT-803 was restored. CD8(+) T cells and NK cells increased again 3-5 fold, and viral loads transiently decreased again, by 1-2 logs.Importance:Overall, our data suggests that ALT-803 has the potential to be used as an immunomodulatory agent to elicit effective immune control of HIV/SIV replication. We identify mechanisms to explain why virus control is transient, so that this model can be used to define a clinically appropriate treatment regimen.