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ALT-803 transiently reduces SIV replication in the absence of antiretroviral treatment.

ALT-803 transiently reduces SIV replication in the absence of antiretroviral treatment.
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Ellis-Connell AL, Balgeman AJ, Zarbock KR, Barry G, Weiler A, Egan JO, Jeng EK, Friedrich T, Miller JS, Haase AT, Schacker TW, Wong HC, Rakasz E, O'Connor SL,


Ellis-Connell AL, Balgeman AJ, Zarbock KR, Barry G, Weiler A, Egan JO, Jeng EK, Friedrich T, Miller JS, Haase AT, Schacker TW, Wong HC, Rakasz E, O'Connor SL, (click to view)

Ellis-Connell AL, Balgeman AJ, Zarbock KR, Barry G, Weiler A, Egan JO, Jeng EK, Friedrich T, Miller JS, Haase AT, Schacker TW, Wong HC, Rakasz E, O'Connor SL,

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Journal of virology 2017 11 08() pii 10.1128/JVI.01748-17

Abstract

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.

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