ALT-803 transiently reduces simian immunodeficiency virus replication in the absence of antiretroviral treatment

Amy L. Ellis-Connell, Alexis J. Balgeman, Katie R. Zarbock, Gabrielle Barry, Andrea Weiler, Jack O. Egan, Emily K. Jeng, Thomas Friedrich, Jeffrey S. Miller, Ashley T. Haase, Timothy W. Schacker, Hing C. Wong, Eva Rakasz, Shelby L. O'Connor

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20 Scopus citations

Abstract

Developing biological interventions to control human immunodeficiency virus (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 interleukin-15 (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 simian immunodeficiency virus (SIV)-positive rhesus macaques, three of whom possessed major histocompatibility complex 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 2 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 γC 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 treatment. During the third treatment cycle, responsiveness to ALT-803 was restored. CD8+ T cells and NK cells increased again 3- to 5-fold, and viral loads transiently decreased again by 1 to 2 logs.

Original languageEnglish (US)
Article numbere01748-17
JournalJournal of virology
Volume92
Issue number3
DOIs
StatePublished - Feb 1 2018

Bibliographical note

Funding Information:
The research was conducted in part at a facility constructed with support from Research Facilities Improvement Program grant numbers RR15459-01 and RR020141-01. We also thank members of the Wisconsin National Primate Research Center, a facility supported by grants P51RR000167 and P51OD011106. This study was funded in part by NIH R01 AI108415.

Publisher Copyright:
© 2018 American Society for Microbiology.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • ALT-803
  • ART-naive
  • IL-15 superagonist
  • Nonhuman primate
  • SIV
  • SIV treatment
  • Virus

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