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

Research output: Contribution to journalArticle

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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

Fingerprint

Simian immunodeficiency virus
Simian Immunodeficiency Virus
Virus Replication
virus replication
T-lymphocytes
T-Lymphocytes
natural killer cells
Natural Killer Cells
viral load
Viral Load
Interleukin-15
Human immunodeficiency virus
HIV
Population
immunosuppressive agents
vector competence
therapeutics
major histocompatibility complex
Immunosuppressive Agents
interleukin-2

Keywords

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Cite this

Ellis-Connell, A. L., Balgeman, A. J., Zarbock, K. R., Barry, G., Weiler, A., Egan, J. O., ... O'Connor, S. L. (2018). ALT-803 transiently reduces simian immunodeficiency virus replication in the absence of antiretroviral treatment. Journal of virology, 92(3), [e01748-17]. https://doi.org/10.1128/JVI.01748-17

ALT-803 transiently reduces simian immunodeficiency virus replication in the absence of antiretroviral treatment. / Ellis-Connell, Amy L.; Balgeman, Alexis J.; Zarbock, Katie R.; Barry, Gabrielle; Weiler, Andrea; Egan, Jack O.; Jeng, Emily K.; Friedrich, Thomas; Miller, Jeffrey S.; Haase, Ashley T.; Schacker, Timothy W.; Wong, Hing C.; Rakasz, Eva; O'Connor, Shelby L.

In: Journal of virology, Vol. 92, No. 3, e01748-17, 01.02.2018.

Research output: Contribution to journalArticle

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 2018, 'ALT-803 transiently reduces simian immunodeficiency virus replication in the absence of antiretroviral treatment', Journal of virology, vol. 92, no. 3, e01748-17. https://doi.org/10.1128/JVI.01748-17
Ellis-Connell, Amy L. ; Balgeman, Alexis J. ; Zarbock, Katie R. ; Barry, Gabrielle ; Weiler, Andrea ; Egan, Jack O. ; Jeng, Emily K. ; Friedrich, Thomas ; Miller, Jeffrey S. ; Haase, Ashley T. ; Schacker, Timothy W. ; Wong, Hing C. ; Rakasz, Eva ; O'Connor, Shelby L. / ALT-803 transiently reduces simian immunodeficiency virus replication in the absence of antiretroviral treatment. In: Journal of virology. 2018 ; Vol. 92, No. 3.
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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.",
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