TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption

Denise C. Hsu; Alexandra Schuetz; Rawiwan Imerbsin; Decha Silsorn; Amarendra Pegu; Dutsadee Inthawong; Jumpol Sopanaporn; Pornsuk Visudhiphan; Weerawan Chuenarom; Boot Keawboon; Wei Shi; Merlin L. Robb; John R. Mascola; Romas Geleziunas; Richard A. Koup; Dan H. Barouch; Nelson L. Michael; Sandhya Vasan

doi:10.1371/JOURNAL.PPAT.1009339

TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption

Denise C. Hsu, Alexandra Schuetz, Rawiwan Imerbsin, Decha Silsorn, Amarendra Pegu, Dutsadee Inthawong, Jumpol Sopanaporn, Pornsuk Visudhiphan, Weerawan Chuenarom, Boot Keawboon, Wei Shi, Merlin L. Robb, John R. Mascola, Romas Geleziunas, Richard A. Koup, Dan H. Barouch, Nelson L. Michael, Sandhya Vasan^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Toll-like receptor 7 (TLR7) agonist and PGT121 (broadly neutralizing antibody, bnAb) administration previously delayed viral rebound and induced SHIV remission. We evaluated the impact of GS-986 (TLR7 agonist) and dual bnAbs on viral rebound after antiretroviral therapy (ART) interruption. Rhesus macaques inoculated with SHIV-1157ipd3N4 were initiated on daily suppressive ART from Day 14 post SHIV inoculation. Active arm animals (n = 8) received GS-986, N6-LS and PGT121 after plasma viral suppression, starting from week 14. GS-986 induced immune activation and SHIV-specific T cell responses but not viral expression in all the active arm animals. After ART interruption, median time to viral rebound was 6 weeks in the active and 3 weeks in the control arm (p = 0.024). In this animal model, the administration of the combination of GS-986 and dual bnAbs was associated with a modest delay in viral rebound. This strategy should be further evaluated to better understand the underlying mechanisms for the induction of virus-specific immune responses and delay in viral rebound.

Original language	English
Article number	e1009339
Journal	PLoS Pathogens
Volume	17
Issue number	2
DOIs	https://doi.org/10.1371/JOURNAL.PPAT.1009339
State	Published - 18 Feb 2021
Externally published	Yes

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Hsu, D. C., Schuetz, A., Imerbsin, R., Silsorn, D., Pegu, A., Inthawong, D., Sopanaporn, J., Visudhiphan, P., Chuenarom, W., Keawboon, B., Shi, W., Robb, M. L., Mascola, J. R., Geleziunas, R., Koup, R. A., Barouch, D. H., Michael, N. L., & Vasan, S. (2021). TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption. PLoS Pathogens, 17(2), Article e1009339. https://doi.org/10.1371/JOURNAL.PPAT.1009339

@article{05a0cbd5d4a1401591e8e24cda36552a,

title = "TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption",

abstract = "Toll-like receptor 7 (TLR7) agonist and PGT121 (broadly neutralizing antibody, bnAb) administration previously delayed viral rebound and induced SHIV remission. We evaluated the impact of GS-986 (TLR7 agonist) and dual bnAbs on viral rebound after antiretroviral therapy (ART) interruption. Rhesus macaques inoculated with SHIV-1157ipd3N4 were initiated on daily suppressive ART from Day 14 post SHIV inoculation. Active arm animals (n = 8) received GS-986, N6-LS and PGT121 after plasma viral suppression, starting from week 14. GS-986 induced immune activation and SHIV-specific T cell responses but not viral expression in all the active arm animals. After ART interruption, median time to viral rebound was 6 weeks in the active and 3 weeks in the control arm (p = 0.024). In this animal model, the administration of the combination of GS-986 and dual bnAbs was associated with a modest delay in viral rebound. This strategy should be further evaluated to better understand the underlying mechanisms for the induction of virus-specific immune responses and delay in viral rebound.",

author = "Hsu, {Denise C.} and Alexandra Schuetz and Rawiwan Imerbsin and Decha Silsorn and Amarendra Pegu and Dutsadee Inthawong and Jumpol Sopanaporn and Pornsuk Visudhiphan and Weerawan Chuenarom and Boot Keawboon and Wei Shi and Robb, {Merlin L.} and Mascola, {John R.} and Romas Geleziunas and Koup, {Richard A.} and Barouch, {Dan H.} and Michael, {Nelson L.} and Sandhya Vasan",

note = "Publisher Copyright: {\textcopyright} This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.",

year = "2021",

month = feb,

day = "18",

doi = "10.1371/JOURNAL.PPAT.1009339",

language = "English",

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Hsu, DC, Schuetz, A, Imerbsin, R, Silsorn, D, Pegu, A, Inthawong, D, Sopanaporn, J, Visudhiphan, P, Chuenarom, W, Keawboon, B, Shi, W, Robb, ML, Mascola, JR, Geleziunas, R, Koup, RA, Barouch, DH, Michael, NL & Vasan, S 2021, 'TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption', PLoS Pathogens, vol. 17, no. 2, e1009339. https://doi.org/10.1371/JOURNAL.PPAT.1009339

TY - JOUR

T1 - TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption

AU - Hsu, Denise C.

AU - Schuetz, Alexandra

AU - Imerbsin, Rawiwan

AU - Silsorn, Decha

AU - Pegu, Amarendra

AU - Inthawong, Dutsadee

AU - Sopanaporn, Jumpol

AU - Visudhiphan, Pornsuk

AU - Chuenarom, Weerawan

AU - Keawboon, Boot

AU - Shi, Wei

AU - Robb, Merlin L.

AU - Mascola, John R.

AU - Geleziunas, Romas

AU - Koup, Richard A.

AU - Barouch, Dan H.

AU - Michael, Nelson L.

AU - Vasan, Sandhya

N1 - Publisher Copyright: © This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

PY - 2021/2/18

Y1 - 2021/2/18

N2 - Toll-like receptor 7 (TLR7) agonist and PGT121 (broadly neutralizing antibody, bnAb) administration previously delayed viral rebound and induced SHIV remission. We evaluated the impact of GS-986 (TLR7 agonist) and dual bnAbs on viral rebound after antiretroviral therapy (ART) interruption. Rhesus macaques inoculated with SHIV-1157ipd3N4 were initiated on daily suppressive ART from Day 14 post SHIV inoculation. Active arm animals (n = 8) received GS-986, N6-LS and PGT121 after plasma viral suppression, starting from week 14. GS-986 induced immune activation and SHIV-specific T cell responses but not viral expression in all the active arm animals. After ART interruption, median time to viral rebound was 6 weeks in the active and 3 weeks in the control arm (p = 0.024). In this animal model, the administration of the combination of GS-986 and dual bnAbs was associated with a modest delay in viral rebound. This strategy should be further evaluated to better understand the underlying mechanisms for the induction of virus-specific immune responses and delay in viral rebound.

AB - Toll-like receptor 7 (TLR7) agonist and PGT121 (broadly neutralizing antibody, bnAb) administration previously delayed viral rebound and induced SHIV remission. We evaluated the impact of GS-986 (TLR7 agonist) and dual bnAbs on viral rebound after antiretroviral therapy (ART) interruption. Rhesus macaques inoculated with SHIV-1157ipd3N4 were initiated on daily suppressive ART from Day 14 post SHIV inoculation. Active arm animals (n = 8) received GS-986, N6-LS and PGT121 after plasma viral suppression, starting from week 14. GS-986 induced immune activation and SHIV-specific T cell responses but not viral expression in all the active arm animals. After ART interruption, median time to viral rebound was 6 weeks in the active and 3 weeks in the control arm (p = 0.024). In this animal model, the administration of the combination of GS-986 and dual bnAbs was associated with a modest delay in viral rebound. This strategy should be further evaluated to better understand the underlying mechanisms for the induction of virus-specific immune responses and delay in viral rebound.

UR - http://www.scopus.com/inward/record.url?scp=85102487101&partnerID=8YFLogxK

U2 - 10.1371/JOURNAL.PPAT.1009339

DO - 10.1371/JOURNAL.PPAT.1009339

M3 - Article

C2 - 33600506

AN - SCOPUS:85102487101

SN - 1553-7366

VL - 17

JO - PLoS Pathogens

JF - PLoS Pathogens

IS - 2

M1 - e1009339

ER -

TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption

Abstract

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