TY - JOUR
T1 - Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir
AU - Rajashekar, Jyothi K.
AU - Richard, Jonathan
AU - Beloor, Jagadish
AU - Prévost, Jérémie
AU - Anand, Sai Priya
AU - Beaudoin-Bussières, Guillaume
AU - Shan, Liang
AU - Herndler-Brandstetter, Dietmar
AU - Gendron-Lepage, Gabrielle
AU - Medjahed, Halima
AU - Bourassa, Catherine
AU - Gaudette, Fleur
AU - Ullah, Irfan
AU - Symmes, Kelly
AU - Peric, Andrew
AU - Lindemuth, Emily
AU - Bibollet-Ruche, Frederic
AU - Park, Jun
AU - Chen, Hung Ching
AU - Kaufmann, Daniel E.
AU - Hahn, Beatrice H.
AU - Sodroski, Joseph
AU - Pazgier, Marzena
AU - Flavell, Richard A.
AU - Smith, Amos B.
AU - Finzi, Andrés
AU - Kumar, Priti
N1 - Funding Information:
The authors thank Jonathan Alderman for administrative assistance in mouse colony management, CRCHUM and Yale School of Medicine Flow cytometry and BSL3 platforms for technical assistance, the FRQS AIDS and Infectious Disease Network and Mario Legault for cohort coordination and clinical samples, and Mark Hogarth for kindly providing recombinant dimeric FcγRIIIa. The SRG-15 mice were generated in collaboration with Regeneron Inc.; we thank G. Yancopoulos, D. Valenzuela, A. Murphy, and W. Auerbach who generated, in collaboration with our groups, the individual knockin alleles combined in SRG-15. This work was funded by CIHR grant # 422148 awarded to A.F., P.K., and D.E.K., by NIH grants R33AI122384 , R01AI145164 , CHEETAH grant ( P50AI150464 ) and R56AI141572 to P.K., by NIH R01 AI150322 and AI148379 and by the American Foundation for AIDS Research (AmfAR, 109343-59-RGRL ) to A.F., R01 AI129769 to M.P. and A.F., by R01 AI116274 to M.P., by R01 AI050529 and UM1 AI126620 to B.H.H. Funding was also provided by P01-GM56550/AI150741 and Gilead via its HIV Cure Program to J.S., A.F., and A.B.S. A.F. is the recipient of a Canada Research Chair on Retroviral Entry. R.A.F. is supported by the Howard Hughes Medical Institute . J.P., S.P.A., and G.B.B. are recipients of CIHR doctoral fellowships. D.E.K. is a FRQS merit Research Scholar. J.R. was supported partially by an AmfAR Mathilde Krim Fellowship # 109720-63-RKRL . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Disclaimer: The views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Uniformed Services University, US Army, the Department of Defense, or the US Government.
Funding Information:
The authors thank Jonathan Alderman for administrative assistance in mouse colony management, CRCHUM and Yale School of Medicine Flow cytometry and BSL3 platforms for technical assistance, the FRQS AIDS and Infectious Disease Network and Mario Legault for cohort coordination and clinical samples, and Mark Hogarth for kindly providing recombinant dimeric Fc?RIIIa. The SRG-15 mice were generated in collaboration with Regeneron Inc.; we thank G. Yancopoulos, D. Valenzuela, A. Murphy, and W. Auerbach who generated, in collaboration with our groups, the individual knockin alleles combined in SRG-15. This work was funded by CIHR grant #422148 awarded to A.F. P.K. and D.E.K. by NIH grants R33AI122384, R01AI145164, CHEETAH grant (P50AI150464) and R56AI141572 to P.K. by NIH R01 AI150322 and AI148379 and by the American Foundation for AIDS Research (AmfAR, 109343-59-RGRL) to A.F. R01 AI129769 to M.P. and A.F. by R01 AI116274 to M.P. by R01 AI050529 and UM1 AI126620 to B.H.H. Funding was also provided by P01-GM56550/AI150741 and Gilead via its HIV Cure Program to J.S. A.F. and A.B.S. A.F. is the recipient of a Canada Research Chair on Retroviral Entry. R.A.F. is supported by the Howard Hughes Medical Institute. J.P. S.P.A. and G.B.B. are recipients of CIHR doctoral fellowships. D.E.K. is a FRQS merit Research Scholar. J.R. was supported partially by an AmfAR Mathilde Krim Fellowship #109720-63-RKRL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Disclaimer: The views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Uniformed Services University, US Army, the Department of Defense, or the US Government. Conceptualization, J.R. A.F. and P.K.; methodology, J.K.R. J.R. J.S. M.P. R.A.F. A.B.S. A.F. and P.K.; investigation, J.K.R. J.R. J.B. J.P. S.P.A. G.B.-B. G.G.-L. H.M. C.B. F.G. I.U. K.S. A.P. E.L. F.B.-R. J.P. and H.-C.C.; writing ? original draft, J.K.R. J.R. A.F. and P.K.; writing ? review & editing, J.K.R. J.R. D.E.K. J.S. M.P. A.B.S. A.F. and P.K.; funding acquisition, J.S. A.B.S. A.F. and P.K.; resources, L.S. D.H.-B. B.H.H. J.S. M.P. R.A.F. A.B.S. A.F. and P.K.; supervision, B.H.H. J.S. M.P. A.B.S. A.F. and P.K. The authors declare no competing interests. We worked to ensure sex balance in the selection of non-human subjects wherever possible. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/6/9
Y1 - 2021/6/9
N2 - Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure.
AB - Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure.
KW - CD4i Abs
KW - HIV-1
KW - NK cell
KW - SRG-15
KW - State 2A
KW - antibody-dependent cellular cytotoxicity
KW - envelope glycoprotein
KW - humanized mice
UR - http://www.scopus.com/inward/record.url?scp=85108124159&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2021.04.014
DO - 10.1016/j.chom.2021.04.014
M3 - Article
C2 - 34019804
AN - SCOPUS:85108124159
SN - 1931-3128
VL - 29
SP - 904-916.e6
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 6
ER -