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HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

Horwitz, Joshua A. and Halper-Stromberg, Ariel and Mouquet, Hugo and Gitlin, Alexander D. and Tretiakova, Anna and Eisenreich, Thomas R. and Malbec, Marine and Gravemann, Sophia and Billerbeck, Eva and Dorner, Marcus and Büning, Hildegard and Schwartz, Olivier and Knops, Elena and Kaiser, Rolf and Seaman, Michael S. and Wilson, James M. and Rice, Charles M. and Ploss, Alexander and Bjorkman, Pamela J. and Klein, Florian and Nussenzweig, Michel C. (2013) HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proceedings of the National Academy of Sciences of the United States of America, 110 (41). pp. 16538-16543. ISSN 0027-8424. PMCID PMC3799352. doi:10.1073/pnas.1315295110.

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Effective control of HIV-1 infection in humans is achieved using combinations of antiretroviral therapy (ART) drugs. In humanized mice (hu-mice), control of viremia can be achieved using either ART or by immunotherapy using combinations of broadly neutralizing antibodies (bNAbs). Here we show that treatment of HIV-1–infected hu-mice with a combination of three highly potent bNAbs not only resulted in complete viremic control but also led to a reduction in cell-associated HIV-1 DNA. Moreover, lowering the initial viral load by coadministration of ART and immunotherapy enabled prolonged viremic control by a single bNAb after ART was withdrawn. Similarly, a single injection of adeno-associated virus directing expression of one bNAb produced durable viremic control after ART was terminated. We conclude that immunotherapy reduces plasma viral load and cell-associated HIV-1 DNA and that decreasing the initial viral load enables single bNAbs to control viremia in hu-mice.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Bjorkman, Pamela J.0000-0002-2277-3990
Nussenzweig, Michel C.0000-0003-0592-8564
Additional Information:© 2013 National Academy of Sciences. Contributed by Michel C. Nussenzweig, August 14, 2013 (sent for review July 30, 2013. Published online before print September 16, 2013. We thank Caroline Eden for protein production and immunoassays; Alexander Abadir, Han Gao, and Xiying Fan for protein production; and Reha-Baris Incesu for hu-mouse screening. We thank Marcus Dorner, Eva Billerbeck, Rachael N. Labitt, Chase Budell, Tamar Friling, Kevin Vega, and Brenna Flatley for assistance with hu-mouse production. F.K. was supported by the Stavros Niarchos Foundation. E.B., M.D., A.P., and C.M.R. were supported by the Starr Foundation. O.S. is supported by grants from the Agence Nationale de Recherche sur le Sida, Sidaction, AREVA Foundation, Vaccine Research Institute, the Labex Integrative Biology of Emerging Infectious Diseases program, the Seventh Framework Programme HIT Hidden HIV (Health-F3-2012-305762), and Institut Pasteur. This work was supported in part by the Bill and Melinda Gates Foundation with Comprehensive Antibody Vaccine Immune Monitoring Consortium Grant 1032144 (to M.S.S.) and Collaboration for AIDS Vaccine Discovery Grants 38660 (to P.J.B.) and 38619s (to M.C.N.). This work was also supported by the German Center for Infection Research (S.G. and H.B.), UL1 TR000043 Translational Science Award (Clinical and Translational Science Award) program, AI 100663-01 (to M.C.N.), Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and AI 100148-01 (to P.J.B. and M.C.N.). P.J.B. and M.C.N. are Howard Hughes Medical Institute Investigators. Author contributions: J.A.H., O.S., P.J.B., F.K., and M.C.N. designed research; J.A.H., A.H.-S., H.M., A.D.G., T.R.E., M.M., E.B., M.D., E.K., R.K., M.S.S., and F.K. performed research; A.T., S.G., H.B., J.M.W., C.M.R., and A.P. contributed new reagents/analytic tools; J.A.H., A.H.-S., F.K., and M.C.N. analyzed data; and J.A.H. and M.C.N. wrote the paper. The authors declare no conflict of interest.
Funding AgencyGrant Number
Stavros Niarchos FoundationUNSPECIFIED
Starr FoundationUNSPECIFIED
Agence Nationale de Recherche sur le SidaUNSPECIFIED
Vaccine Research InstituteUNSPECIFIED
Labex Integrative Biology of Emerging Infectious Diseases programUNSPECIFIED
Seventh Framework Programme HIT Hidden HIVHealth-F3-2012-305762
Institut PasteurUNSPECIFIED
Bill and Melinda Gates Foundation1032144
Collaboration for AIDS Vaccine Discovery38660
Collaboration for AIDS Vaccine Discovery38619s
German Center for Infection ResearchUL1 TR000043
NIHAI 100663-01
NIHAI 100148-01
Subject Keywords:CD4bs; glycan; gp160
Issue or Number:41
PubMed Central ID:PMC3799352
Record Number:CaltechAUTHORS:20131105-095202612
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Official Citation:Joshua A. Horwitz, Ariel Halper-Stromberg, Hugo Mouquet, Alexander D. Gitlin, Anna Tretiakova, Thomas R. Eisenreich, Marine Malbec, Sophia Gravemann, Eva Billerbeck, Marcus Dorner, Hildegard Büning, Olivier Schwartz, Elena Knops, Rolf Kaiser, Michael S. Seaman, James M. Wilson, Charles M. Rice, Alexander Ploss, Pamela J. Bjorkman, Florian Klein, and Michel C. Nussenzweig HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice PNAS 2013 110 (41) 16538-16543; published ahead of print September 16, 2013, doi:10.1073/pnas.1315295110
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:42247
Deposited On:06 Nov 2013 22:01
Last Modified:10 Nov 2021 16:20

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