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Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques

Nature Medicine volume 22, pages 362–368 (2016)Cite this article

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Abstract

Prevention of mother-to-child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested HIV-1–specific human neutralizing monoclonal antibodies (NmAbs) as a post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with the simian-human immunodeficiency virus SHIVSF162P3. On days 1, 4, 7 and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h after antibody administration. Replicating virus was found in multiple tissues by day 1 in animals that were not treated. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged after CD8+ T cell depletion. These results suggest that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs.

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Figure 1: NmAb cocktail dosing and kinetics in plasma.
Figure 2: Viral kinetics and tissue distribution during the first 2 weeks after oral SHIV exposure.
Figure 3: SHIVSF162P3-associated viremia is not established in plasma or PBMC of NmAb-treated infants.
Figure 4: NmAb cocktail lowers tissue-associated viremia within 24 h after s.c. delivery.

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Acknowledgements

We thank D. Malherbe for helpful discussions and C. Corbacci for graphic design work. We appreciate the expertise, dedication and thoughtful care provided to the infant macaques by H. Sidener and the ONPRC nursery animal care technicians. Titrated stocks of SHIVSF162P3 (passage 3) virus were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases NIAID), NIH (catalog number 6526; contributors J. Harouse, C. Cheng-Mayer and R. Pal) for each study. The SIVsmE660 stock was kindly provided by V.M. Hirsch. The linearized pBSII-SIVgag was kindly gifted by Michael Piatak, National Cancer Institute at the NIH. Funding was provided by US Public Health Service grants from the NIH (grant no. R01-HD080459 (N.L.H.), P51-OD011092 (J. Robertson), P51-OD011092 pilot funding (E.E.)), the Elizabeth Glaser Pediatric AIDS Foundation (N.L.H.) and the American Foundation for AIDS Research (amfAR) (grant no. 108823-55-RGRL; N.L.H.). This work was also funded, in part, by the intramural research program of the Vaccine Research Center (B.S.G. and J.R.M.) and the Laboratory of Molecular Microbiology, NIAID, NIH, Division of Health and Human Services, US Public Health Service (V.M.H.).

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Authors and Affiliations

  1. Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA

    Ann J Hessell, J Pablo Jaworski, Erin Epson, Shilpi Pandey, Christoph Kahl, William F Sutton, Tracy A Cheever, Philip T Barnette, Alfred W Legasse, Shannon Planer, Jeffrey J Stanton, Don Siess, David Burke, Byung S Park, Michael K Axthelm, Anne Lewis, Jonah B Sacha & Nancy L Haigwood

  2. Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA

    Ann J Hessell, Jason Reed, Katherine B Hammond, Michael K Axthelm, Jonah B Sacha & Nancy L Haigwood

  3. Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA

    Kenta Matsuda & Vanessa M Hirsch

  4. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Amarendra Pegu, Xuejun Chen, Keyun Wang, Barney S Graham & John R Mascola

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Contributions

Studies were designed and planned by N.L.H. and A.J.H.; experimental work was done by A.J.H., J.P.J., E.E., K.M., S.P., J.R., W.F.S., K.B.H., T.A.C., P.T.B., A.W.L., S.P., X.C., K.W., D.S., D.B.; pathology was described by A.W.L.; veterinary care was provided by J.J.S.; A.J.H., N.L.H., J.B.S., J.R.M. and B.S.G. wrote the manuscript; A.J.H., J.P.J., E.E., C.K., M.K.A., V.M.H., A.P., J.B.S. and N.L.H. analyzed the data; B.S.P. performed statistical analyses.

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Correspondence to Nancy L Haigwood.

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Hessell, A., Jaworski, J., Epson, E. et al. Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques. Nat Med 22, 362–368 (2016). https://doi.org/10.1038/nm.4063

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