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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.

References

  1. Mofenson, L.M. Prevention of mother-to-child HIV-1 transmission—why we still need a preventive HIV immunization strategy. J. Acquir. Immune Defic. Syndr. 58, 359–362 (2011).

    Article  PubMed  Google Scholar 

  2. Safrit, J.T. et al. Immunoprophylaxis to prevent mother-to-child transmission of HIV-1. J. Acquir. Immune Defic. Syndr. 35, 169–177 (2004).

    Article  PubMed  Google Scholar 

  3. Voronin, Y. et al. HIV monoclonal antibodies: a new opportunity to further reduce mother-to-child HIV transmission. PLoS Med. 11, e1001616 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Mofenson, L.M. & Watts, D.H. Safety of pediatric HIV elimination: the growing population of HIV- and antiretroviral-exposed, but uninfected, infants. PLoS Med. 11, e1001636 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kumwenda, N.I. et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N. Engl. J. Med. 359, 119–129 (2008).

    Article  CAS  PubMed  Google Scholar 

  6. Persaud, D. et al. Slower clearance of nevirapine-resistant virus in infants failing extended nevirapine prophylaxis for prevention of mother-to-child HIV transmission. AIDS Res. Hum. Retroviruses 27, 823–829 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Carias, A.M. et al. Defining the interaction of HIV-1 with the mucosal barriers of the female reproductive tract. J. Virol. 87, 11388–11400 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Demberg, T. & Robert-Guroff, M. Mucosal immunity and protection against HIV-SIV infection: strategies and challenges for vaccine design. Int. Rev. Immunol. 28, 20–48 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Haase, A.T. Early events in sexual transmission of HIV and SIV, and opportunities for interventions. Annu. Rev. Med. 62, 127–139 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Milush, J.M. et al. Rapid dissemination of SIV following oral inoculation. AIDS 18, 2371–2380 (2004).

    PubMed  Google Scholar 

  11. Abel, K. et al. Rapid virus dissemination in infant macaques after oral simian immunodeficiency virus exposure in the presence of local innate immune responses. J. Virol. 80, 6357–6367 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Devito, C. et al. Mucosal and plasma IgA from HIV-1-exposed uninfected individuals inhibit HIV-1 transcytosis across human epithelial cells. J. Immunol. 165, 5170–5176 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Mascola, J.R. et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1–SIV chimeric virus by passive infusion of neutralizing antibodies. Nat. Med. 6, 207–210 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Baba, T.W. et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat. Med. 6, 200–206 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Hessell, A.J. et al. Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nat. Med. 15, 951–954 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hessell, A.J. et al. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog. 5, e1000433 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shingai, M. et al. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J. Exp. Med. 211, 2061–2074 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pegu, A. et al. Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor. Sci. Transl. Med. 6, 243ra88 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Frankel, S.S. et al. Neutralizing monoclonal antibodies block human immunodeficiency virus type 1 infection of dendritic cells and transmission to T cells. J. Virol. 72, 9788–9794 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Veazey, R.S. et al. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat. Med. 9, 343–346 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Bomsel, M. et al. Immunization with HIV-1 gp41 subunit virosomes induces mucosal antibodies protecting nonhuman primates against vaginal SHIV challenges. Immunity 34, 269–280 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Parren, P.W. & Burton, D.R. The antiviral activity of antibodies in vitro and in vivo. Adv. Immunol. 77, 195–262 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shingai, M. et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viremia. Nature 503, 277–280 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ferrantelli, F. et al. Post-exposure prophylaxis with human monoclonal antibodies prevented SHIV89.6P infection or disease in neonatal macaques. AIDS 17, 301–309 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Barouch, D.H. et al. Therapeutic efficacy of potent neutralizing HIV-1–specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503, 224–228 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Caskey, M. et al. Viremia suppressed in HIV-1–infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487–491 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bolton, D.L. et al. Human immunodeficiency virus type 1 monoclonal antibodies suppress acute simian-human immunodeficiency virus viremia and limit seeding of cell-associated viral reservoirs. J. Virol. 90, 1321–1332 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Haigwood, N.L. et al. Passive immunotherapy in simian immunodeficiency virus–infected macaques accelerates the development of neutralizing antibodies. J. Virol. 78, 5983–5995 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ng, C.T. et al. Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques. Nat. Med. 16, 1117–1119 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jaworski, J.P. et al. Neutralizing polyclonal IgG present during acute infection prevents rapid disease onset in simian-human immunodeficiency virus SHIVSF162P3-infected infant rhesus macaques. J. Virol. 87, 10447–10459 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kong, R. et al. Improving neutralization potency and breadth by combining broadly reactive HIV-1 antibodies targeting major neutralization epitopes. J. Virol. 89, 2659–2671 (2015).

    Article  CAS  PubMed  Google Scholar 

  32. Rudicell, R.S. et al. Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo. J. Virol. 88, 12669–12682 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Walker, L.M. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Julien, J.P. et al. Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS Pathog. 9, e1003342 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Moldt, B. et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl. Acad. Sci. USA 109, 18921–18925 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Jayaraman, P. et al. Evidence for persistent, occult infection in neonatal macaques following perinatal transmission of simian-human immunodeficiency virus SF162P3. J. Virol. 81, 822–834 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Hansen, S.G. et al. Profound early control of highly pathogenic SIV by an effector memory T cell vaccine. Nature 473, 523–527 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Okwundu, C.I., Uthman, O.A. & Okoromah, C.A. Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals. Cochrane Database Syst. Rev. 7, CD007189 (2012).

    Google Scholar 

  39. Migueles, S.A. & Connors, M. Small molecules and big killers: the challenge of eliminating the latent HIV reservoir. Immunity 36, 320–321 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Allers, K. et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood 117, 2791–2799 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Hansen, S.G. et al. Immune clearance of highly pathogenic SIV infection. Nature 502, 100–104 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Whitney, J.B. et al. Rapid seeding of the viral reservoir prior to SIV viremia in rhesus monkeys. Nature 512, 74–77 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shah, S.K. et al. Research on very early ART in neonates at risk of HIV infection. Lancet Infect. Dis. 14, 797 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Persaud, D. et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N. Engl. J. Med. 369, 1828–1835 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Miller, C.J. et al. Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus. J. Virol. 79, 9217–9227 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hessell, A.J. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Ledgerwood, J.E. et al. Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin. Exp. Immunol. 182, 289–301 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lynch, R.M. et al. The development of CD4–binding site antibodies during HIV-1 infection. J. Virol. 86, 7588–7595 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals 8th edn. (The National Academies Press, Washington, D.C., 2011).

  50. Leary, S. et al. AVMA Guidelines for the Euthanasia of Animals: 2013 Edition (American Veterinary Medical Association, Schaumburg, Illinois, USA, 2013).

  51. Wu, X. et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856–861 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Harouse, J.M. et al. Mucosal transmission and induction of simian AIDS by CCR5-specific simian-human immunodeficiency virus SHIVSF162P3 . J. Virol. 75, 1990–1995 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cline, A.N., Bess, J.W., Piatak, M. Jr. & Lifson, J.D. Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations and application to reverse-engineering of vaccines for AIDS. J. Med. Primatol. 34, 303–312 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Malouli, D. et al. Cytomegalovirus pp65 limits dissemination but is dispensable for persistence. J. Clin. Invest. 124, 1928–1944 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kozlowski, P.A., Cu-Uvin, S., Neutra, M.R. & Flanigan, T.P. Mucosal vaccination strategies for women. J. Infect. Dis. 179 (suppl. 3), S493–S498 (1999).

    Article  PubMed  Google Scholar 

  56. Malherbe, D.C. et al. Sequential immunization with a subtype B HIV-1 envelope quasispecies partially mimics the in vivo development of neutralizing antibodies. J. Virol. 85, 5262–5274 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hirsch, V.M. et al. Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication. J. Virol. 69, 955–967 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhou, T. et al. Transplanting supersites of HIV-1 vulnerability. PLoS One 9, e99881 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Malherbe, D.C. et al. Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits. J. Virol. 88, 12949–12967 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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