Broadly Neutralizing Anti-HIV-1 Antibodies Require Fc Effector Functions for in Vivo Activity

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Sep 13

PMID 25215485

Citations 322

Authors

Stylianos Bournazos

Florian Klein

John Pietzsch

Michael S Seaman

Michel C Nussenzweig

Jeffrey V Ravetch

Affiliations

Soon will be listed here.

Abstract

Broadly neutralizing antibodies (bNAbs) against HIV-1 provide both effective pre-exposure prophylaxis and treatment of HIV-1 infection in murine and nonhuman primate models, suggesting their potential use in humans. Although much is known about the role of variable domains in the neutralization breadth and potency of these bNAbs, the contribution of Fc domains to their activities is, by contrast, poorly characterized. Assessment of the in vivo activity of several bNAbs revealed that FcγR-mediated effector function contributes substantially to their capacity to block viral entry, suppress viremia, and confer therapeutic activity. Enhanced in vivo potency of anti-HIV-1 bNAbs was associated with preferential engagement of activating, but not inhibitory FcγRs, and Fc domain-engineered bNAb variants with selective binding capacity for activating FcγRs displayed augmented protective activity. These findings reveal key roles for Fc effector function in the in vivo activity of anti-HIV-1 bNAbs and provide strategies for generating bNAbs with improved efficacy.

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References

Forthal D, Gach J, Landucci G, Jez J, Strasser R, Kunert R . Fc-glycosylation influences Fcγ receptor binding and cell-mediated anti-HIV activity of monoclonal antibody 2G12. J Immunol. 2010; 185(11):6876-82. DOI: 10.4049/jimmunol.1002600. View

Horwitz J, Halper-Stromberg A, Mouquet H, Gitlin A, Tretiakova A, Eisenreich T . HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A. 2013; 110(41):16538-43. PMC: 3799352. DOI: 10.1073/pnas.1315295110. View

Ackerman M, Dugast A, McAndrew E, Tsoukas S, Licht A, Irvine D . Enhanced phagocytic activity of HIV-specific antibodies correlates with natural production of immunoglobulins with skewed affinity for FcγR2a and FcγR2b. J Virol. 2013; 87(10):5468-76. PMC: 3648186. DOI: 10.1128/JVI.03403-12. View

Barouch D, Whitney J, Moldt B, Klein F, Oliveira T, Liu J . Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature. 2013; 503(7475):224-8. PMC: 4017780. DOI: 10.1038/nature12744. View

Corti D, Voss J, Gamblin S, Codoni G, Macagno A, Jarrossay D . A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science. 2011; 333(6044):850-6. DOI: 10.1126/science.1205669. View

Baenziger S, Tussiwand R, Schlaepfer E, Mazzucchelli L, Heikenwalder M, Kurrer M . Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-gamma c-/- mice. Proc Natl Acad Sci U S A. 2006; 103(43):15951-6. PMC: 1635108. DOI: 10.1073/pnas.0604493103. View

Balazs A, Chen J, Hong C, Rao D, Yang L, Baltimore D . Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature. 2011; 481(7379):81-4. PMC: 3253190. DOI: 10.1038/nature10660. View

Casadevall A, Janda A . Immunoglobulin isotype influences affinity and specificity. Proc Natl Acad Sci U S A. 2012; 109(31):12272-3. PMC: 3412040. DOI: 10.1073/pnas.1209750109. View

Bournazos S, Chow S, Abboud N, Casadevall A, Ravetch J . Human IgG Fc domain engineering enhances antitoxin neutralizing antibody activity. J Clin Invest. 2014; 124(2):725-9. PMC: 3904629. DOI: 10.1172/JCI72676. View

10.

Scheid J, Mouquet H, Feldhahn N, Seaman M, Velinzon K, Pietzsch J . Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature. 2009; 458(7238):636-40. DOI: 10.1038/nature07930. View

11.

Abboud N, Chow S, Saylor C, Janda A, Ravetch J, Scharff M . A requirement for FcγR in antibody-mediated bacterial toxin neutralization. J Exp Med. 2010; 207(11):2395-405. PMC: 2964574. DOI: 10.1084/jem.20100995. View

12.

Pejchal R, Doores K, Walker L, Khayat R, Huang P, Wang S . A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield. Science. 2011; 334(6059):1097-103. PMC: 3280215. DOI: 10.1126/science.1213256. View

13.

Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti J, Lanzavecchia A . Development of a human adaptive immune system in cord blood cell-transplanted mice. Science. 2004; 304(5667):104-7. DOI: 10.1126/science.1093933. View

14.

Klein F, Gaebler C, Mouquet H, Sather D, Lehmann C, Scheid J . Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein. J Exp Med. 2012; 209(8):1469-79. PMC: 3409500. DOI: 10.1084/jem.20120423. View

15.

Wardemann H, Yurasov S, Schaefer A, Young J, Meffre E, Nussenzweig M . Predominant autoantibody production by early human B cell precursors. Science. 2003; 301(5638):1374-7. DOI: 10.1126/science.1086907. View

16.

DiLillo D, Tan G, Palese P, Ravetch J . Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo. Nat Med. 2014; 20(2):143-51. PMC: 3966466. DOI: 10.1038/nm.3443. View

17.

Pietzsch J, Gruell H, Bournazos S, Donovan B, Klein F, Diskin R . A mouse model for HIV-1 entry. Proc Natl Acad Sci U S A. 2012; 109(39):15859-64. PMC: 3465400. DOI: 10.1073/pnas.1213409109. View

18.

Walker L, Phogat S, Chan-Hui P, Wagner D, Phung P, Goss J . Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science. 2009; 326(5950):285-9. PMC: 3335270. DOI: 10.1126/science.1178746. View

19.

Nimmerjahn F, Ravetch J . Translating basic mechanisms of IgG effector activity into next generation cancer therapies. Cancer Immun. 2012; 12:13. PMC: 3380343. View

20.

Lazar G, Dang W, Karki S, Vafa O, Peng J, Hyun L . Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci U S A. 2006; 103(11):4005-10. PMC: 1389705. DOI: 10.1073/pnas.0508123103. View