Fc-dependent functions are redundant to efficacy of anti-HIV antibody PGT121 in macaques
Matthew S. Parsons, … , Miles P. Davenport, Stephen J. Kent
Matthew S. Parsons, … , Miles P. Davenport, Stephen J. Kent
Published January 2, 2019; First published November 26, 2018
Citation Information: J Clin Invest. 2019;129(1):182-191. https://doi.org/10.1172/JCI122466.
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Research Article AIDS/HIV Immunology

Fc-dependent functions are redundant to efficacy of anti-HIV antibody PGT121 in macaques

Abstract

A considerable body of evidence suggests that Fc-dependent functions improve the capacity of broadly neutralizing antibodies (BnAbs) to protect against and control HIV-1 infection. This phenomenon, however, has not been formally tested in robust cell-associated macaque simian-human immunodeficiency virus (SHIV) models with newer-generation BnAbs. We studied both the WT BnAb PGT121 and a LALA mutant of PGT121 (which has impaired Fc-dependent functions) for their ability to protect pigtail macaques from an i.v. high-dose cell-associated SHIVSF162P3 challenge. We found that both WT and LALA PGT121 completely protected all 12 macaques studied. Further, partial depletion of NK cells, key mediators of Fc-dependent functions, did not abrogate the protective efficacy of PGT121 in 6 macaques. Additionally, in animals with established SHIVSF162P3 infection, SHIV viremia levels were equally rapidly reduced by LALA and WT PGT121. Our studies suggest that the potent neutralizing capacity of PGT121 renders the Fc-dependent functions of the Ab at least partially redundant. These findings have implications for Ab-mediated protection from and control of HIV-1 infection.

Authors

Matthew S. Parsons, Wen Shi Lee, Anne B. Kristensen, Thakshila Amarasena, Georges Khoury, Adam K. Wheatley, Arnold Reynaldi, Bruce D. Wines, P. Mark Hogarth, Miles P. Davenport, Stephen J. Kent

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Figure 1

Capacity of WT and LALA PGT121 to engage FcγRIIIa and mediate Fc-dependent functions in vitro.

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Capacity of WT and LALA PGT121 to engage FcγRIIIa and mediate Fc-depende...
(A) Graph depicts the relative ability of WT and LALA versions of PGT121 and b12 to engage pigtail macaque FcγRIIIa, as determined by ELISA. (B) Ab-dependent activation of macaque (n = 16) NK cells through recognition of antigen-bound WT or LALA PGT121. NK cell activation was measured by flow cytometry as the percentage of NK cells expressing the degranulation marker CD107a after a 5-hour incubation in the presence or absence of WT or LALA PGT121 (20 μg/ml) bound to HIV-1SF162 gp140 protein. (C) The capacity of WT and LALA PGT121 to facilitate ADCC was assessed using a flow cytometry–based infected cell elimination assay. ADCC against HIV-1LAV–infected 8E5/LAV cells by macaque PBMCs (n = 16) was measured in the presence of human IVIG (lacking anti–HIV-1 Abs), WT, or LALA PGT121 (20 μg/ml). Data were compared using a Friedman test followed by Dunn’s post hoc tests. P < 0.05 was considered statistically significant. Box-and-whisker plots display the median (horizontal line within the box), IQR (top and bottom edges of the box), and range (horizontal lines on whiskers) of each condition.