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 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 3

Impact of partial NK cell depletion on the capacity of WT PGT121 to prevent cell-associated SHIVSF162P3 infection in macaques.

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Impact of partial NK cell depletion on the capacity of WT PGT121 to prev...
Depletion of macaque FcγRIIIa+ NK cells was performed using a murine anti-FcγRIIIa Ab (clone 3G8). Nine pigtail macaques were infused with anti-FcγRIIIa Ab (10 mg/kg), and two control animals were infused with saline. To assess the impact of partial NK cell depletion on the capacity of WT PGT121 to protect macaques from cell-associated SHIVSF162P3, one day after anti-FcγRIIIa Ab infusion, six of the nine NK cell–depleted animals were infused with 1 mg/kg WT PGT121 Ab (red; middle panels), and the other three were infused with 1 mg/kg isotype control Ab (black; left panels). As a positive control for protection, the 2 animals not depleted of NK cells were infused with WT PGT121 (green; right panels). All 11 macaques were challenged with cell-associated SHIVSF162P3 one hour following infusion with WT PGT121 or isotype control Ab. (A) Graphs depict the percentage of change in NK cell frequency up to 7 weeks after anti-FcγRIIIa Ab or saline infusion in all 11 animals. (B) Plasma viral loads and (C) cell-associated viral DNA of the animals in the weeks following SHIV challenge. Dotted black lines represent the sensitivity cutoffs for the assays used. (D) Seroconversion of the animals was assessed by screening plasma samples for the presence of anti-gp41 Abs. Graphs show the relative ODs for 1:1,000 dilution of plasma samples in the weeks after challenge. (E) The presence of infused WT PGT121 Abs in plasma (1:50 dilution) was assessed in the weeks after infusion. The rise in OD in the animals infused with isotype control Abs reflects seroconversion against HIV-1 gp120. (F) Weekly plasma concentrations of PGT121 are depicted in the graph for all animals infused with WT PGT121.