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 2

Protection from cell-associated SHIVSF162P3 challenge by WT and LALA PGT121.

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Protection from cell-associated SHIVSF162P3 challenge by WT and LALA PGT...
Sixteen pigtail macaques were infused with 1 mg/kg isotype control Ab (n = 4; black; left panel), WT PGT121 (n = 6; red; middle panel), or LALA PGT121 (n = 6; blue; right panel) 1 hour before being i.v. challenged with cell-associated SHIVSF162P3. Graphs depict (A) plasma viral loads and (B) cell-associated viral DNA of the animals in the weeks after challenge. Dotted black lines in the graphs represent the sensitivity cutoffs. (C) Seroconversion against HIV-1 gp41 in the weeks after challenge with cell-associated SHIVSF162P3 was measured with an ELISA using a 1:1,000 dilution of plasma. (D) The presence of infused WT and LALA PGT121 Abs was assessed using an ELISA to detect gp120-specific Abs. Graphs depict the relative ODs for 1:50 dilutions of plasma samples in the weeks after infusion. The rise in OD in the animals infused with isotype control Ab reflects seroconversion against HIV-1 gp120. (E) Plasma concentrations of WT and LALA PGT121 before infusion and 30 minutes after infusion in all 16 animals. (F) Plasma PGT121 concentration over a 10-week period after infusion in the animals that received WT and LALA PGT121.