Spotlights

In vivo protection by broadly neutralizing HIV antibodies Marit J. van Gils1 and Rogier W. Sanders1,2 1

Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, The Netherlands 2 Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA

Passive immunization studies, including a recent one by Pegu et al., have repeatedly shown that HIV-specific broadly neutralizing antibodies (bnAbs) protect rhesus macaques from HIV acquisition. In vitro neutralization potency and in vivo protection correlate very strongly, supporting the quest for an HIV vaccine that induces potent bnAbs. The recent discovery of a large number of very potent and broad anti-HIV neutralizing antibodies (bnAbs) has reinvigorated the battle against HIV. The HIV bnAb collection has increased from 4 known bnAbs before 2009 to >100 in 2014. These bnAbs are being exploited in three different ways. First, they quite literally serve as templates for the design of vaccines to be included in active vaccination strategies [1]. Second, they can be used for passive immunization, immunotherapy, and microbicides. Third, bnAbs can be employed in quasi-active immunization strategies, by delivering them through gene therapy approaches [2]. For all these purposes, knowledge on which bnAbs provide strong protection in vivo is of paramount importance. Pegu et al. [3] recently tested three bnAbs and an antibody against the CD4 receptor, 2D5, for their ability to protect against infection in rhesus macaques. The animals were challenged intrarectally with simian-human immunodeficiency virus (SHIV) strains SF162P3 or SHIV BaLP4 1 or 2 days after passive immunization with 2D5 (at 40 mg/kg) or bnAbs VRC01, PG9 or 10E8 (at 20, 5, or 0.3 mg/kg). The anti-CD4 receptor antibody 2D5 was included based on three considerations. First, all primary HIV strains should be sensitive to 2D5 because all viruses depend on CD4 for entry, while bnAbs do not inhibit all virus strains. In addition, another anti-CD4 antibody, ibalizumab, has been shown to work as an HIV therapeutic in humans [4]. Moreover, Pegu and colleagues showed that 2D5 inhibits the SHIV challenge virus about 30-fold more potently in vitro compared to bnAb VRC01, which targets the CD4 binding site on the HIV envelope glycoprotein. Despite these findings, 2D5 provided poor protection (two out of four animals were protected at an average serum concentration of 352 mg/ml at challenge), whereas the three HIV-1 bnAbs conferred a similar degree of protection at 100-fold lower serum concentrations. The probable Corresponding author: Sanders, R.W. ([email protected]) 0966-842X/ ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tim.2014.08.006

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drawback of 2D5 and other anti-CD4 antibodies is the need to block all CD4 receptors at the site of challenge to achieve protection, which probably requires higher serum concentrations compared to bnAbs, which target HIV directly. Passive immunization studies using bnAbs against HIV have been performed multiple times allowing for a more thorough analysis of the protective capacity of bnAbs. We considered four additional studies that used a similar approach (bnAb passively transferred 1–2 days prior to a single high dose mucosal challenge in rhesus macaques) and in which the bnAbs were titrated and/or used at a concentration in which partial protection was observed [5–8]. The serum concentrations that provided 50% protection in vivo and the concentrations that provided 50% neutralization inhibition in vitro, assessed in the standard TZM-bl reporter cell based neutralization assay, as reported in these studies, were plotted (Figure 1). We found a strong and highly significant correlation between in vitro and in vivo potency for the HIV specific bnAbs, that is, excluding 2D5 (Pearson r = 0.9722, P = 0.0002; Figure 1). Although the number of studies is relatively low this correlation plot provides valuable information. The correlation not only underlines the strong protective value of antibody-mediated virus neutralization, but also shows that the in vitro TZM-bl-based neutralization assay is highly predictive for protection in vivo. There was a 2log difference between the in vitro derived IC50s and the in vivo protection IC50s in the animal sera at time of challenge, but if one considers that antibody concentrations in the mucosa, the site of challenge, are usually 2-log lower compared to the concentrations in serum [8], the TZM-bl assay is surprisingly accurate in predicting protection from mucosal challenge. Remarkably, 10E8 was 35-fold less effective in vitro compared to VRC01 and PG9, but provided the strongest protection in vivo, being the one outlier in the correlation plot (excluding 2D5; Figure 1). It will be very interesting to further study this observation by Pegu and colleagues. Does 10E8 have specific characteristics or is the greater protection related to its epitope? BnAbs 4E10 and 2F5, which also target the membrane-proximal external region (MPER), have been shown to provide complete protection in passive immunization studies, but titration studies have not been performed and these studies could therefore not be included in the correlation. It will also be interesting to see protection data on some of the newer bnAbs that are now available.

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Trends in Microbiology October 2014, Vol. 22, No. 10

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2G12

In vitro neurtralizaon IC50 (µg/ml)

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Pearson r = 0.9722 P = 0.0002

PGT121 0.001

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In vivo protecon IC50 (µg/ml)

Key:

Pegu et al. [3] Parren et al. [5]

Hessell et al. [6] Mascola et al. [7]

Moldt et al. [8]

TRENDS in Microbiology

Figure 1. Correlation between in vitro neutralization and in vivo protection by HIVspecific bnAbs and 2D5. The data were obtained from multiple passive immunization studies in rhesus macaques, each study represented with a different symbol [3,5–8]. The half maximal inhibitory concentrations (IC50) against the challenge virus derived from in vitro neutralization assays using TZM-bl reporter cells are plotted on the y-axis. The average serum concentrations at the time of challenge at which half of the animals were protected as specified in the respective studies are plotted on the x-axis. The Pearson correlation coefficient was calculated for all bnAbs, that is, excluding 2D5 (in red). All bnAbs were tested as human IgG.

Whether bnAbs are the only type of antibodies that we should aim to generate or whether non-neutralizing antibodies (non-nAbs) could mediate protection through other effector functions is controversial (reviewed in [9]). NonnAbs were not included in the correlation plot (Figure 1) for the simple reason that an in vivo IC50 could not be established because non-nAbs have repeatedly failed to protect rhesus macaques from challenge, that is, by extrapolation they would be beyond the top-right corner of the correlation plot. However, the correlation between neutralization potency and in vivo protection does not mean that other effector functions do not contribute to the protection. In fact, effector functions have been shown to contribute to protection by bnAb b12 [10]. Nevertheless, the correlation does imply that if antibody effector functions play a role in protection, they are likely to do so in the context of neutralization only.

Passive immunization studies have revealed the potential of bnAbs for protection against HIV. They support the search for vaccine immunogens that elicit bnAbs, and also show the potential of bnAbs as therapeutics and microbicides in, for example, gel or ring formulations to deliver these antibodies at the site of exposure. Furthermore, the strong correlation of in vitro and in vivo potency indicates that it might be valuable to select bnAbs with the highest possible potency for in vivo use. Furthermore, bnAbs will not only need to be very potent, but also very broad to overcome the major obstacle of HIV diversity. This requires the continued search for new bnAbs with even greater potency and breadth. Acknowledgements MJG is a recipient of a research grant from the Aids Fonds Netherlands (#2012041) and RWS is a recipient of a Vidi fellowship from the Netherlands Organization for Scientific Research (NWO) and a Starting Investigator Grant from the European Research Council (ERC-StG-2011280829-SHEV).

References 1 van Gils, M.J. and Sanders, R.W. (2013) Broadly neutralizing antibodies against HIV-1: templates for a vaccine. Virology 435, 46–56 2 Berkhout, B. and Sanders, R.W. (2012) Gene therapy as a vaccine for HIV-1. Expert Opin. Biol. Ther. 12, 1315–1321 3 Pegu, A. et al. (2014) Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor. Sci. Transl. Med. 6, 243ra288 4 Fessel, W.J. et al. (2011) The efficacy of an anti-CD4 monoclonal antibody for HIV-1 treatment. Antiviral Res. 92, 484–487 5 Parren, P.W.H.I. et al. (2001) Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J. Virol. 75, 8240–8347 6 Hessell, A.J. et al. (2009) 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 7 Mascola, J.R. et al. (2000) 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 8 Moldt, B. et al. (2012) Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl. Acad. Sci. U.S.A. 109, 18921–18925 9 Lewis, G.K. et al. (2014) Epitope target structures of Fc-mediated effector function during HIV-1 acquisition. Curr. Opin. HIV AIDS 9, 263–270 10 Hessell, A.J. et al. (2007) Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104

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In vivo protection by broadly neutralizing HIV antibodies.

Passive immunization studies, including a recent one by Pegu et al., have repeatedly shown that HIV-specific broadly neutralizing antibodies (bnAbs) p...
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