A number of monoclonal antibodies with broad neutralizing activity against HIV have been identified, and given names suggestive of characters from a futuristic George Lucas movie: 2F5, b12, 4E10 and 2G12. Despite their broad activity, macaque experiments in which the antibodies are infused prior to a virus challenge have shown that, in most cases, dauntingly high antibody titers are required to obtain sterilizing protection. Even if a means to induce similar antibodies via vaccination can be found, it is unlikely that such high antibody levels could be achieved, or sustained. But all may not be lost, because one study – conducted by John Mascola and colleagues many years ago - has hinted that the antibody 2G12 may be an exception to this rule. 2G12 is unique among the broadly neutralizing monoclonals because it targets the glycan structures on HIV’s envelope that usually function to shield the virus from antibody-mediated neutralization (a glycan is a large carbohydrate molecule composed of many smaller sugar molecules linked together).
Ann Hessell and colleagues from Dennis Burton’s research group decided to follow up on Mascola’s lead, and have now published their results in PLoS Pathogens. They note that the original experiment used the much-maligned X4-using SHIV89.6P as a challenge virus, and the goal of the new study was to test the concentration of 2G12 required to protect against SHIVSF162p3, which has an R5-using HIV envelope that is only mildly susceptible to 2G12 in vitro. Five macaques received an infusion of 2G12 prior to intravaginal challenge, while two controls received control antibody and two additional controls were untreated. All four controls became infected, whereas three out of five 2G12 recipients were completely protected from infection. One of the remaining macacques had a delay in the appearance of virus and diminished replication, while the other displayed a viral load peak and set point that was indistinguishable from the control group. The antibody titer required to achieve this outcome was 1:1, substantially lower than the level of around 1:100 previously reported for b12.
In discussing the results, Hessell et al evaluate several potential explanations for the apparent ability of 2G12 to protect at lower titers. Enhanced antibody trafficking to the site of exposure and superior antibody-dependent cellular cytotoxicity (ADCC) did not appear to account for the outcome. The researchers currently favor a role for the enhanced neutralization kinetics that are observed in vitro with 2G12 compared to other antibodies. They also note that 2G12 has the ability to block the interaction between gp120 and the dendritic cell molecule DC-SIGN, which could also contribute to superior protective efficacy. Additional experiments are needed to fully explore these possibilities, but as the authors state: “the results are provocative in suggesting the glycan shield as a potentially favorable HIV vaccine target.”
PLoS Pathog 5(5): e1000433. doi:10.1371/journal.ppat.1000433
Ann J. Hessell1, Eva G. Rakasz2, Pascal Poignard1,3, Lars Hangartner1,4, Gary Landucci5, Donald N. Forthal5, Wayne C. Koff3, David I. Watkins2, Dennis R. Burton1*
1 Department of Immunology and Microbial Science, and IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California, United States of America, 2 Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America, 3 International AIDS Vaccine Initiative (IAVI), New York, New York, United States of America, 4 Institute of Medical Virology, University of Zürich, Zürich, Switzerland, 5 Division of Infectious Diseases, Department of Medicine, UC Irvine School of Medicine, University of California Irvine, Irvine, California, United States of America
Developing an immunogen that elicits broadly neutralizing antibodies (bNAbs) is an elusive but important goal of HIV vaccine research, especially after the recent failure of the leading T cell based HIV vaccine in human efficacy trials. Even if such an immunogen can be developed, most animal model studies indicate that high serum neutralizing concentrations of bNAbs are required to provide significant benefit in typical protection experiments. One possible exception is provided by the anti-glycan bNAb 2G12, which has been reported to protect macaques against CXCR4-using SHIV challenge at relatively low serum neutralizing titers. Here, we investigated the ability of 2G12 administered intravenously (i.v.) to protect against vaginal challenge of rhesus macaques with the CCR5-using SHIVSF162P3. The results show that, at 2G12 serum neutralizing titers of the order of 1:1 (IC90), 3/5 antibody-treated animals were protected with sterilizing immunity, i.e. no detectable virus replication following challenge; one animal showed a delayed and lowered primary viremia and the other animal showed a course of infection similar to 4 control animals. This result contrasts strongly with the typically high titers observed for protection by other neutralizing antibodies, including the bNAb b12. We compared b12 and 2G12 for characteristics that might explain the differences in protective ability relative to neutralizing activity. We found no evidence to suggest that 2G12 transudation to the vaginal surface was significantly superior to b12. We also observed that the ability of 2G12 to inhibit virus replication in target cells through antibody-mediated effector cell activity in vitro was equivalent or inferior to b12. The results raise the possibility that some epitopes on HIV may be better vaccine targets than others and support targeting the glycan shield of the envelope.