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.
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