In recent years, new technologies have facilitated the
discovery of an expanding number of antibodies capable of neutralizing a broad
array of primary HIV isolates from different clades. As covered previously on the blog, these broadly neutralizing antibodies (bNAbs) have
been fished from the plasma of individuals with chronic HIV infection and, in
most cases, do not seem to be present at titers sufficient to control viral
load or retard disease progression; however, there are reasons to hope that if
similar antibodies could be induced by vaccination, they could rebuff the
relatively small amount of HIV that enters the body during a typical exposure.
A common feature of the bNAbs is that the B cells that
produce them have gone through many more rounds of somatic hypermutation than is typically seen in other infections. Somatic
hypermutation is the process by which the B cell’s antibody-producing genetic
code is progressively revised, potentially leading to an increase in the
affinity of the antibody for its target. The genetic code that the B cell
starts out with is known as the germline sequence (or unmutated common ancestor
or UCA), and it is typically altered by around 5–15% to produce antibodies
against common infections, whereas the range is 19–46% for the bNAbs
against HIV. This requirement for extensive mutation appears to be connected to
the unusual shapes the bNAbs must form to access the hard-to-reach conserved
areas of the HIV envelope (Env) protein, which are cloaked by highly variable decoy
targets.
In a paper published yesterday in the journal Nature,
researchers report tracking the development of a bNAb response in an
HIV-positive person, in parallel with documenting the evolution of the
infecting virus. The study shows that the Env protein of the virus at the time
of acute infection was able to activate B cells with a germline sequence that
then underwent progressive somatic hypermation, leading to the appearance of antibodies
with increasing breadth of activity against a panel of HIV isolates during weeks
41-92 of follow-up. Driving the B-cell somatic hypermutation process was stimulation of the cells by the
ever-mutating Env protein of the infecting virus, which evolved and became more
diverse over time (as is typical in untreated HIV infection). The researchers
were able to demonstrate that the diversification of the Env protein preceded
the appearance of bNAb response.
This brief description greatly simplifies a complicated
study, but the implication for HIV vaccines is that it may be possible
to try and mimic the process observed in this individual using sequential
immunization with vaccines containing similar Env proteins of increasing
diversity. The hope would be to initially activate the right B cell, and then
push it along a somatic hyermutation pathway that would lead to the eventual
generation of bNAbs.
Whether this is actually feasible, however, remains to be
seen. Because there is a degree of randomness involved, it may be that
the relatively rare individuals who develop bNAbs represent instances of B cells essentially hitting the somatic hypermutation jackpot as a result of
repeated stimulation. But, given the implications for HIV vaccines if bNAbs
could be successfully induced with some reliability, it will be essential to
fully pursue the idea. In addition to the Nature paper, several other recently
published studies report data relevant to this pursuit (abstracts and links
also appended below).
Nature (2013) doi:10.1038/nature12053
Co-evolution of a broadly neutralizing HIV-1 antibody and
founder virus
Hua-Xin Liao, Rebecca Lynch, Tongqing Zhou, Feng Gao, S.
Munir Alam, Scott D. Boyd, Andrew Z. Fire, Krishna M. Roskin, Chaim A. Schramm,
Zhenhai Zhang, Jiang Zhu, Lawrence Shapiro, NISC Comparative Sequencing
Program, James C. Mullikin, S. Gnanakaran, Peter Hraber, Kevin Wiehe, Garnett
Kelsoe, Guang Yang, Shi-Mao Xia, David C. Montefiori, Robert Parks, Krissey E.
Lloyd, Richard M. Scearce, Kelly A. Soderberg, Myron Cohen, Gift Kamanga, Mark
K. Louder, Lillian M. Tran, Yue Chen, Fangping Cai, Sheri Chen, Stephanie
Moquin, Xiulian Du, M. Gordon Joyce, Sanjay Srivatsan, Baoshan Zhang, Anqi
Zheng, George M. Shaw, Beatrice H. Hahn, Thomas B. Kepler, Bette T. M. Korber,
Peter D. Kwong, John R. Mascola & Barton F. Haynes
ABSTRACT
Current human immunodeficiency virus-1 (HIV-1) vaccines
elicit strain-specific neutralizing antibodies. However, cross-reactive
neutralizing antibodies arise in approximately 20% of HIV-1-infected
individuals, and details of their generation could provide a blueprint for
effective vaccination. Here we report the isolation, evolution and structure of
a broadly neutralizing antibody from an African donor followed from the time of
infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1
isolates, and its co-crystal structure with the HIV-1 envelope protein gp120
revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and
antibody gene sequencing revealed concomitant virus evolution and antibody
maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly
bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of
antibody neutralization breadth was preceded by extensive viral diversification
in and near the CH103 epitope. These data determine the viral and antibody
evolution leading to induction of a lineage of HIV-1 broadly neutralizing
antibodies, and provide insights into strategies to elicit similar antibodies
by vaccination.
Nature (2013) doi:10.1038/nature12091
HIV: Roadmaps to a vaccine
Hugo Mouquet and Michel C. Nussenzweig
More than 30 years since the AIDS pandemic began, there is
still no effective vaccine. But analysis of broadly acting, potent human
antibodies obtained from single cells suggests a rational approach to vaccine
development.
Science. 2013 Mar 29. [Epub ahead of print]
Rational HIV Immunogen Design to Target Specific Germline B
Cell Receptors.
Jardine J, Julien JP, Menis S, Ota T, Kalyuzhniy O, McGuire
A, Sok D, Huang PS, Macpherson S, Jones M, Nieusma T, Mathison J, Baker D, Ward
AB, Burton DR, Stamatatos L, Nemazee D, Wilson IA, Schief WR.
Department of Immunology and Microbial Science, The Scripps
Research Institute, La Jolla, CA 92037, USA.
ABSTRACT
Vaccine development to induce broadly neutralizing
antibodies (bNAbs) against HIV-1 is a global health priority. Potent VRC01-class
bNAbs against the CD4 binding site of HIV gp120 have been isolated from
HIV-1-infected individuals; however, such bNAbs have not been induced by
vaccination. Wild-type gp120 proteins lack detectable affinity for predicted
germline precursors of VRC01-class bNAbs, making them poor immunogens to prime
a VRC01-class response. We employed computation-guided, in vitro screening to
engineer a germline-targeting gp120 outer domain immunogen that binds to
multiple VRC01-class bNAbs and germline precursors and elucidated
germline-binding crystallographically. When multimerized on nanoparticles, this
immunogen (eOD-GT6) activates germline and mature VRC01-class B cells. Thus,
eOD-GT6 nanoparticles have promise as a vaccine prime. In principle,
germline-targeting strategies could be applied to other epitopes and pathogens.
J Exp Med. 2013 Mar 27. [Epub ahead of print]
Engineering HIV envelope protein to activate germline B cell
receptors of broadly neutralizing anti-CD4 binding site antibodies.
McGuire AT, Hoot S, Dreyer AM, Lippy A, Stuart A, Cohen KW,
Jardine J, Menis S, Scheid JF, West AP, Schief WR, Stamatatos L.
Seattle Biomedical Research Institute, Seattle, WA 98109.
ABSTRACT
Broadly neutralizing antibodies (bnAbs) against HIV are
believed to be a critical component of the protective responses elicited by an
effective HIV vaccine. Neutralizing antibodies against the evolutionarily
conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are
capable of inhibiting infection of diverse HIV strains, and have been isolated
from HIV-infected individuals. Despite the presence of anti-CD4-BS broadly
neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so
far failed to elicit such antibodies. Here, we show that Env immunogens fail to
engage the germline-reverted forms of known bnAbs that target the CD4-BS.
However, we found that the elimination of a conserved glycosylation site
located in Loop D and two glycosylation sites located in variable region 5 of
Env allows Env-binding to, and activation of, B cells expressing the
germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and
NIH45-46. Our results offer a possible explanation as to why Env immunogens
have been ineffective in stimulating the production of such bNAbs. Importantly,
they provide key information as to how such immunogens can be engineered to
initiate the process of antibody-affinity maturation against one of the most conserved
Env regions.
Proc Natl Acad Sci U S A. 2013 Mar 22. [Epub ahead of print]
Structural basis for HIV-1 gp120 recognition by a germ-line
version of a broadly neutralizing antibody. (free full text)
Scharf L, West AP Jr, Gao H, Lee T, Scheid JF, Nussenzweig
MC, Bjorkman PJ, Diskin R.
Division of Biology, California Institute of Technology,
Pasadena, CA 91125.
ABSTRACT
Efforts to design an effective antibody-based vaccine
against HIV-1 would benefit from understanding how germ-line B-cell receptors
(BCRs) recognize the HIV-1 gp120/gp41 envelope spike. Potent VRC01-like (PVL)
HIV-1 antibodies derived from the VH1-2*02 germ-line allele target the
conserved CD4 binding site on gp120. A bottleneck for design of immunogens
capable of eliciting PVL antibodies is that VH1-2*02 germ-line BCR interactions
with gp120 are uncharacterized. Here, we report the structure of a VH1-2*02
germ-line antibody alone and a germ-line heavy-chain/mature light-chain chimeric
antibody complexed with HIV-1 gp120. VH1-2*02 residues make extensive contacts
with the gp120 outer domain, including all PVL signature and CD4 mimicry
interactions, but not critical CDRH3 contacts with the gp120 inner domain and
bridging sheet that are responsible for the improved potency of NIH45-46 over
closely related clonal variants, such as VRC01. Our results provide insight
into initial recognition of HIV-1 by VH1-2*02 germ-line BCRs and may facilitate
the design of immunogens tailored to engage and stimulate broad and potent CD4
binding site antibodies.
Cell. 2013 Mar 28;153(1):126-38. doi:
10.1016/j.cell.2013.03.018.
Somatic Mutations of the Immunoglobulin Framework Are
Generally Required for Broad and Potent HIV-1 Neutralization.
Klein F, Diskin R, Scheid JF, Gaebler C, Mouquet H, Georgiev
IS, Pancera M, Zhou T, Incesu RB, Fu BZ, Gnanapragasam PN, Oliveira TY, Seaman
MS, Kwong PD, Bjorkman PJ, Nussenzweig MC.
Laboratory of Molecular Immunology, The Rockefeller
University, New York, NY 10065, USA.
ABSTRACT
Broadly neutralizing antibodies (bNAbs) to HIV-1 can prevent
infection and are therefore of great importance for HIV-1 vaccine design.
Notably, bNAbs are highly somatically mutated and generated by a fraction of
HIV-1-infected individuals several years after infection. Antibodies typically
accumulate mutations in the complementarity determining region (CDR) loops,
which usually contact the antigen. The CDR loops are scaffolded by canonical
framework regions (FWRs) that are both resistant to and less tolerant of
mutations. Here, we report that in contrast to most antibodies, including those
with limited HIV-1 neutralizing activity, most bNAbs require somatic mutations
in their FWRs. Structural and functional analyses reveal that somatic mutations
in FWR residues enhance breadth and potency by providing increased flexibility
and/or direct antigen contact. Thus, in bNAbs, FWRs play an essential role
beyond scaffolding the CDR loops and their unusual contribution to potency and
breadth should be considered in HIV-1 vaccine design.
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