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
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
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
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]
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.
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]
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.
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]
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.
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.
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.
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.