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Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies
 
 
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Nature May 1 2014
 
Nicole A. Doria-Rose1*, Chaim A. Schramm2*, Jason Gorman1*, Penny L. Moore3,4,5*, Jinal N. Bhiman3,4, Brandon J. DeKosky6, Michael J. Ernandes1, Ivelin S. Georgiev1, Helen J. Kim7,8,9, Marie Pancera1, Ryan P. Staupe1, Han R. Altae-Tran1, Robert T. Bailer1, Ema T. Crooks10, Albert Cupo11, Aliaksandr Druz1, Nigel J. Garrett5, Kam H. Hoi12, Rui Kong1, Mark K. Louder1, Nancy S. Longo1, Krisha McKee1, Molati Nonyane3, Sijy O’Dell1, Ryan S. Roark1, Rebecca S. Rudicell1, Stephen D. Schmidt1, Daniel J. Sheward13, Cinque Soto1, Constantinos KurtWibmer3,4, Yongping Yang1, Zhenhai Zhang2, NISC Comparative Sequencing Program, James C. Mullikin14,15, James M. Binley10, Rogier W. Sanders16, Ian A. Wilson7,8,9,17, John P. Moore11, Andrew B.Ward7,8,9, George Georgiou6,12,18, CarolynWilliamson5,13, Salim S. Abdool Karim5,19, Lynn Morris3,4,5, Peter D. Kwong1, Lawrence Shapiro1,2 & John R. Mascola1
 
"This work also suggests that although an appropriate trimeric V1V2 construct may elicit neutralizing V1V2 antibodies, sequential immunogens that mirror viral evolution may be needed to drive the development of breadth. Overall, the precise delineation of the developmental pathway for the CAP256-VRC26 lineage should provide a basis for attempts to elicit broad V1V2-directed HIV-1-neutralizing antibodies.”
 
Editor’s Summary: A better understanding of how HIV-1-neutralizing antibodies are generated could be a useful contribution to the design of improved AIDS vaccines. John Mascola and colleagues have now elucidated the immunological pathway of an important category of HIV-1-neutralizing antibody — those that target the variable V1V2 region of the viral envelope. These antibodies are more frequently elicited than CD4-binding site antibodies in the early stages of HIV infection and feature modest affinity maturation, a process that favours mutations in antibody variable domains that enhance antigen binding.
 
Abstract
 
Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.
 
Vaccine Implications
 
The V1V2 region of HIV-1 is a common target of serum neutralizing antibodies6, 16, 17, 18. In the RV144 Thai vaccine trial, an increased level of binding antibodies to the V1V2 region was associated with a reduced risk of infection36 and viral sieve analysis showed immune pressure in the same region37. Although the vaccine in the RV144 trial did not elicit broadly neutralizing V1V2-directed antibodies similar to those described here and elsewhere19, 20, 21, a more effective vaccine would ideally elicit cross-reactive neutralizing antibodies1, 2, 3, 38. Previously described V1V2 neutralizing antibodies, and the CAP256-VRC26 lineage, all have long CDR H3 regions that are necessary to penetrate the glycan shield and engage a V1V2 epitope (Extended Data Table 1). An important unanswered question has been whether these long CDR H3s are fully formed by VDJ recombination, as has been seen in HIV-uninfected donors39, or emerge by insertions during the process of affinity maturation. We show here that the 35-residue CDR H3 of the CAP256-VRC26 UCA was produced during initial gene rearrangement and therefore existed at the level of the naive B cell receptor.
 
A potential rate-limiting developmental step in the CAP256-VRC26 lineage is the gene rearrangement that generated its UCA. By one estimate, human B cells with recombined antibody genes encoding long (≥24 amino acids, international immunogenetics database (IMGT)40 definition) or very long (≥28 amino acids) CDR H3s constitute ~3.5% and 0.4%, respectively, of naive B cells39. These long B cell receptors have been associated with autoreactivity, and are subject to both central and peripheral deletion, resulting in an even smaller population of IgG+ memory B cells39, 41. We therefore tested the UCA and all 12 CAP256-VRC26 cloned antibodies for autoreactivity42. The UCA and mature CAP256-VRC26 antibodies demonstrated little or no reactivity with Hep2 cells or with cardiolipin (Extended Data Fig. 6b, c). In addition, NGS of CAP256 peripheral B cells indicated that <0.4% of sequences had CDR H3s of ≥ 28 amino acids (Extended Data Fig. 6d) suggesting that this donor did not have an unusually high frequency of clonal lineages with long CDR H3 regions.
 
We also inferred the virological events leading to the stimulation and evolution of the CAP256-VRC26 lineage by the superinfecting virus. Similar to the CH103 CD4-binding site lineage in donor CH505 (ref. 15), the autologous virus in CAP256 showed extensive diversification before the development of breadth. Subsequent antibody-virus interactions appeared to drive somatic mutation and development of cross-reactive neutralization. Finally, the ontogeny of V1V2-directed neutralizing antibodies revealed by the CAP256-VRC26 lineage indicates that neutralization potency and breadth can be achieved without extraordinary levels of somatic hypermutation. Although some neutralizing antibodies appear to require years of maturation1, 3, 43, 44, we show that a V1V2-directed B cell lineage can acquire HIV-1 neutralization breadth within months rather than years. The critical event appears to be an uncommon gene rearrangement that produces a B-cell receptor with a protruding, tyrosine-sulphated, anionic CDR H3. Identifying features of antigens able to engage naive B cells with such CDR H3s is a critical step in design of vaccines targeting V1V2. Such antigens could be screened for binding to the UCA versions of neutralizing antibodies as an indicator of the ability to engage an appropriate naive B cell receptor. This work also suggests that although an appropriate trimeric V1V2 construct may elicit neutralizing V1V2 antibodies, sequential immunogens that mirror viral evolution may be needed to drive the development of breadth. Overall, the precise delineation of the developmental pathway for the CAP256-VRC26 lineage should provide a basis for attempts to elicit broad V1V2-directed HIV-1-neutralizing antibodies.

 
 
 
 
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