Evolutionary Origins of a Potent Broadly-Neutralizing Antibody to HIV-1

Two recent papers published online at scienceexpress.org describe studies of antibodies claimed to interfere with infection of host cells by a wide range of HIV-1 strains.  These studies strongly suggest that the evolutionary potential of the humoral immune response may be necessary to combat the diversity of HIV-1 antigens that results from the extraordinary pace of HIV-1 evolution.

The first study, Wu et al. (Science. 2010 Jul 8), describes the methods used to identify antibodies with such “broad neutralization” profiles in human sera and the process then employed to produce functionally-comparable monoclonal antibodies.  The second paper, Zhou et al. (Science. 2010 Jul 8), describes the X-ray crystallographic structure of a complex of one antibody Fab fragment, derived from monoclonal antibody VRC01, with an HIV-1 gp120 core molecule in order to determine the structural features that contribute to the breadth and potency of neutralizing activity exhibited by this monoclonal antibody.  Two other monoclonal antibodies, VRC02 and VRC03 were also studied in the first paper (Wu et al.).  Of these two, VRC02 was the more similar to VRC01 in terms of both breadth and potency of neutralizing activity for HIV-1.

Both the immunochemical and crystallographic analyses revealed that VRC01 partially mimicked CD4 in binding to the CD4-binding site on HIV-1 gp120.  VRC02 also seemed, on the basis of the immunochemical studies, to be a partial mimic of CD4 in interacting with gp120.  This ability to mimic the natural host receptor undoubtedly contributes to the ability of VRC01 to neutralize 91% of a comprehensive panel of HIV-1 envelope protein pseudoviruses, including strains derived from all genetic subtypes of HIV-1.

The key finding, among many of interest to immunologists, virologists, and vaccinologists, from the point of view of those interested in evolutionary medicine is that VRC01, VRC02 and VRC03 all exhibit extensive somatic mutations, presumably contributing to affinity maturation.  VRC01 and VRC02 are variants of the same IgG1 clone.  Wu et al. note that an impressive 32% of the nucleotides encoding the heavy chain variable domain were divergent from the putative germline gene sequence and 17-19% of the nucleotides encoding the light chain variable domain were divergent from the corresponding germline gene sequence.  Furthermore, Zhou et al. perform a thorough analysis of the contributions of different somatic mutations to the affinity (for gp120) and neutralization activity of VRC01.  They are able to show that there is an impressive correlation (p<0.0001) between the number of such amino acid substitutions and the magnitudes of both the affinity for gp120 and the neutralization potency for HIV-1.  As the authors state, “Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies.”

In other words, extensive somatic antibody evolution may be necessary for the generation of potent and broadly neutralizing antibodies to HIV-1.  This conclusion is consistent with the results of previous studies that revealed higher than average extents of somatic mutation for the variable domains of antibodies with specificity for HIV-1 (Scheid et al.) and noted especially increased numbers of variable domain mutations for antibodies with broadly neutralizing activity for HIV-1 (Huang et al.).

References

Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, Zhou T, Schmidt SD, Wu L, Xu L, Longo NS, McKee K, O’Dell S, Louder MK, Wycuff DL, Feng Y, Nason M, Doria-Rose N, Connors M, Kwong PD, Roederer M, Wyatt RT, Nabel GJ, Mascola JR. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. 2010 Jul 8. [Epub ahead of print] PubMed PMID:20616233.

Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, Do Kwon Y, Scheid J, Shi W,Xu L, Yang Y, Zhu J, Nussenzweig MC, Sodroski J, Shapiro L, Nabel GJ, Mascola JR, Kwong PD. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science. 2010 Jul 8. [Epub ahead of print] PubMed PMID: 20616231.

Huang CC, Venturi M, Majeed S, Moore MJ, Phogat S, Zhang MY, Dimitrov DS, Hendrickson WA, Robinson J, Sodroski J, Wyatt R, Choe H, Farzan M, Kwong PD. Structural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2706-11. Epub 2004 Feb 23. PubMed PMID: 14981267; PubMed Central PMCID: PMC365685.

Scheid JF, Mouquet H, Feldhahn N, Seaman MS, Velinzon K, Pietzsch J, Ott RG, Anthony RM, Zebroski H, Hurley A, Phogat A, Chakrabarti B, Li Y, Connors M, Pereyra F, Walker BD, Wardemann H, Ho D, Wyatt RT, Mascola JR, Ravetch JV,Nussenzweig MC. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature. 2009 Apr 2;458(7238):636-40. Epub 2009 Mar 15. PubMed PMID: 19287373.