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Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch.

ABSTRACT: The high-mannose patch on HIV Env is a preferred target for broadly neutralizing antibodies (bnAbs), but to date, no vaccination regimen has elicited bnAbs against this region. Here, we present the development of a bnAb lineage targeting the high-mannose patch in an HIV-1 subtype-C-infected donor from sub-Saharan Africa. The Abs first acquired autologous neutralization, then gradually matured to achieve breadth. One Ab neutralized >47% of HIV-1 strains with only ?11% somatic hypermutation and no insertions or deletions. By sequencing autologous env, we determined key residues that triggered the lineage and participated in Ab-Env coevolution. Next-generation sequencing of the Ab repertoire showed an early expansive diversification of the lineage followed by independent maturation of individual limbs, several of them developing notable breadth and potency. Overall, the findings are encouraging from a vaccine standpoint and suggest immunization strategies mimicking the evolution of the entire high-mannose patch and promoting maturation of multiple diverse Ab pathways.

SUBMITTER: MacLeod DT

PROVIDER: S-EPMC5003182 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch.

MacLeod Daniel T DT Choi Nancy M NM Briney Bryan B Garces Fernando F Ver Lorena S LS Landais Elise E Murrell Ben B Wrin Terri T Kilembe William W Liang Chi-Hui CH Ramos Alejandra A Bian Chaoran B CB Wickramasinghe Lalinda L Kong Leopold L Eren Kemal K Wu Chung-Yi CY Wong Chi-Huey CH Kosakovsky Pond Sergei L SL Wilson Ian A IA Burton Dennis R DR Poignard Pascal P

Immunity 20160501 5

The high-mannose patch on HIV Env is a preferred target for broadly neutralizing antibodies (bnAbs), but to date, no vaccination regimen has elicited bnAbs against this region. Here, we present the development of a bnAb lineage targeting the high-mannose patch in an HIV-1 subtype-C-infected donor from sub-Saharan Africa. The Abs first acquired autologous neutralization, then gradually matured to achieve breadth. One Ab neutralized >47% of HIV-1 strains with only ∼11% somatic hypermutation and no ...[more]

PMID: 27192579

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Project description:BackgroundMajor modifications to the pharyngeal jaw apparatus are widely regarded as a recurring evolutionary key innovation that has enabled adaptive radiation in many species-rich clades of percomorph fishes. However one of the central predictions of this hypothesis, that the acquisition of a modified pharyngeal jaw apparatus will be positively correlated with explosive lineage diversification, has never been tested. We applied comparative methods to a new time-calibrated phylogeny of labrid fishes to test whether diversification rates shifted at two scales where major pharyngeal jaw innovations have evolved: across all of Labridae and within the subclade of parrotfishes.ResultsDiversification patterns within early labrids did not reflect rapid initial radiation. Much of modern labrid diversity stems from two recent rapid diversification events; one within julidine fishes and the other with the origin of the most species-rich clade of reef-associated parrotfishes. A secondary pharyngeal jaw innovation was correlated with rapid diversification within the parrotfishes. However diversification rate shifts within parrotfishes are more strongly correlated with the evolution of extreme dichromatism than with pharyngeal jaw modifications.ConclusionThe temporal lag between pharyngeal jaw modifications and changes in diversification rates casts doubt on the key innovation hypothesis as a simple explanation for much of the richness seen in labrids and scarines. Although the possession of a secondarily modified PJA was correlated with increased diversification rates, this pattern is better explained by the evolution of extreme dichromatism (and other social and behavioral characters relating to sexual selection) within Scarus and Chlorurus. The PJA-innovation hypothesis also fails to explain the most dominant aspect of labrid lineage diversification, the radiation of the julidines. We suggest that pharyngeal jaws might have played a more important role in enabling morphological evolution of the feeding apparatus in labrids and scarines rather than in accelerating lineage diversification.

Project description:UNLABELLED:The high-mannose patch of human immunodeficiency virus (HIV) envelope (Env) elicits broadly neutralizing antibodies (bnAbs) during natural infection relatively frequently, and consequently, this region has become a major target of vaccine design. However, it has also become clear that antibody recognition of the region is complex due, at least in part, to variability in neighboring loops and glycans critical to the epitopes. bnAbs against this region have some shared features and some distinguishing features that are crucial to understand in order to design optimal immunogens that can induce different classes of bnAbs against this region. Here, we compare two branches of a single antibody lineage, in which all members recognize the high-mannose patch. One branch (prototype bnAb PGT128) has a 6-amino-acid insertion in CDRH2 that is crucial for broad neutralization. Antibodies in this branch appear to favor a glycan site at N332 on gp120, and somatic hypermutation is required to accommodate the neighboring V1 loop glycans and glycan heterogeneity. The other branch (prototype bnAb PGT130) lacks the CDRH2 insertion. Antibodies in this branch are noticeably effective at neutralizing viruses with an alternate N334 glycan site but are less able to accommodate glycan heterogeneity. We identify a new somatic variant within this branch that is predominantly dependent on N334. The crystal structure of PGT130 offers insight into differences from PGT128. We conclude that different immunogens may be required to elicit bnAbs that have the optimal characteristics of the two branches of the lineage described. IMPORTANCE:Development of an HIV vaccine is of vital importance for prevention of new infections, and it is thought that elicitation of HIV bnAbs will be an important component of an effective vaccine. Increasingly, bnAbs that bind to the cluster of high-mannose glycans on the HIV envelope glycoprotein, gp120, are being highlighted as important templates for vaccine design. In particular, bnAbs from IAVI donor 36 (PGT125 to PGT131) have been shown to be extremely broad and potent. Combination of these bnAbs enhanced neutralization breadth considerably, suggesting that an optimal immunogen should elicit several antibodies from this family. Here we study the evolution of this antibody family to inform immunogen design. We identify two classes of bnAbs that differ in their recognition of the high-mannose patch and show that different immunogens may be required to elicit these different classes.

Project description:Mannose-binding lectin (MBL) is a key soluble pathogen recognition protein of the innate immune system that binds specific mannose-containing glycans on the surfaces of microbial agents and initiates complement activation via the lectin pathway. Prior studies showed that MBL-dependent activation of the complement cascade neutralized insect cell-derived West Nile virus (WNV) in cell culture and restricted pathogenesis in mice. Here, we investigated the antiviral activity of MBL in infection by dengue virus (DENV), a related flavivirus. Using a panel of naïve sera from mouse strains deficient in different complement components, we showed that inhibition of infection by insect cell- and mammalian cell-derived DENV was primarily dependent on the lectin pathway. Human MBL also bound to DENV and neutralized infection of all four DENV serotypes through complement activation-dependent and -independent pathways. Experiments with human serum from naïve individuals with inherent variation in the levels of MBL in blood showed a direct correlation between the concentration of MBL and neutralization of DENV; samples with high levels of MBL in blood neutralized DENV more efficiently than those with lower levels. Our studies suggest that allelic variation of MBL in humans may impact complement-dependent control of DENV pathogenesis. IMPORTANCE Dengue virus (DENV) is a mosquito-transmitted virus that causes a spectrum of clinical disease in humans ranging from subclinical infection to dengue hemorrhagic fever and dengue shock syndrome. Four serotypes of DENV exist, and severe illness is usually associated with secondary infection by a different serotype. Here, we show that mannose-binding lectin (MBL), a pattern recognition molecule that initiates the lectin pathway of complement activation, neutralized infection of all four DENV serotypes through complement activation-dependent and -independent pathways. Moreover, we observed a direct correlation with the concentration of MBL in human serum and neutralization of DENV infection. Our studies suggest that common genetic polymorphisms that result in disparate levels and function of MBL in humans may impact DENV infection, pathogenesis, and disease severity.

Dataset Information

Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch.

Publications

Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch.

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