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Coevolution of HIV-1 and Broadly Neutralizing Antibodies

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Coevolution of HIV-1 and Broadly Neutralizing Antibodies HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Curr Opin Manuscript Author HIV AIDS. Author Manuscript Author manuscript; available in PMC 2020 October 13. Published in final edited form as: Curr Opin HIV AIDS. 2019 July ; 14(4): 286–293. doi:10.1097/COH.0000000000000550. Coevolution of HIV-1 and broadly neutralizing antibodies Nicole A. Doria-Rosea, Elise Landaisb aVaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland bIAVI Neutralizing Antibody Center, Immunology and Microbiology Department, The Scripps Research Institute, La Jolla, California, USA Abstract Purpose of review—Exploring the molecular details of the coevolution of HIV-1 Envelope with broadly neutralizing antibodies (bNAbs) in infected individuals over time provides insights for vaccine design. Since mid-2017, the number of individuals described in such publications has nearly tripled. New publications have extended such studies to new epitopes on Env and provided more detail on previously known sites. Recent findings—Studies of two donors – one of them an infant, the other with three lineages targeting the same site – has deepened our understanding of V3-glycan-directed lineages. A V2- apex-directed lineage showed remarkable similarity to a lineage from a previously described donor, revealing general principles for this class of bNAbs. Understanding development of CD4 binding site antibodies has been enriched by the study of a VRC01-class lineage. Finally, the membrane-proximal external region is a new addition to the set of epitopes studied in this manner, with early development events explored in a study of three lineages from a single donor. Summary—These studies provide templates for immunogen design to elicit bNAbs against a widened set of epitopes, generating new directions in the quest for an HIV vaccine. Keywords evolution; HIV; neutralizing antibody; next-generation sequencing INTRODUCTION The last decade was marked by the groundbreaking discovery of HIV-1 broadly neutralizing antibodies (bNAbs) with exceptional potency and breadth, neutralizing most circulating HIV-1 strains [1]. Their effectiveness at preventing infection and reducing viral load in passive transfer animal models renewed hope that an HIV-1 vaccine might be achievable [2]. However, unusual features exhibited by many bNAbs including long heavy chain complementarity determining region 3s (CDRH3s), high levels of somatic hypermutation Correspondence to Nicole A. Doria-Rose, PhD, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 40 Convent Drive, Bethesda, MD 20892, USA. Tel: +1 (301) 761-5279; [email protected]. Conflicts of interest There are no conflicts of interest. Doria-Rose and Landais Page 2 (SHM), insertion–deletion events (indels), and auto- or poly-reactivity, suggested long and Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author complex maturation pathways not easily reproducible by vaccination. These observations, along with the failure of traditional vaccine strategies, led the field to consider vaccine regimens based on detailed studies of bNAb ontogeny during infection [3]. This approach relies on the identification and characterization of antibody precursors (unmutated common ancestors or UCAs) and key intermediates, as well as the relevant viral Envelope (Env) variants eliciting and driving the maturation of bNAb lineages. Enabled by technologies include rapid mAb isolation from single B-cells, next-generation sequencing (NGS) of the B-cell repertoire and viral Env populations, and functional and structural analyses of antibody/Env interactions, such studies reveal a roadmap for vaccine design. Given the limited number of donors for whom samples exist allowing full Env/bNAb coevolution studies – the small fraction of individuals that develop bNAbs, the small number of longitudinal cohorts of untreated individuals, and the lack of new cohorts with the advent of early antiretroviral treatment – many studies lack one or more of these elements. Some use NGS samples from chronic-infection timepoints, or cloned antibodies only, to reconstruct precursors known as germline revertants [4-10]. Such constructs generally use mature CDRH3s and are therefore less relevant than true UCAs, yet some have provided important insights later validated by coevolution studies. This review focuses on studies of donors with longitudinal samples from the time of infection, in which both Envs and bNAb lineages were evaluated at a richly detailed molecular level. INSIGHTS INTO SPECIFIC EPITOPES The Env/bNAb coevolution studies reported to date and reviewed here describe the development of bNAb lineages targeting four epitope regions [11-14] (Fig. 1 and Table 1): the CD4-binding site (CD4bs) (CH103 and CH235 from donor CH505; PCIN63 from donor PC63), the V2-apex (CAP256-VRC26 from donor CAP256; PCT64 from donor PC64), the V3-glycan high-mannose patch (PCDN from donor PC76; DH270 from donor CH848; BF520.1 from infant donor BF520; PCIN39 from donor PC39), and the membrane-proximal external region (MPER) (VRC42, VRC43, and VRC46 from donor RV217-40512). CD4bS BNAbs to the CD4bs typically develop after more than 5 years of infection and are typically highly somatically hypermutated – often 30% or more [15] – suggesting a long and complex maturation process. Two types of CD4bs bNAbs have been identified: CD4bs bNAbs classically using CDRH3 for epitope recognition; and CD4bs bNAbs with heavy chain variable gene (VH)-restricted recognition, including the VRC01 multidonor class, mostly relying on V-gene encoded structural features mimicking CD4 [15,16]. Immunogens eOD- GT8 and 426c, designed to bind VRC01-class germline revertants [5,6] have already succeeded in eliciting VRC01-like antibody responses in transgenic mouse models [17-21]. However, defining boosting immunogens capable of driving lineage maturation toward neutralization breadth remains a challenge. A major roadblock is the acquisition of mutations in the light-chain complementarity determining region 1 (CDRL1) loop to avoid structural clashes with Env V5-loops and Loop D glycans [22]. Curr Opin HIV AIDS. Author manuscript; available in PMC 2020 October 13. Doria-Rose and Landais Page 3 The detailed development of CD4bs bNAbs was first described in a series of articles Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author demonstrating how two CD4bs bNAb lineages, CH103 (CDRH3 binder) and CH235 (VH1-46 gene restriction) cooperated in donor CH505 by restricting the possibilities of escape through distinct binding modes [23-25]. Each lineage induced an intense epitope diversification supporting the maturation of the other lineage. These groundbreaking studies were the first to trace Env/bNAb coevolution, and several features observed in the most recent studies were first noted for CH505. The genetic and structural similarities shared by VRC01-class bNAbs, along with their breadth and potency, make them a particularly attractive target [15]. The first coevolution study of a VRC01-class bNAb, PCIN63 [26■■], showed that unlike most VRC01-class bNAbs, the PCIN63 antibodies achieved equivalent neutralization with only 13% SHM, mostly focused on residues previously shown to be minimally required for VRC01 neutralization. Although the heavy chain UCA sequence was determined with near certainty, several unmutated light chain sequences could correspond to a putative UCA; only two of the reconstructed UCA candidates bound with low affinity to eOD-GT8. One Env variant lacking both the N276-glycan and V5-glycans isolated ~6 months before the first detection of the lineage appeared to be the eliciting variant. However, in contrast to most VRC01-class bNAbs, PCIN63 antibodies appear to be partially dependent on the presence of the N276- glycan. These data suggest a shorter pathway more compatible with vaccination. V2-apex The V2-apex bNAbs are characterized by long CDRH3s (24–39 amino acids) which are typically very rare in the human repertoire. Nevertheless, such bNAbs are detected in ~10% of broad neutralizers [27] and include some of the most potent bNAbs isolated to date [28,29]. These bNAbs target V2 loop-strand C peptide positively charged residues and typically require binding to the N160 and/or N156-glycans as well as accommodation to V1- loop glycans. Located at the trimer apex, their epitopes often span more than one protomer such that these antibodies prefer (PG9, VRC38, and CH01) or require (PGT145 and CAP256) intact trimer for binding. The initial study of V2-apex bNAb development described one of the most potently neutralizing bNAb lineages, CAP256-VRC26 [11,28,30]. The CAP256 donor was infected and superinfected by clade C viruses but the Env variants implicated in the elicitation and development of breadth derived entirely from the superinfecting virus [30,31■]. Viral diversity – overall and at the epitope – coincided with diversification in the antibody lineage and the appearance of breadth. Early escape mutations at key epitope residues 166 and 169 were tolerated by the broader lineage members, suggesting a mechanism for acquisition of breadth [30,31■]. Additional studies suggested a role for sialic-acid binding [32] and Env escape fitness cost [33] in supporting CAP256-VRC26 lineage maturation, although the association with breadth was unclear. The study of PCT64 bNAb lineage development [34■■,35■■] confirmed the
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