co evolution of a broadly neutralizing hiv 1 antibody and founder virus pdf

Co evolution of a broadly neutralizing hiv 1 antibody and founder virus pdf

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Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus

A broadly neutralizing macaque monoclonal antibody against the HIV-1 V3-Glycan patch

The Neutralizing Antibody Response to the HIV-1 Env Protein

HIV Vaccine Research: The Challenge and the Way Forward

Strain-specific neutralizing antibodies develop in all human immunodeficiency virus type 1 HIV-1 -infected individuals.

Author s : Penny L. DOI : Background: A vaccine able to elicit broadly neutralizing antibodies capable of blocking infection by global viruses has not been achieved, and remains a key public health challenge. Objective: During infection, a robust strain-specific neutralizing response develops in most people, but only a subset of infected people develop broadly neutralizing antibodies.

Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus

Metrics details. Broadly neutralizing antibodies bNAbs , able to prevent viral entry by diverse global viruses, are a major focus of HIV vaccine design, with data from animal studies confirming their ability to prevent HIV infection.

However, traditional vaccine approaches have failed to elicit these types of antibodies. During chronic HIV infection, a subset of individuals develops bNAbs, some of which are extremely broad and potent. The features, targets and developmental pathways of bNAbs from their precursors have been defined through extraordinarily detailed within-donor studies.

These have enabled the identification of epitope-specific commonalities in bNAb precursors, their intermediates and Env escape patterns, providing a template for vaccine discovery. The unusual features of bNAbs, such as high levels of somatic hypermutation, and precursors with unusually short or long antigen-binding loops, present significant challenges in vaccine design.

However, the use of new technologies has led to the isolation of more than bNAbs, including some with genetic profiles more representative of the normal immunoglobulin repertoire, suggesting alternate and shorter pathways to breadth.

The insights from these studies have been harnessed for the development of optimized immunogens, novel vaccine regimens and improved delivery schedules, which are providing encouraging data that an HIV vaccine may soon be a realistic possibility. The design of a preventative HIV vaccine is one of the major current public health challenges. Despite the global successes of antiretroviral therapy, rates of new infections, especially in sub-Saharan Africa, show little sign of abating, and indeed in some areas as many as half of young women are HIV infected [ 1 ].

Despite a massive effort, no vaccine has thus far been able to elicit protective neutralizing antibodies. However, extraordinary progress has been made in understanding the immune response to HIV infection and in defining viral targets.

We now have a detailed understanding of the obstacles we face in eliciting protective antibodies, and this has enabled the design of new immunogens and vaccine strategies, many of which are based on studies of infection, and will enter clinical trials in the next months and years.

The major focus for HIV vaccine design is the elicitation of broadly neutralizing antibodies bNAbs , capable of preventing entry by diverse viruses by binding to conserved regions on the HIV envelope glycoprotein trimer, which is the sole entry complex for HIV. This focus on bNAbs is based on the narrow window between HIV infection and the establishment of latency, ideally requiring antibodies to block viral entry.

In contrast, although CTL responses have been shown to contribute to HIV control and slow disease progression [ 2 , 3 , 4 ], these responses are unlikely to protect from infection. Compelling evidence from animal studies shows that passive administration of bNAbs into non-human primates provides complete protection from mucosal challenge [ 5 ]. Non-broadly neutralizing antibodies, though capable of Fc effector functions such as antibody dependent cellular cytotoxicity, do not protect as well [ 6 , 7 , 8 ], further supporting a focus on neutralization.

These findings, which are currently being further tested in the first human clinical trials of bNAbs as prophylaxis, suggest that such antibodies, if elicited at sufficiently high titers by vaccination, would be protective.

However, eliciting such bNAbs is fraught with difficulties. The Env protein, which consists of three gp and three gp41 molecules, has formidable defenses that hinder bNAb development [ 9 ]. The trimer is conformationally dynamic, extremely sequence variable, particularly in the antibody accessible regions of the envelope, sparsely arrayed on viral particles [ 10 ] and massively glycosylated, with glycans so tightly packed that they occlude much of the underlying protein surface [ 11 ].

Immunological decoys in the form of non-functional envelope proteins such as gp41 stumps, monomeric forms of gp and non-native protomers such as uncleaved trimers that expose non-neutralizing epitopes normally buried in the trimer, add a further layer of complexity [ 12 ].

Despite these barriers, infected individuals mount a vigorous neutralizing response though these initial responses are almost entirely strain-specific, targeting highly variable regions of Env [ 13 , 14 , 15 , 16 , 17 ]. Extensive functional binding and neutralization and structural electron microscope, crystallography and glycobiology characterization of these antibodies, and their precursors, has shed light on the complex molecular mechanisms by which they achieved breadth.

Our increased understanding of the unusual features of bNAbs, and the failure of traditional vaccine strategies, have led the field to consider next-generation vaccine regimens which are based on the deep understanding of the host and viral factors leading the development of such antibodies. In this review, we provide a summary of these studies, and define some gaps that need to be addressed to develop an effective HIV vaccine.

One of the major reasons to study elite neutralizers has been the opportunity to define the targets of bNAbs on the HIV envelope. Epitope mapping was initially conducted using polyclonal plasma [ 19 , 20 , 21 ] Fig. These data show that much of the Env can be targeted by bNAbs, with six distinct target regions identified on the HIV-1 envelope, almost all of which involve glycans.

These are the V2-glycan site, the V3-glycan super-epitope, the membrane proximal external region MPER , the CD4 binding site CD4bs and the gpgp41 interface, including the fusion peptide [ 22 , 23 , 24 ]. However, plasma mapping studies suggest that further epitopes or sub-epitopes may remain to be identified. Novel approaches which do not rely on our knowledge of existing epitopes, such as the recently described use of cryo-electron microscopy of antibody-trimer complexes to map the specificities of plasma responses [ 26 ], will be informative in defining additional targets and designing more specific baits for B cell isolation.

Reproduced with permission from [ 21 ]. Identification of HIV-1 elite neutralizers and epitope mapping. Typically, plasma samples collected from HIV-1 infected individuals are tested for neutralization against panels of global env-pseudotyped viruses.

Volunteers are ranked based on a their neutralization breadth and potency. The broad neutralizing activity in the top neutralizers is then mapped for epitope specificity using mutant viruses, and peptide and protein adsorptions. For some bNAb epitopes, there is a degree of promiscuity with which an epitope can be recognized [ 9 , 27 ].

For example, the V3-glycan supersite is relatively accessible to antibodies, perhaps explaining the prevalence of these bNAbs in infection Fig. BNAbs to this epitope show variable angles of approach centered around a series of conserved glycans at N and N, but incorporating more variable elements in V1, V3 and V4 [ 28 , 28 , 29 , 31 ].

However, other epitopes can only be accessed through very constrained angles of approach, forcing the immune system to utilize unusual structural features to access these. The stringent requirements for accessing these epitopes are reflected in the features of bNAb precursors, many of which have unusual features that are rare in the human immunoglobulin repertoire. The best examples of this are the VRClike CD4bs bNAbs that are characterized by conserved genetic and structural features which enable a common angle of approach [ 36 , 36 , 38 ].

This includes short antigen binding loops, required to avoid steric clashes with hypervariable regions and glycans [ 39 ]. In contrast, V2-directed bNAbs require a long anionic CDRH3 to penetrate the glycans protecting the apex of the trimer [ 40 , 40 , 41 , 43 ]. MPER bNAbs also use long variable loops and often develop membrane binding in order to access their epitopes [ 44 , 45 ].

However, long loops and hydrophobic surfaces are associated with autoreactivity, such that these precursors are frequently deleted through tolerance mechanisms [ 43 , 46 , 46 , 47 , 48 , 49 , 50 , 52 ]. Ongoing studies of immunoglobulin repertoires in diverse populations will provide insights into the possibility of reliably eliciting such bNAbs. One feature that is common to bNAbs to several epitopes is an unusually high level of somatic hypermutation SHM.

Mutations are acquired in the complementarity determining regions of the antibodies which generally form the paratope, but also in the framework regions of antibodies which are normally more conserved [ 57 ]. The isolation of less mutated antibodies, described below, may therefore fill an important gap in the field.

Notably, engineering bNAbs to achieve enhanced breadth and potency sometimes results in enhanced polyreactivity, suggesting that maturation towards breadth is balanced by the need to avoid polyreactivity in the maturation of these lineages [ 63 , 64 ]. Together, these features suggest complex developmental pathways that pose challenges to traditional vaccine strategies. This prolonged process suggests that extensive evolution of antibody responses is needed. Indeed, breadth has been associated with high viral loads, duration of infection, viral diversity and low CD4 T cell counts [ 19 , 21 , 65 , 65 , 66 , 68 ].

Furthermore, high overall plasma IgG levels and anti-Env IgG binding titers correlate with breadth, suggesting donors with breadth may access a more diverse repertoire of anti-Env Ab responses [ 21 ]. These findings emphasize the high levels of antigenic stimulation required to drive the extensive SHM often seen in bNAbs. However, there is also evidence that more specific viral attributes contribute to the development of breadth, with infection with subtype C viruses associated with enhanced breadth, and a bias to V2-glycan directed responses compared to the CD4bs responses more commonly observed in subtype B infected individuals [ 21 , 65 ].

Another key factor associated with bNAb development is the level of circulating T follicular helper cells and germinal center GC function, which likely supports the SHM required for continued maturation [ 69 , 70 ].

Conversely, low levels of T regulatory cells, possibly enabling survival of B-cell intermediates with potential for autoreactivity, were also associated with development of bNAbs [ 72 ]. Superinfection has also been associated with broader antibody responses in some cohorts [ 73 , 74 ], but not others [ 75 ].

This is an appealing observation for vaccine design, suggesting the possibility that superinfection boosts responses primed by the initial infecting virus, analogous to heterologous prime boost vaccines. However, a detailed comparison of the kinetics and targets of plasma antibodies in four superinfected donors suggested that superinfection was associated with de novo responses to both viral variants, and did not drive neutralization breadth Sheward, Moore and Williamson, in press.

This is further supported by the isolation of monoclonal antibodies mAbs from two superinfected donors, CAP and QA In CAP, who developed extraordinarily potent bNAbs [ 76 ], these were directed only at the superinfecting virus [ 47 ].

Similarly, mAbs isolated from donor QA neutralized either primary infecting or superinfecting viruses, with none cross-neutralizing both. Furthermore, bNAbs in QA were largely attributable to mAbs targeting the superinfecting virus, with the mAbs that arose to the primary infecting virus only making a minor contribution to plasma breadth [ 77 ]. This suggests that HIV superinfection may enhance breadth through additive responses to each individual virus, consistent with the small effect seen in cohort studies [ 73 ], rather than through the boosting of memory responses, a distinction that is important for HIV vaccine design.

Chronically infected children frequently have an unusual phenotype of consistently high viral loads but normal CD4 counts, which may be highly conducive to the development of breadth [ 78 ]. Mapping studies show that bNAbs in children largely target previously defined epitopes, including the V2-glycan, V3-glycan, CD4bs and gpgp41 interface [ 81 ].

Remarkably, however, three quarters of children had antibodies targeting as many as four distinct bNAb epitopes with breadth mediated by a combination of these specificities. This polyclonality, which is also sometimes seen in adults [ 20 , 21 , 82 , 82 , 83 , 85 ], may be more pronounced in chronically infected children due to persistently high viral loads in this group, which is strongly linked to the development of neutralization breadth in adults [ 21 , 65 , 86 , 86 , 88 ].

The extraordinary breadth in these donors may suggest fundamental differences in their development described in more detail below. This is supported by the isolation of mAb BF The polyclonal nature of pediatric bNAbs may suggest that the immunoglobulin repertoire in children is more diverse than that of adults, or that maternal antibodies may shape the maturation of bNAbs, as has been observed in passive antibody administration in adults [ 89 , 90 ].

Lastly, studies of GCs in children will shed light into whether these are functionally distinct from those of adults. Several recent studies suggest that children may be fundamentally better at generating antibody responses in vaccination and infection [ 78 , 79 , 91 , 91 , 92 , 94 ], which may be valuable for HIV vaccine design.

Additional studies will therefore be important in providing insights into whether HIV infection, and therefore vaccination, may induce unique antibody responses in pediatric donors. A major focus has been the need to define the cellular and molecular mechanisms leading to the development of bNAbs. Recent advances in next-generation sequencing NGS technologies have been key for such studies, allowing unprecedented analysis of the memory B-cell repertoire and of the viral envelope diversity within individuals [ 95 ].

This has enabled comprehensive, multidimensional studies deciphering the molecular interplay between the virus and B-cell response over the course of infection Fig. HIV and bNAb co-evolution studies. In parallel, corresponding longitudinal plasma samples are used to sequence and clone viral env variants. NGS data are used to re-construct the Ab and Env phylogenies over the course of infection.

Cloned bNAbs and Env variants are functionally and structurally evaluated, both individually and in complex, to retrace the evolution of the virus-antibody interaction from elicitation to acquisition of neutralization breadth and inform vaccine design. Such studies of the longitudinal development of bNAbs were a unique opportunity, especially as clinical guidelines have moved towards early treatment of HIV infection, and were extremely valuable for the HIV vaccine effort.

A key aspect for vaccine design has been the use of longitudinal memory B-cell NGS to accurately infer the sequence of the unmutated common ancestor UCA for several bNAb lineages. The accuracy of this inference is highly dependent on the availability of early, less mutated bnAb lineage sequences.

This observation led to the hypothesis that some of these bNAbs may have matured from responses to other pathogens, however it is also possible that affinity undetectable in existing assays might have been sufficient to induce BCR signaling and initiate clonal expansion in vivo [ 99 ]. Moreover, this low affinity, mainly due to the sub-optimal epitope presentation on the Env protein, can be overcome by synthetic minimal epitope molecules such as CD4bs mimics eOD-GT8 and c VRC01 [ 54 , , ], short V3-glycopeptides DH [ , ] and V2-apex scaffolds [ 40 , 41 ], providing opportunities for immunogen design.

Memory B-cell repertoire analyses have revealed subsequent multi-limb maturation as the early antibody intermediates undergo different fates, depending on whether they can still recognize emerging new viral variants [ 47 , 59 ]. Other branches continue to accumulate SHM in distinct parallel pathways through continual adaptation to new variants in the autologous virus population [ 47 , 59 , 96 ]. However, continued maturation is not always associated with neutralization breadth.

Bhiman et al. Similar observations have been made in other bNAb lineages [ 58 , , ], and as mAb isolation methodologies are specifically designed to recover bNAbs, the proportion of bNAb lineages that are off-track is unknown. Structural studies carried out in parallel to the repertoire analyses have also provided critical insights into the molecular basis of affinity maturation reviewed in [ ]. The detailed molecular mechanisms allowing neutralization breadth via epitope focusing and by adaptation to the glycan shield through direct contact or by reducing steric clashes have been better defined, and exploited for immunogen design see below.

A broadly neutralizing macaque monoclonal antibody against the HIV-1 V3-Glycan patch

Metrics details. Broadly neutralizing antibodies bNAbs , able to prevent viral entry by diverse global viruses, are a major focus of HIV vaccine design, with data from animal studies confirming their ability to prevent HIV infection. However, traditional vaccine approaches have failed to elicit these types of antibodies. During chronic HIV infection, a subset of individuals develops bNAbs, some of which are extremely broad and potent. The features, targets and developmental pathways of bNAbs from their precursors have been defined through extraordinarily detailed within-donor studies.

Therefore, the development of a safe and effective HIV-1 vaccine is on top of the global health priority. We believe that an effective HIV-1 vaccine, together with other prevention approaches, will bring an end to this epidemic in the near future. Now there are more than 35 million people living with HIV and 25 million individuals died of it. In , over people become newly infected with HIV every day [ 3 ]. Therefore, HIV cure is not possible until this reservoir is purged [ 7 ]. Therefore, the development of a safe and effective prophylactic HIV-1 vaccine would be the best for the ultimate elimination of the AIDS pandemic. However, no fully effective HIV vaccine is available till now.

The Neutralizing Antibody Response to the HIV-1 Env Protein

Developing HIV-1 vaccines that trigger broadly neutralizing antibodies bnAbs is a priority as bnAbs are considered key to elicitation of a protective immune response. To investigate whether the breadth of a neutralizing antibody nAb depended on the conservation of its epitope among circulating viruses, we examined Antibody:Envelope Ab:Env interactions and worldwide Env diversity. Neutralization breadth did not stem from the overall conservation of Ab epitopes but depended instead on the conservation of key sites of the Ab:Env interaction, revealing a mechanistic basis for neutralization breadth that could be exploited for vaccine design. So far, no HIV-1 vaccine has elicited broadly neutralizing antibodies bnAbs in humans. HIV-1, one of the most rapidly evolving pathogens, is remarkable for its high variability across individuals and adaptability within hosts.

Pritchard, Robyn L. Stanfield, Max Crispin, Andrew B. Moore, David Nemazee, Michel C.

Broadly neutralizing antibodies bNAbs are essential for a preventative HIV-1 vaccine but have not been elicited through vaccination. In these individuals, virus-antibody co-evolution is thought to drive the maturation of antibody lineages to neutralization breadth. We used deep sequencing of env genes and antibody transcripts from fourteen time points spanning the first 3 years of infection to characterize the virus-antibody co-evolution in donor CAP who developed V3-glycan-specific bNAbs. Sequencing and cloning of env genes, followed by neutralization assays, were used to identify Env mutations associated with neutralization escape from two bNAbs CAP

HIV Vaccine Research: The Challenge and the Way Forward

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5 comments

  • Matteo N. 17.11.2020 at 03:08

    Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing.

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