HIV Broadly Neutralizing Antibodies: Taking Good Care Of The 98%

Sok, Devin; Burton, Dennis R.

doi:10.1016/j.immuni.2016.10.033

Cited by 13 publications

(11 citation statements)

References 10 publications

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“…GT-vaccinology has been used to elicit a specific class of HIV-1 gp120 CD4-binding site specific-bnAbs known as VRC01, through the use of engineered outer domain germline-targeting (eOD-GT) peptides (33). The interest to prime VRC01-bnAbs arises from their ability to mimic the CD4-binding to the gp120 receptor binding site and their capability to potently neutralize (median IC50 40 ng/mL) up to 98% of a large panel of global HIV-1 isolates (34, 35). An in-depth analysis of the VRC01 genetic features has shown peculiarities in this class of bnAbs.…”

Section: Use Of Peptide-antigen Derived For Germline Targeting Vaccinmentioning

confidence: 99%

Vaccine Evolution and Its Application to Fight Modern Threats

et al. 2019

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Before the development of the first vaccine, infectious diseases were a major cause of death around the globe with life expectancy estimated to be <50 years. Three measures have helped to drastically reduce the burden of infectious diseases but only vaccines have proven to be able to eradicate infectious agents. Herein, we describe new methodologies that have paved the way for what is currently known as modern vaccinology and the use of vaccines to tackle antimicrobial resistance, the biggest global threat of our time.

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Section: Use Of Peptide-antigen Derived For Germline Targeting Vaccinmentioning

confidence: 99%

Vaccine Evolution and Its Application to Fight Modern Threats

et al. 2019

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“…Till date, a number of bnAbs have been discovered from elite neutralizers and a few of them have been found to be able to prevent acquisition as well as significantly reduce plasma viral loads, when tested both in animal models and humans [1][2][3], thus justifying their importance as products for prevention and treatment. Some of the bnAbs that are currently being evaluated through human clinical trials will provide additional possibilities for prevention [4,5], such as their extent, in addition to virus neutralization, in persistent viral clearance [6,7] and eliminating HIV-1 infected cells [2,8,9]. While some single bnAbs have been found to show significant breadth across subtypes, combination of bnAbs with distinct epitope-specificity is believed to provide the most effective response against globally diverse HIV-1 subtypes and also would likely prevent the development of antibody-escape variants [2].…”

Section: Introductionmentioning

confidence: 99%

Geospatial HIV-1 subtype C gp120 sequence diversity and its predicted impact on broadly neutralizing antibody sensitivity

et al. 2021

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Evolving diversity in globally circulating HIV-1 subtypes presents a formidable challenge in defining and developing neutralizing antibodies for prevention and treatment. HIV-1 subtype C is responsible for majority of global HIV-1 infections. In the present study, we examined the diversity in genetic signatures and attributes that differentiate region-specific HIV-1 subtype C gp120 sequences associated with virus neutralization outcomes to key bnAbs having distinct epitope specificities. A total of 1814 full length HIV-1 subtype C gp120 sequence from 37 countries were retrieved from Los Alamos National Laboratory HIV database (www.hiv.lanl.gov). The amino acid sequences were assessed for their phylogenetic association, variable loop lengths and prevalence of potential N-linked glycosylation sites (pNLGS). Responses of these sequences to bnAbs were predicted with a machine learning algorithm ‘bNAb-ReP’ and compared with those reported in the CATNAP database. Subtype C sequences from Asian countries including India differed phylogenetically when compared with that from African countries. Variable loop lengths and charges within Indian and African clusters were also found to be distinct from each other, specifically for V1, V2 and V4 loops. Pairwise analyses at each of the 25 pNLG sites indicated distinct country specific profiles. Highly significant differences (p<0.001***) were observed in prevalence of four pNLGS (N130, N295, N392 and N448) between South Africa and India, having most disease burden associated with subtype C. Our findings highlight that distinctly evolving clusters within global intra-subtype C gp120 sequences are likely to influence the disparate region-specific sensitivity of circulating HIV-1 subtype C to bnAbs.

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“…Kumar et al 2018a; Mendoza et al 2018), thus justifying their importance as products for prevention and treatment. Some of the bnAbs that are currently being evaluated through human clinical trials should provide additional possibilities for prevention (Sok and Burton 2016, 2018), such as their extent, in addition to virus neutralization, in persistent viral clearance (Caskey et al 2019; Nishimura and Martin 2017) and eliminating HIV-1 infected cells (Caskey et al 2015; Caskey et al 2017; R. Kumar et al 2018a).…”

Section: Introductionmentioning

confidence: 99%

Geospatial HIV-1 subtype C gp120 sequence diversity and its predicted impact on broadly neutralizing antibody sensitivity

Sutar

Deshpande

Mullick

et al. 2020

Preprint

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Evolving diversity in globally circulating HIV-1 subtypes presents formidable challenge in defining and developing neutralizing antibodies for prevention and treatment. HIV-1 subtype C is responsible for majority of global HIV-1 infections. Broadly neutralizing antibodies (bnAbs) capable of neutralizing distinct HIV-1 subtypes by targeting conserved vulnerable epitopes on viral envelope protein (Env) are being considered as promising antiviral agents for prevention and treatment. In the present study, we examined the diversity in genetic signatures and attributes that differentiate region-specific global HIV-1 subtype C gp120 sequences associated with virus neutralization outcomes to key bnAbs having distinct epitope specificities. A total of 1814 full length HIV-1 subtype C gp120 sequence from 37 countries were retrieved from Los Alamos National Laboratory HIV database (www.hiv.lanl.gov). The amino acid sequences were assessed for their phylogenetic association, variable loop lengths and prevalence of potential N-linked glycosylation sites (pNLGS). Responses of these sequences to bnAbs were predicted with a machine learning algorithm ‘bNAb-ReP’ and compared with those reported in the CATNAP database. Phylogenetically, sequences from Asian countries including India clustered together however differed significantly when compared with pan African subtype C sequences. Variable loop lengths within Indian and African clusters were distinct from each other, specifically V1, V2 and V4 loops. Furthermore, V1V2 and V2 alone sequences were also found to vary significantly in their charges. Pairwise analyses at each of the 25 pNLG sites indicated distinct country specific profiles. Highly significant differences (p<0.001***) were observed in prevalence of four pNLGS (N130, N295, N392 and N448) between South Africa and India, having most disease burden associated with subtype C. Our findings highlight that the distinctly evolving clusters within global intra-subtype C gp120 sequences are likely to influence the disparate regionspecific sensitivity of circulating HIV-1 subtype C to bnAbs.Author SummaryBroadly neutralizing antibodies (bnAbs) that act on viral envelope protein and prevent establishment of infection have emerged as an attractive choice for HIV-1 treatment and prophylaxis over and above existing antiretroviral drug therapy. While HIV-1 subtype C accounts for nearly half of the global infection, the degree of intra-clade C variability across different geographical boundaries with particular reference to env gene (which is the target of neutralizing antibodies) is poorly understood. Through a systematic approach and by applying standardized computational algorithms, we carried out comprehensive comparison of the genetic properties of the gp120 sequences that represent globally circulating HIV-1 subtype C towards accurately predicating their degree of susceptibility to most broad and potent neutralizing monoclonal antibodies having different target specificities across gp120. Our data not only revealed significant intra-clade C diversity but also highlighted neutralization diversities. These observations provide insights that warrant greater and continued surveillance of evolving HIV-1 globally circulating subtype C variants that will inform selection of bnAbs that will best dissect the region-specific genetic and neutralization diversities towards selecting appropriate bnAb combination for clinical use.

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HIV Broadly Neutralizing Antibodies: Taking Good Care Of The 98%

Cited by 13 publications

References 10 publications

Vaccine Evolution and Its Application to Fight Modern Threats

Vaccine Evolution and Its Application to Fight Modern Threats

Geospatial HIV-1 subtype C gp120 sequence diversity and its predicted impact on broadly neutralizing antibody sensitivity

Geospatial HIV-1 subtype C gp120 sequence diversity and its predicted impact on broadly neutralizing antibody sensitivity

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