CD4 binding site broadly neutralizing antibody selection of HIV-1 escape mutants

Dreja, Hanna; Pade, Corinna; Chen, Lei

doi:10.1099/vir.0.000120

Cited by 10 publications

(7 citation statements)

References 28 publications

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“…Escape can also occur via impaired recognition of viral peptide-MHC complexes by cytotoxic T cells [ 39 , 40 ], or mutations that compromise intracellular epitope processing, for instance, by preventing NH 2 -terminal trimming of the epitope [ 41 ]. Antibody escape patterns are also heterogeneous; site-directed mutagenesis has identified multiple resistant variants within the viral envelope CD4 binding site [ 42 ]. A considerable amount of sequence variation within the D, V1 and V5 loops, and the CD4-binding site of the HIV-1 envelope has been reported within a subject who developed broadly neutralizing antibody responses [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular clock of HIV-1 envelope genes under early immune selection

et al. 2016

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BackgroundThe molecular clock hypothesis that genes or proteins evolve at a constant rate is a key tool to reveal phylogenetic relationships among species. Using the molecular clock, we can trace an infection back to transmission using HIV-1 sequences from a single time point. Whether or not a strict molecular clock applies to HIV-1’s early evolution in the presence of immune selection has not yet been fully examined.ResultsWe identified molecular clock signatures from 1587 previously published HIV-1 full envelope gene sequences obtained since acute infection in 15 subjects. Each subject’s sequence diversity linearly increased during the first 150 days post infection, with rates ranging from to with a mean of per base per day. The rate of diversification for 12 out of the 15 subjects was comparable to the neutral evolution rate. While temporal diversification was consistent with evolution patterns in the absence of selection, mutations from the founder virus were highly clustered on statistically identified selection sites, which diversified more than 65 times faster than non-selection sites. By mathematically quantifying deviations from the molecular clock under various selection scenarios, we demonstrate that the deviation from a constant clock becomes negligible as multiple escape lineages emerge. The most recent common ancestor of a virus pair from distinct escape lineages is most likely the transmitted founder virus, indicating that HIV-1 molecular dating is feasible even after the founder viruses are no longer detectable.ConclusionsThe ability of HIV-1 to escape from immune surveillance in many different directions is the driving force of molecular clock persistence. This finding advances our understanding of the robustness of HIV-1’s molecular clock under immune selection, implying the potential for molecular dating.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0269-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Molecular clock of HIV-1 envelope genes under early immune selection

et al. 2016

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“…4 C ), suggesting that the mutations reduced the ability of Env to bind CD4, thereby potentially allowing escape from CD4-based reagents. Indeed, the G366E ( 33 ), G458D ( 34 ), and G471R ( 13 ) mutations have been reported to confer partial resistance against CD4-based inhibitors. No recurrent mutations were found near the coreceptor-binding site, indicating that selective pressure was exerted primarily by CD4 on the CD4-CCR5-VLPs.…”

Section: Resultsmentioning

confidence: 99%

Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells

Hoffmann

Bar-On

Yang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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CD4-based decoy approaches against HIV-1 are attractive options for long-term viral control, but initial designs, including soluble CD4 (sCD4) and CD4-Ig, were ineffective. To evaluate a therapeutic that more accurately mimics HIV-1 target cells compared with monomeric sCD4 and dimeric CD4-Ig, we generated virus-like nanoparticles that present clusters of membrane-associated CD4 (CD4-VLPs) to permit high-avidity binding of trimeric HIV-1 envelope spikes. In neutralization assays, CD4-VLPs were >12,000-fold more potent than sCD4 and CD4-Ig and >100-fold more potent than the broadly neutralizing antibody (bNAb) 3BNC117, with >12,000-fold improvements against strains poorly neutralized by 3BNC117. CD4-VLPs also neutralized patient-derived viral isolates that were resistant to 3BNC117 and other bNAbs. Intraperitoneal injections of CD4-CCR5-VLP produced only subneutralizing plasma concentrations in HIV-1–infected humanized mice but elicited CD4-binding site mutations that reduced viral fitness. All mutant viruses showed reduced sensitivity to sCD4 and CD4-Ig but remained sensitive to neutralization by CD4-VLPs in vitro. In vitro evolution studies demonstrated that CD4-VLPs effectively controlled HIV-1 replication at neutralizing concentrations, and viral escape was not observed. Moreover, CD4-VLPs potently neutralized viral swarms that were completely resistant to CD4-Ig, suggesting that escape pathways that confer resistance against conventional CD4-based inhibitors are ineffective against CD4-VLPs. These findings suggest that therapeutics that mimic HIV-1 target cells could prevent viral escape by exposing a universal vulnerability of HIV-1: the requirement to bind CD4 on a target cell. We propose that therapeutic and delivery strategies that ensure durable bioavailability need to be developed to translate this concept into a clinically feasible functional cure therapy.

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“…These strategies have created the most successful non-vaccine HIV-1 treatments to date [100]. Among these triumphs, VRC01 has been shown to be safe and well-tolerated in phase I studies and for multiple HIV-1 escape mutants [100,101]. VRC01 targets the HIV-1 CD4 + binding site and proves able to neutralize HIV strains, capture virions, and facilitate ADCC [102].…”

Section: Hiv-1 Bnabs As a Response To The High Risk Of Cancermentioning

confidence: 99%

Antibody and Cell-Based Therapies against Virus-Induced Cancers in the Context of HIV/AIDS

Joseph,

Sandel,

Kulkarni

et al. 2023

Pathogens

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Infectious agents, notably viruses, can cause or increase the risk of cancer occurrences. These agents often disrupt normal cellular functions, promote uncontrolled proliferation and growth, and trigger chronic inflammation, leading to cancer. Approximately 20% of all cancer cases in humans are associated with an infectious pathogen. The International Agency for Research on Cancer (IARC) recognizes seven viruses as direct oncogenic agents, including Epstein–Barr Virus (EBV), Kaposi’s Sarcoma-associated herpesvirus (KSHV), human T-cell leukemia virus type-1 (HTLV-1), human papilloma virus (HPV), hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus type 1 (HIV-1). Most viruses linked to increased cancer risk are typically transmitted through contact with contaminated body fluids and high-risk behaviors. The risk of infection can be reduced through vaccinations and routine testing, as well as recognizing and addressing risky behaviors and staying informed about public health concerns. Numerous strategies are currently in pre-clinical phases or undergoing clinical trials for targeting cancers driven by viral infections. Herein, we provide an overview of risk factors associated with increased cancer incidence in people living with HIV (PLWH) as well as other chronic viral infections, and contributing factors such as aging, toxicity from ART, coinfections, and comorbidities. Furthermore, we highlight both antibody- and cell-based strategies directed against virus-induced cancers while also emphasizing approaches aimed at discovering cures or achieving complete remission for affected individuals.

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CD4 binding site broadly neutralizing antibody selection of HIV-1 escape mutants

Cited by 10 publications

References 28 publications

Molecular clock of HIV-1 envelope genes under early immune selection

Molecular clock of HIV-1 envelope genes under early immune selection

Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells

Antibody and Cell-Based Therapies against Virus-Induced Cancers in the Context of HIV/AIDS

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