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Long-Term and Low-Level Envelope C2V3 Stimulation by Highly Diverse Virus Isolates Leads to Frequent Development of Broad and Elite Antibody Neutralization in HIV-1-Infected Individuals

2022-11-29Artigo científico Acesso aberto
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dc.contributor.authorMartin, Francisco
dc.contributor.authorMarcelino, José Maria
dc.contributor.authorPalladino, Claudia
dc.contributor.authorBártolo, Inês
dc.contributor.authorTracana, Susana
dc.contributor.authorMoranguinho, Inês
dc.contributor.authorGonçalves, Paloma
dc.contributor.authorMateus, Rita
dc.contributor.authorCalado, Rita
dc.contributor.authorBorrego, Pedro
dc.contributor.authorLeitner, Thomas
dc.contributor.authorClemente, Sofia
dc.contributor.authorTaveira, Nuno
dc.date.accessioned2023-08-18T17:00:57Z
dc.date.available2023-08-18T17:00:57Z
dc.date.issued2022-11-29
dc.date.updated2023-02-03T12:02:59Z
dc.description.abstractA minority of HIV-1-infected patients produce broadly neutralizing antibodies (bNAbs). Identification of viral and host correlates of bNAb production may help develop vaccines. We aimed to characterize the neutralizing response and viral and host-associated factors in Angola, which has one of the oldest, most dynamic, and most diverse HIV-1 epidemics in the world. Three hundred twenty-two HIV-1-infected adults from Angola were included in this retrospective study. Phylogenetic analysis of C2V3C3 env gene sequences was used for virus subtyping. Env-binding antibody reactivity was tested against polypeptides comprising the C2, V3, and C3 regions. Neutralizing-antibody responses were determined against a reference panel of tier 2 Env pseudoviruses in TZM-bl cells; neutralizing epitope specificities were predicted using ClustVis. All subtypes were found, along with untypeable strains and recombinant forms. Notably, 56% of the patients developed cross neutralizing, broadly neutralizing, or elite neutralizing responses. Broad and elite neutralization was associated with longer infection time, subtype C, lower CD4+ T cell counts, higher age, and higher titer of C2V3C3-specific antibodies relative to failure to develop bNAbs. Neutralizing antibodies targeted the V3-glycan supersite in most patients. V3 and C3 regions were significantly less variable in elite neutralizers than in weak neutralizers and nonneutralizers, suggesting an active role of V3C3-directed bNAbs in controlling HIV-1 replication and diversification. In conclusion, prolonged and low-level envelope V3C3 stimulation by highly diverse and ancestral HIV-1 isolates promotes the frequent elicitation of bNAbs. These results provide important clues for the development of an effective HIV-1 vaccine. IMPORTANCE Studies on neutralization by antibodies and their determinants in HIV-1-infected individuals have mostly been conducted in relatively recent epidemics caused by subtype B and C viruses. Results have suggested that elicitation of broadly neutralizing antibodies (bNAbs) is uncommon. The mechanisms underlying the elicitation of bNAbs are still largely unknown. We performed the first characterization of the plasma neutralizing response in a cohort of HIV-1-infected patients from Angola. Angola is characterized by an old and dynamic epidemic caused by highly diverse HIV-1 variants. Remarkably, more than half of the patients produced bNAbs, mostly targeting the V3-glycan supersite in HIV-1. This was associated with higher age, longer infection time, lower CD4+ T cell counts, subtype C infection, or higher titer of C2V3C3-specific antibodies relative to patients that did not develop bNAbs. These results may help develop the next generation of vaccine candidates for HIV-1.pt_PT
dc.description.sponsorshipThis work was supported by ADEIM-FFUL (Associação para o Ensino e a Investigação em Microbiologia) and by Fundação para a Ciência e a Tecnologia (FCT), Portugal, under project grants UIDB/04138/2020 and UIDP/04138/2020. This study was in part supported by the NIH/NIAID under grant R01AI087520. F.M. was supported by FCT under PhD grant number SFRH/BD/87488/2012. I.B. and C.P. are funded by FCT under a contract program as defined by DL no. 57/2016 and law no. 57/2017. The funding source was not involved in study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMartin F, Marcelino JM, Palladino C, Bártolo I, Tracana S, Moranguinho I, et al. Long-term and low-level envelope c2v3 stimulation by highly diverse virus isolates leads to frequent development of broad and elite antibody neutralization in hiv-1-infected individuals. Sui Y, editor. Microbiol Spectr [Internet]. 21 de dezembro de 2022;10(6):e01634-22. Disponível em: https://journals.asm.org/doi/10.1128/spectrum.01634-22pt_PT
dc.identifier.doi10.1128/spectrum.01634-22pt_PT
dc.identifier.issn2165-0497
dc.identifier.slugcv-prod-3091872
dc.identifier.urihttp://hdl.handle.net/10451/58930
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Society for Microbiologypt_PT
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationHIV EPIDEMIOLOGY AND PATHOGENESIS IN WOMEN AND CHILDREN IN LUANDA, ANGOLA
dc.relation.publisherversionhttps://journals.asm.org/doi/10.1128/spectrum.01634-22pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAngolapt_PT
dc.subjectEnv diversitypt_PT
dc.subjectHIV-1 infectionpt_PT
dc.subjectbroadly neutralizing antibodiespt_PT
dc.subjectbNAbspt_PT
dc.subjectEnv-specific antibodiespt_PT
dc.subjectneutralizing epitopespt_PT
dc.titleLong-Term and Low-Level Envelope C2V3 Stimulation by Highly Diverse Virus Isolates Leads to Frequent Development of Broad and Elite Antibody Neutralization in HIV-1-Infected Individualspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleHIV EPIDEMIOLOGY AND PATHOGENESIS IN WOMEN AND CHILDREN IN LUANDA, ANGOLA
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F87488%2F2012/PT
oaire.citation.issue6pt_PT
oaire.citation.startPagee01634-22pt_PT
oaire.citation.titleMicrobiology Spectrumpt_PT
oaire.citation.volume10pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
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