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1.
EBioMedicine ; 98: 104867, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37939456

RESUMO

BACKGROUND: The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the mechanisms remain unclear. The difficulty in elucidating the evolutionary origin of the earliest X4 viruses limits our understanding of this phenomenon. METHODS: We tracked the evolution of the transmitted/founder (T/F) HIV-1 in RV217 participants identified in acute infection. The origin of the X4 viruses was elucidated by single genome amplification, deep sequencing and coreceptor assay. Mutations responsible for coreceptor switch were confirmed by mutagenesis. Viral susceptibility to neutralization was determined by neutralization assay. Virus CD4 subset preference was demonstrated by sequencing HIV-1 RNA in sorted CD4 subsets. FINDINGS: We demonstrated that the earliest X4 viruses evolved de novo from the T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive the X4 variants to replicate mainly in the central memory (CM) and naïve CD4 subsets. Likely due to the smaller viral burst size of the CM and naïve subsets, the X4 variants existed at low frequency in plasma. The origin of the X4 viruses preceded accelerated CD4 decline. All except one X4 virus identified in the current study lost the conserved V3 N301 glycan site. INTERPRETATIONS: The findings demonstrate co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting which have implications for HIV-1 therapeutics and functional cure. The observations provide evidence that coreceptor switch can function as an evolutionary mechanism of immune evasion. FUNDING: Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Thai Red Cross AIDS Research Centre, Gilead Sciences, Merck, and ViiV Healthcare.


Assuntos
Síndrome da Imunodeficiência Adquirida , Soropositividade para HIV , HIV-1 , Evasão da Resposta Imune , Humanos , Síndrome da Imunodeficiência Adquirida/imunologia , Estudos de Coortes , HIV-1/genética , HIV-1/imunologia , Receptores CCR5/genética , Receptores CXCR4/genética
2.
bioRxiv ; 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37745406

RESUMO

Nearly all transmitted/founder (T/F) HIV-1 are CCR5 (R5)-tropic. While previous evidence suggested that CXCR4 (X4)-tropic HIV-1 are transmissible, detection was not at the earliest stages of acute infection. Here, we identified an X4-tropic T/F HIV-1 in a participant in acute infection cohort. Coreceptor assays demonstrated that this T/F virus is strictly CXCR4 tropic. The participant experienced significantly faster CD4 depletion compared with R5 virus infected participants in the same cohort. Naïve and central memory CD4 subsets declined faster than effector and transitional memory subsets. All CD4 subsets, including naïve, were productively infected. Increased CD4 + T cell activation was observed over time. This X4-tropic T/F virus is resistant to broadly neutralizing antibodies (bNAbs) targeting V1/V2 and V3 regions. These findings demonstrate that X4-tropic HIV-1 is transmissible through the mucosal route in people with the wild-type CCR5 genotype and have implications for understanding the transmissibility and immunopathogenesis of X4-tropic HIV-1.

3.
bioRxiv ; 2023 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-36712089

RESUMO

The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the underlying mechanisms remain unclear. The difficulty in capturing the earliest moment of coreceptor switch in vivo limits our understanding of this phenomenon. Here, by tracking the evolution of the transmitted/founder (T/F) HIV-1 in a prospective cohort of individuals at risk for HIV-1 infection identified very early in acute infection, we investigated this process with high resolution. The earliest X4 variants evolved from the R5 tropic T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive X4 variants to replicate mainly in the central memory and naïve CD4+ T cells. We propose a novel concept to explain the co-evolution of virus antigenicity and entry tropism termed "escape by shifting". This concept posits that for viruses with receptor or coreceptor flexibility, entry tropism alteration represents a mechanism of immune evasion in vivo .

4.
Virology ; 568: 72-76, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35144109

RESUMO

The ability of HIV-1 to evade neutralizing antibodies (NAbs) in vivo is well demonstrated, but the impact of NAb escape mutations on HIV-1 phenotype other than immune escape itself has rarely been studied. Here, we show that immune escape mutations selected by V3-glycan specific NAbs in vivo can alter coreceptor usage repertoire of the transmitted/founder (T/F) HIV-1. In a participant developed V3-glycan NAb response, naturally selected escape mutations at the V3 N301 and N332 glycan sites abrogated CCR8 usage while conferred APJ usage on the cognate T/F strain. Mutations at the N301 glycan also impaired CCR3 usage and partially compromised the efficiency in using CCR5, which could be fully restored by a single escape mutation at the N332 glycan site. Our study demonstrates the link between NAb escape and coreceptor usage alteration in natural HIV-1 infection and indicates that NAb response could drive virus entry tropism evolution in vivo.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/fisiologia , Evasão da Resposta Imune , Mutação , Sequência de Aminoácidos , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/transmissão , Interações Hospedeiro-Patógeno , Humanos
5.
Nat Med ; 27(11): 1893-1898, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34711975

RESUMO

Certain infected individuals suppress human immunodeficiency virus (HIV) in the absence of anti-retroviral therapy (ART). Elucidating the underlying mechanism(s) is of high interest. Here we present two contrasting case reports of HIV-infected individuals who controlled plasma viremia for extended periods after undergoing analytical treatment interruption (ATI). In Participant 04, who experienced viral blips and initiated undisclosed self-administration of suboptimal ART detected shortly before day 1,250, phylogenetic analyses of plasma HIV env sequences suggested continuous viral evolution and/or reactivation of pre-existing viral reservoirs over time. Antiviral CD8+ T cell activities were higher in Participant 04 than in Participant 30. In contrast, Participant 30 exhibited potent plasma-IgG-mediated neutralization activity against autologous virus that became ineffective when he experienced sudden plasma viral rebound 1,434 d after ATI due to HIV superinfection. Our data provide insight into distinct mechanisms of post-treatment interruption control and highlight the importance of frequent monitoring of undisclosed use of ART and superinfection during the ATI phase.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Cooperação do Paciente , Adulto , Anticorpos Neutralizantes/sangue , Contagem de Linfócito CD4 , Infecções por HIV/imunologia , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Carga Viral/imunologia , Viremia/tratamento farmacológico , Viremia/imunologia , Ativação Viral/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/sangue , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
6.
Cell Rep Med ; 2(7): 100315, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34337555

RESUMO

Study of evolution and selection pressure on HIV-1 in fetuses will lead to a better understanding of the role of immune responses in shaping virus evolution and vertical transmission. Detailed genetic analyses of HIV-1 env gene from 12 in utero transmission pairs show that most infections (67%) occur within 2 months of childbirth. In addition, the env sequences from long-term-infected fetuses are highly divergent and form separate phylogenetic lineages from their cognate maternal viruses. Host-selection sites unique to neonate viruses are identified in regions frequently targeted by neutralizing antibodies and T cell immune responses. Identification of unique selection sites in the env gene of fetal viruses indicates that the immune system in fetuses is capable of exerting selection pressure on viral evolution. Studying selection and evolution of HIV-1 or other viruses in fetuses can be an alternative approach to investigate adaptive immunity in fetuses.


Assuntos
Evolução Biológica , Feto/imunologia , Feto/virologia , HIV-1/fisiologia , Transmissão Vertical de Doenças Infecciosas , Mães , Adolescente , Adulto , Sequência de Bases , Linhagem Celular , Feminino , Variação Genética , Infecções por HIV/sangue , Infecções por HIV/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Recém-Nascido , Testes de Neutralização , Motivos de Nucleotídeos/genética , Filogenia , Placenta/metabolismo , Gravidez , Adulto Jovem , Produtos do Gene env do Vírus da Imunodeficiência Humana
7.
Sci Adv ; 6(27)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32937441

RESUMO

COVID-19 has become a global pandemic caused by the novel coronavirus SARS-CoV-2. Understanding the origins of SARS-CoV-2 is critical for deterring future zoonosis, discovering new drugs, and developing a vaccine. We show evidence of strong purifying selection around the receptor binding motif (RBM) in the spike and other genes among bat, pangolin, and human coronaviruses, suggesting similar evolutionary constraints in different host species. We also demonstrate that SARS-CoV-2's entire RBM was introduced through recombination with coronaviruses from pangolins, possibly a critical step in the evolution of SARS-CoV-2's ability to infect humans. Similar purifying selection in different host species, together with frequent recombination among coronaviruses, suggests a common evolutionary mechanism that could lead to new emerging human coronaviruses.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Recombinação Genética , Sequência de Aminoácidos , Enzima de Conversão de Angiotensina 2 , Animais , Betacoronavirus/classificação , Betacoronavirus/crescimento & desenvolvimento , Sítios de Ligação , COVID-19 , Quirópteros/virologia , Infecções por Coronavirus/virologia , Evolução Molecular , Genoma Viral , Humanos , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Filogenia , Pneumonia Viral/virologia , Estrutura Terciária de Proteína , SARS-CoV-2 , Alinhamento de Sequência
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