RESUMO
We analyze data from the fall 2020 pandemic response efforts at the University of Colorado Boulder, where more than 72,500 saliva samples were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using qRT-PCR. All samples were collected from individuals who reported no symptoms associated with COVID-19 on the day of collection. From these, 1,405 positive cases were identified. The distribution of viral loads within these asymptomatic individuals was indistinguishable from what has been previously observed in symptomatic individuals. Regardless of symptomatic status, â¼50% of individuals who test positive for SARS-CoV-2 seem to be in noninfectious phases of the disease, based on having low viral loads in a range from which live virus has rarely been isolated. We find that, at any given time, just 2% of individuals carry 90% of the virions circulating within communities, serving as viral "supercarriers" and possibly also superspreaders.
Assuntos
COVID-19/virologia , Portador Sadio/virologia , SARS-CoV-2 , Infecções Assintomáticas/epidemiologia , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/transmissão , Portador Sadio/diagnóstico , Portador Sadio/epidemiologia , Portador Sadio/transmissão , Colorado/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Programas de Rastreamento/estatística & dados numéricos , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Saliva/virologia , Universidades , Carga Viral , VírionRESUMO
Individuals chronically infected with HIV-1 harbor complex viral populations within their bloodstreams. Recently, it has come to light that when these people infect others, the new infection is typically established by only one or a small number of virions from within this complex viral swarm. An important goal is to characterize the biological properties of HIV-1 virions that seed and exist early in new human infections because these are potentially the only viruses against which a prophylactic HIV-1 vaccine would need to elicit protection. This includes understanding how the Envelope (Env) protein of these virions interacts with the T-cell receptor CD4, which supports attachment and entry of HIV-1 into target cells. We examined early HIV-1 isolates for their ability to infect cells via the CD4 receptor of 15 different primate species. Primates were the original source of HIV-1 and now serve as valuable animal models for studying HIV-1. We find that most primary isolates of HIV-1 from the blood, including early isolates, are highly selective and enter cells through some primate CD4 receptor orthologs but not others. This phenotype is remarkably consistent, regardless of route of transmission, viral subtype, or time of isolation post infection. We show that the weak CD4 binding affinity of blood-derived HIV-1 isolates is what makes them sensitive to the small sequence differences in CD4 from one primate species to the next. To substantiate this, we engineered an early HIV-1 Env to have high, medium, or low binding affinity to CD4, and we show that it loses the ability to enter cells via the CD4 receptor of many primate species as the binding affinity gets weaker. Based on the phenotype of selective use of primate CD4, we find that weak CD4 binding appears to be a nearly universal property of HIV-1 circulating in the bloodstream. Therefore, weak binding to CD4 must be a selected and important property in the biology of HIV-1 in the body. We identify six primate species that encode CD4 receptors that fully support the entry of early HIV-1 isolates despite their low binding affinity for CD4. These findings will help inform long-standing efforts to model HIV-1 transmission and early disease in primates.
Assuntos
Antígenos CD4/imunologia , Infecções por HIV/imunologia , HIV-1/genética , Animais , Aotidae , Antígenos CD4/genética , Linhagem Celular , Modelos Animais de Doenças , Células HEK293 , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/genética , Soropositividade para HIV/genética , Soropositividade para HIV/imunologia , HIV-1/imunologia , Humanos , Macaca mulatta , Primatas/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismoRESUMO
Pandemic HIV-1 (group M) emerged following the cross-species transmission of a simian immunodeficiency virus from chimpanzees (SIVcpz) to humans. Primate lentiviruses (HIV/SIV) require the T cell receptor CD4 to enter into target cells. By surveying the sequence and function of CD4 in 50 chimpanzee individuals, we find that all chimpanzee CD4 alleles encode a fixed, chimpanzee-specific substitution (34T) that creates a glycosylation site on the virus binding surface of the CD4 receptor. Additionally, a single nucleotide polymorphism (SNP) has arisen in chimpanzee CD4 (68T) that creates a second glycosylation site on the same virus-binding interface. This substitution is not yet fixed, but instead alleles containing this SNP are still circulating within chimpanzee populations. Thus, all allelic versions of chimpanzee CD4 are singly glycosylated at the virus binding surface, and some allelic versions are doubly glycosylated. Doubly glycosylated forms of chimpanzee CD4 reduce HIV-1 and SIVcpz infection by as much as two orders of magnitude. Full restoration of virus infection in cells bearing chimpanzee CD4 requires reversion of both threonines at sites 34 and 68, destroying both of the glycosylation sites, suggesting that the effects of the glycans are additive. Differentially glycosylated CD4 receptors were biochemically purified and used in neutralization assays and microscale thermophoresis to show that the glycans on chimpanzee CD4 reduce binding affinity with the lentiviral surface glycoprotein, Env. These glycans create a shield that protects CD4 from being engaged by viruses, demonstrating a powerful form of host resistance against deadly primate lentiviruses.
Assuntos
Antígenos CD4/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Pan troglodytes/imunologia , Pan troglodytes/virologia , Polissacarídeos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Animais , Linhagem Celular , Glicosilação , Células HEK293 , Infecções por HIV/virologia , Humanos , Polimorfismo de Nucleotídeo Único/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologiaRESUMO
HIV-1 arose as the result of spillover of simian immunodeficiency viruses (SIVs) from great apes in Africa, namely from chimpanzees and gorillas. Chimpanzees and gorillas were, themselves, infected with SIV after virus spillover from African monkeys. During spillover events, SIV is thought to require adaptation to the new host species. The host barriers that drive viral adaptation have predominantly been attributed to restriction factors, rather than cofactors (host proteins exploited to promote viral replication). Here, we consider the role of one cofactor, RanBP2, in providing a barrier that drove viral genome evolution during SIV spillover events. RanBP2 (also known as Nup358) is a component of the nuclear pore complex known to facilitate nuclear entry of HIV-1. Our data suggest that transmission of SIV from monkeys to chimpanzees, and then from chimpanzees to gorillas, both coincided with changes in the viral capsid that allowed interaction with RanBP2 of the new host species. However, human RanBP2 subsequently provided no barrier to the zoonotic transmission of SIV from chimpanzees or gorillas, indicating that chimpanzee- and gorilla-adapted SIVs are pre-adapted to humans in this regard. Our observations are in agreement with RanBP2 driving virus evolution during cross-species transmissions of SIV, particularly in the transmissions to and between great ape species.
Assuntos
Evolução Biológica , Infecções por HIV/virologia , Chaperonas Moleculares/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Zoonoses/virologia , África , Sequência de Aminoácidos , Animais , Infecções por HIV/metabolismo , Infecções por HIV/transmissão , HIV-1/patogenicidade , Especificidade de Hospedeiro , Humanos , Chaperonas Moleculares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Filogenia , Primatas , Homologia de Sequência , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/patogenicidade , Especificidade da Espécie , Replicação Viral , Zoonoses/metabolismo , Zoonoses/transmissãoRESUMO
[This corrects the article DOI: 10.1371/journal.ppat.1006906.].
RESUMO
Over evolutionary time, both host- and virus-encoded genes have been continually selected to modify their interactions with one another. This has resulted in the rapid evolution of the specific codons that govern the physical interactions between host and virus proteins. Virologists have discovered that these evolutionary signatures, acquired in nature, can provide a shortcut in the functional dissection of host-virus interactions in the laboratory. However, the use of evolution studies in this way is complicated by the fact that many nonhuman primate species are endangered, and biomaterials are often difficult to acquire. Here, we assess how the species representation in primate gene data sets affects the detection of positive natural selection. Our results demonstrate how targeted primate sequencing projects could greatly enhance research in immunology, virology, and beyond.
Assuntos
Evolução Molecular , Interações Hospedeiro-Patógeno/genética , Primatas/genética , Seleção Genética , Vírus/genética , Animais , Genes , Primatas/virologia , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
UNLABELLED: Most HIV-1 variants isolated from early-stage human infections do not use nonhuman primate versions of the CD4 receptor for cellular entry, or they do so poorly. We and others have previously shown that CD4 has experienced strong natural selection over the course of primate speciation, but it is unclear whether this selection has influenced the functional characteristics of CD4 as an HIV-1 receptor. Surprisingly, we find that selection on CD4 has been most intense in the New World monkeys, animals that have never been found to harbor lentiviruses related to HIV-1. Based on this, we sampled CD4 genetic diversity within populations of individuals from seven different species, including five species of New World monkeys. We found that some, but not all, CD4 alleles found in Spix's owl monkeys (Aotus vociferans) encode functional receptors for early-stage human HIV-1 isolates representing all of the major group M clades (A, B, C, and D). However, only some isolates of HIV-1 subtype C can use the CD4 receptor encoded by permissive Spix's owl monkey alleles. We characterized the prevalence of functional CD4 alleles in a colony of captive Spix's owl monkeys and found that 88% of surveyed individuals are homozygous for permissive CD4 alleles, which encode an asparagine at position 39 of the receptor. We found that the CD4 receptors encoded by two other species of owl monkeys (Aotus azarae and Aotus nancymaae) also serve as functional entry receptors for early-stage isolates of HIV-1. IMPORTANCE: Nonhuman primates, particularly macaques, are used for preclinical evaluation of HIV-1 vaccine candidates. However, a significant limitation of the macaque model is the fact that most circulating HIV-1 variants cannot use the macaque CD4 receptor to enter cells and have to be adapted to these species. This is particularly true for viral variants from early stages of infection, which represent the most relevant vaccine targets. In this study, we found that some individuals from captive owl monkey populations harbor CD4 alleles that are compatible with a broad collection of HIV-1 isolates, including those isolated from early in infection in highly affected populations and representing diverse subtypes.
Assuntos
Aotidae/genética , Antígenos CD4/metabolismo , Evolução Molecular , Variação Genética , HIV-1/metabolismo , Animais , Sequência de Bases , Antígenos CD4/genética , Primers do DNA/genética , Citometria de Fluxo , Genótipo , Dados de Sequência Molecular , Seleção Genética , Análise de Sequência de DNA , Especificidade da EspécieRESUMO
The antiviral factor CPSF6-358 restricts human immunodeficiency virus type 1 (HIV-1) infection through an interaction with capsid (CA), preventing virus nuclear entry and integration. HIV-1 acquires resistance to CPSF6-358 through an N74D mutation of CA that impairs binding of the antiviral factor. Here we examined the determinants within CPSF6-358 that are necessary for CA-specific interaction. Residues 314 to 322 include amino acids that are essential for CPSF6-358 restriction of HIV-1. Fusion of CPSF6 residues 301 to 358 to rhesus TRIM5α is also sufficient to restrict wild-type but not N74D HIV-1. Restriction is lost if CPSF6 residues in the amino acid 314 to 322 interaction motif are mutated. Examination of the CA targeting motif in CPSF6-358 did not reveal evidence of positive selection. Given the sensitivity of different primate lentiviruses to CPSF6-358 and apparent conservation of this interaction, our data suggest that CPSF6-358-mediated targeting of HIV-1 could provide a broadly effective antiviral strategy.
Assuntos
Capsídeo/metabolismo , Infecções por HIV/metabolismo , HIV-1/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/genética , Humanos , Dados de Sequência Molecular , Primatas , Ligação Proteica , Estrutura Terciária de ProteínaRESUMO
The COVID-19 pandemic demonstrated the poor ability of body temperature to reliably identify SARS-CoV-2-infected individuals, an observation that has been made before in the context of other infectious diseases. While acute infection does not always cause fever, it does reliably drive host transcriptional responses as the body responds at the site of infection. These transcriptional changes can occur both in cells that are directly harboring replicating pathogens and in cells elsewhere that receive a molecular signal that infection is occurring. Here, we identify a core set of approximately 70 human genes that are together upregulated in cultured human cells infected by a broad array of viral, bacterial, and fungal pathogens. We have named these "core response" genes. In theory, transcripts from these genes could serve as biomarkers of infection in the human body, in a way that is agnostic to the specific pathogen causing infection. As such, we perform human studies to show that these infection-induced human transcripts can be measured in the saliva of people harboring different types of infections. The number of these transcripts in saliva can correctly classify infection status (whether a person harbors an infection) 91% of the time. Furthermore, in the case of SARS-CoV-2 specifically, the number of core response transcripts in saliva correctly identifies infectious individuals even when enrollees, themselves, are asymptomatic and do not know they are infected.IMPORTANCEThere are a variety of clinical and laboratory criteria available to clinicians in controlled healthcare settings to help them identify whether an infectious disease is present. However, in situations such as a new epidemic caused by an unknown infectious agent, in health screening contexts performed within communities and outside of healthcare facilities or in battlefield or potential biowarfare situations, this gets more difficult. Pathogen-agnostic methods for rapid screening and triage of large numbers of people for infection status are needed, in particular methods that might work on an easily accessible biospecimen like saliva. Here, we identify a small, core set of approximately 70 human genes whose transcripts serve as saliva-based biomarkers of infection in the human body, in a way that is agnostic to the specific pathogen causing infection.
RESUMO
BACKGROUND: The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. RESULTS: We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, "induction" genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. CONCLUSION: Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.
Assuntos
Interferon Tipo I , Vírus , Animais , Interações Hospedeiro-Patógeno , Interferon Tipo I/genética , Primatas/genética , Seleção GenéticaRESUMO
Here, we develop a simple molecular test for SARS-CoV-2 in saliva based on reverse transcription loop-mediated isothermal amplification. The test has two steps: (1) heat saliva with a stabilization solution and (2) detect virus by incubating with a primer/enzyme mix. After incubation, saliva samples containing the SARS-CoV-2 genome turn bright yellow. Because this test is pH dependent, it can react falsely to some naturally acidic saliva samples. We report unique saliva stabilization protocols that rendered 295 healthy saliva samples compatible with the test, producing zero false positives. We also evaluated the test on 278 saliva samples from individuals who were infected with SARS-CoV-2 but had no symptoms at the time of saliva collection, and from 54 matched pairs of saliva and anterior nasal samples from infected individuals. The Saliva TwoStep test described herein identified infections with 94% sensitivity and >99% specificity in individuals with sub-clinical (asymptomatic or pre-symptomatic) infections.
Assuntos
COVID-19/diagnóstico , COVID-19/virologia , Portador Sadio/diagnóstico , Portador Sadio/virologia , SARS-CoV-2/isolamento & purificação , Saliva/virologia , COVID-19/metabolismo , Teste para COVID-19 , Humanos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , RNA Viral/genética , SARS-CoV-2/genética , Sensibilidade e Especificidade , Manejo de Espécimes/métodosRESUMO
Here, we develop a simple molecular test for SARS-CoV-2 in saliva based on reverse transcription loop-mediated isothermal amplification (RT-LAMP). The test has two steps: 1) heat saliva with a stabilization solution, and 2) detect virus by incubating with a primer/enzyme mix. After incubation, saliva samples containing the SARS-CoV-2 genome turn bright yellow. Because this test is pH dependent, it can react falsely to some naturally acidic saliva samples. We report unique saliva stabilization protocols that rendered 295 healthy saliva samples compatible with the test, producing zero false positives. We also evaluated the test on 278 saliva samples from individuals who were infected with SARS-CoV-2 but had no symptoms at the time of saliva collection, and from 54 matched pairs of saliva and anterior nasal samples from infected individuals. The Saliva TwoStep test described herein identified infections with 94% sensitivity and >99% specificity in individuals with sub-clinical (asymptomatic or pre-symptomatic) infections.
RESUMO
We analyze data from the Fall 2020 pandemic response efforts at the University of Colorado Boulder (USA), where more than 72,500 saliva samples were tested for SARS-CoV-2 using quantitative RT-PCR. All samples were collected from individuals who reported no symptoms associated with COVID-19 on the day of collection. From these, 1,405 positive cases were identified. The distribution of viral loads within these asymptomatic individuals was indistinguishable from what has been previously reported in symptomatic individuals. Regardless of symptomatic status, approximately 50% of individuals who test positive for SARS-CoV-2 seem to be in non-infectious phases of the disease, based on having low viral loads in a range from which live virus has rarely been isolated. We find that, at any given time, just 2% of individuals carry 90% of the virions circulating within communities, serving as viral "super-carriers" and possibly also super-spreaders.
RESUMO
Tripartite motif-containing protein 5α (TRIM5α) is a cellular antiviral restriction factor that prevents early events in retrovirus replication. The activity of TRIM5α is thought to be limited to retroviruses as a result of highly specific interactions with capsid lattices. In contrast to this current understanding, we show that both human and rhesus macaque TRIM5α suppress replication of specific flaviviruses. Multiple viruses in the tick-borne encephalitis complex are sensitive to TRIM5α-dependent restriction, but mosquito-borne flaviviruses, including yellow fever, dengue, and Zika viruses, are resistant. TRIM5α suppresses replication by binding to the viral protease NS2B/3 to promote its K48-linked ubiquitination and proteasomal degradation. Importantly, TRIM5α contributes to the antiviral function of IFN-I against sensitive flaviviruses in human cells. Thus, TRIM5α possesses remarkable plasticity in the recognition of diverse virus families, with the potential to influence human susceptibility to emerging flaviviruses of global concern.
Assuntos
Infecções por Flavivirus/metabolismo , Peptídeo Hidrolases/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais/metabolismo , Replicação Viral , Animais , Fatores de Restrição Antivirais , Gatos , Chlorocebus aethiops , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Flavivirus/patogenicidade , Flavivirus/fisiologia , Infecções por Flavivirus/virologia , Células HEK293 , Humanos , Ligação Proteica , Proteólise , Especificidade por Substrato , Ubiquitinação , Células VeroRESUMO
Human dengue viruses emerged from primate reservoirs, yet paradoxically dengue does not reach high titers in primate models. This presents a unique opportunity to examine the genetics of spillover versus reservoir hosts. The dengue virus 2 (DENV2) - encoded protease cleaves human STING, reducing type I interferon production and boosting viral titers in humans. We find that both human and sylvatic (reservoir) dengue viruses universally cleave human STING, but not the STING of primates implicated as reservoir species. The special ability of dengue to cleave STING is thus specific to humans and a few closely related ape species. Conversion of residues 78/79 to the human-encoded 'RG' renders all primate (and mouse) STINGs sensitive to viral cleavage. Dengue viruses may have evolved to increase viral titers in the dense and vast human population, while maintaining decreased titers and pathogenicity in the more rare animals that serve as their sustaining reservoir in nature.
Assuntos
Vírus da Dengue/enzimologia , Proteínas de Membrana/metabolismo , Peptídeo Hidrolases/metabolismo , Proteínas Virais/metabolismo , Células A549 , Sequência de Aminoácidos , Animais , Dengue/metabolismo , Dengue/virologia , Vírus da Dengue/genética , Vírus da Dengue/fisiologia , Especificidade de Hospedeiro , Humanos , Proteínas de Membrana/genética , Camundongos , Peptídeo Hidrolases/genética , Primatas/classificação , Primatas/metabolismo , Primatas/virologia , Homologia de Sequência de AminoácidosRESUMO
TRIM25 is an E3 ubiquitin ligase that activates RIG-I to promote the antiviral interferon response. The NS1 protein from all strains of influenza A virus binds TRIM25, although not all virus strains block the interferon response, suggesting alternative mechanisms for TRIM25 action. Here we present a nuclear role for TRIM25 in specifically restricting influenza A virus replication. TRIM25 inhibits viral RNA synthesis through a direct mechanism that is independent of its ubiquitin ligase activity and the interferon pathway. This activity can be inhibited by the viral NS1 protein. TRIM25 inhibition of viral RNA synthesis results from its binding to viral ribonucleoproteins (vRNPs), the structures containing individual viral RNA segments, the viral polymerase, and multiple viral nucleoproteins. TRIM25 binding does not inhibit initiation of capped-RNA-primed viral mRNA synthesis by the viral polymerase. Rather, the onset of RNA chain elongation is inhibited because TRIM25 prohibits the movement of RNA into the polymerase complex.
Assuntos
Influenza Humana/metabolismo , RNA Viral/efeitos dos fármacos , RNA Viral/metabolismo , Ribonucleoproteínas/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Transcrição Gênica/efeitos dos fármacos , Proteínas com Motivo Tripartido/antagonistas & inibidores , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Células A549 , Antivirais/metabolismo , Fatores de Restrição Antivirais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Proteína DEAD-box 58/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Vírus da Influenza A Subtipo H3N2/metabolismo , Vírus da Influenza A/metabolismo , Vírus da Influenza A/patogenicidade , Interferons/metabolismo , Modelos Moleculares , Ligação Proteica , RNA Mensageiro/metabolismo , Receptores Imunológicos , Proteína SUMO-1/genética , Proteína SUMO-1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismoRESUMO
Humans occasionally transmit herpes simplex virus 1 (HSV-1) to captive primates, who reciprocally harbor alphaherpesviruses poised for zoonotic transmission to humans. To understand the basis for the species-specific restriction of HSV-1 in primates, we simulated what might happen during the cross-species transmission of HSV-1 and found that the DNA repair protein Nbs1 from only some primate species is able to promote HSV-1 infection. The Nbs1 homologs that promote HSV-1 infection also interact with the HSV-1 ICP0 protein. ICP0 interaction mapped to a region of structural disorder in the Nbs1 protein. Chimeras reversing patterns of disorder in Nbs1 reversed titers of HSV-1 produced in the cell. By extending this analysis to 1,237 virus-interacting mammalian proteins, we show that proteins that interact with viruses are highly enriched in disorder, suggesting that viruses commonly interact with host proteins through intrinsically disordered domains.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia , Interações Hospedeiro-Patógeno , Proteínas Imediatamente Precoces/metabolismo , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Replicação Viral , Animais , Proteínas de Ciclo Celular/genética , Linhagem Celular , Enzimas Reparadoras do DNA/genética , Humanos , Proteínas Nucleares/genética , Primatas , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Mapeamento de Interação de Proteínas , Homologia de Sequência de Aminoácidos , Carga ViralRESUMO
Evolutionary analyses have revealed that most host-encoded restriction factors against HIV have experienced virus-driven selection during primate evolution. However, HIV also depends on the function of many human proteins, called host factors, for its replication. It is not clear whether virus-driven selection shapes the evolution of host factor genes to the extent that it is known to shape restriction factor genes. We show that five out of 40 HIV host factor genes (13%) analyzed do bear strong signatures of positive selection. Some of these genes (CD4, NUP153, RANBP2/NUP358) have been characterized with respect to the HIV lifecycle, while others (ANKRD30A/NY-BR-1 and MAP4) remain relatively uncharacterized. One of these, ANKRD30A, shows the most rapid evolution within this set of genes and is induced by interferon stimulation. We discuss how evolutionary analysis can aid the study of host factors for viral replication, just as it has the study of host immunity systems.
Assuntos
HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Replicação Viral , Animais , Humanos , Primatas , Seleção GenéticaRESUMO
Recent studies have identified ancient virus genomes preserved as fossils within diverse animal genomes. These fossils have led to the revelation that a broad range of mammalian virus families are older and more ubiquitous than previously appreciated. Long-term interactions between viruses and their hosts often develop into genetic arms races where both parties continually jockey for evolutionary dominance. It is difficult to imagine how mammalian hosts have kept pace in the evolutionary race against rapidly evolving viruses over large expanses of time, given their much slower evolutionary rates. However, recent data has begun to reveal the evolutionary strategy of slowly-evolving hosts. We review these data and suggest a modified arms race model where the evolutionary possibilities of viruses are relatively constrained. Such a model could allow more accurate forecasting of virus evolution.