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PubMed1998

Caspar carboxylates: the structural basis of tobamovirus disassembly.

Carboxylate groups have been known for many years to drive the disassembly of simple viruses, including tobacco mosaic virus (TMV). The identities of the carboxylate groups involved and the mechanism by which they initiate disassembly have not, however, been clear. Structures have been determined at resolutions between 2.9 and 3.5 A for five tobamoviruses by fiber diffraction methods. Site-directed mutagenesis has also been used to change numerous carboxylate side chains in TMV to the corresponding amides. Comparison of the stabilities of the various mutant viruses shows that disassembly is driven by a much more complex set of carboxylate interactions than had previously been postulated. Despite the importance of the carboxylate interactions, they are not conserved during viral evolution. Instead, it appears that during evolution, patches of electrostatic interaction drift across viral subunit interfaces. The flexibility of these interactions confers a considerable advantage on the virus, enabling it to change its surface structure rapidly and thus evade host defenses.

Binding Sites↗

PubMed2005

A subset of human immunodeficiency virus type 1 long-term non-progressors is characterized by the unique presence of ancestral sequences in the viral population.

Within human immunodeficiency virus type 1 (HIV-1)-infected patients, there are those who have been infected for more than 10 years with a CD4+ cell count of >500 cells microl(-1) and who remain asymptomatic without antiretroviral therapy; these patients are designated long-term non-progressors (LTNPs). In a set of 16 LTNPs, viral dating, DNA viral load, quasispecies heterogeneity and antibody (Ab) titres against gp160 and beta2 microglobulin (beta2m) were determined. Plasma viral RNA and CD4+ and CD8+ T-cell numbers were estimated in more than three samples per patient. Host genetic characteristics, such as Delta32-CCR5 genotype and human leukocyte antigen (HLA) genotype and supertypes, and clinical-epidemiological factors were evaluated. Dating of global populations and of DNA and RNA viral quasispecies identified two subsets of patients: one displaying only ancestral sequences and the other displaying predominantly modern sequences. The ancestral patients displayed a significant reduction in RNA and DNA viral loads, quasispecies heterogeneity, CD8+ cell number, anti-gp160 Ab titres and beta2m level, and they were also associated with better use of safe-sex practices and higher presence of the HLA sB58 supertype than the modern subset. Viral dating has therefore permitted the segregation of LTNPs into two subsets that show very different virological, immunological, host and clinical-epidemiological characteristics. Moreover, whereas the modern subset displayed low levels of virus replication, the ancestral group displayed not only a very limited virus replication, often to undetectable levels, but also very slow or arrested viral evolution, maintaining the close relationship of the viral population to the transmitted virus.

CD4-CD8 Ratio↗

PubMed1999

TT virus infection in patients with hepatitis C: frequency, persistence, and sequence heterogeneity.

TT virus (TTV) was recently identified in the serum of a patient with hepatitis. The role of TTV in liver disease has not been established. Three polymerase chain reaction (PCR) protocols were used to detect TTV DNA in sera of persons infected with hepatitis C virus (HCV) and in blood donors. Sera from 11.5% of HCV-infected patients and 7.7% of blood donors were positive by protocols 1 or 2. In contrast, 48.7% and 57.7% of sera, respectively, were positive when tested by protocol 3. There was no difference in the severity of hepatitis in persons coinfected with TTV and HCV when compared with those infected with HCV alone, regardless of which TTV PCR protocol was used. TTV DNA persisted in serum samples taken up to 6 years apart in individual patients. Sequence analysis indicated that most viral sequences were distinct between patients, and there was evidence of genetic heterogeneity and viral evolution within individuals.

Adolescent↗

PubMed2025

Diversity and evolutionary history of endogenous retroviruses in the genome of Manis pentadactyla.

Endogenous retroviruses (ERVs), remnants of ancient viral infections integrated into host genomes, serve as invaluable molecular fossils for studying viral evolution. In this study, we performed a genomic analysis of the Chinese pangolin (Manis pentadactyla), identifying novel full-length endogenous retroviruses, designated as Manis pentadactyla ERVs (MPERVs). MPERVs span three retroviral genera: Alpha-, Beta-, and Gamma-retroviruses. Using genomic screening and phylogenetic analysis, we classified MPERVs and reconstructed their evolutionary history, uncovering evidence of complex recombination events and cross-species transmission. Estimated insertion times for MPERVs range from very recent to 18.38 million years ago. MPERVs exhibit diverse structural features, notably including conserved retroviral domains and functional motifs and highlighting their preservation across extensive evolutionary periods. These findings shed light on the evolutionary dynamics of ERVs in Chinese pangolin and suggest the potential for expanded host ranges among certain retrovirus genera.IMPORTANCEEndogenous retroviruses are unique viruses distinguished by the fact that they are retained as part of the host genome after an exogenous retrovirus infects the host. The Chinese pangolin, as a host with a long independent evolutionary history, likely holds valuable insights in its genome regarding retrovirus endogenization and transmission. In this study, we identified the footprints of exogenous retroviruses from three different genera in the pangolin genome: Alpharetrovirus, Betaretrovirus, and Gammaretrovirus. Additionally, by calculating the integration times of the pangolin's endogenous retroviruses and analyzing the domains of the three main functional proteins (GAG, POL, and ENV), we found that the insertions are relatively young. This suggests that these endogenous retroviruses infected the Chinese pangolin long before their endogenization. This study represents the exploration of endogenous retroviruses in the Chinese pangolin genome, expanding our understanding of endogenous retroviruses in mammals. Furthermore, our findings provide new evidence for the phenomenon of the cross-species transmission of retroviruses prior to endogenization.

Endogenous Retroviruses↗

PubMed2006

Stochastic processes are key determinants of short-term evolution in influenza a virus.

Understanding the evolutionary dynamics of influenza A virus is central to its surveillance and control. While immune-driven antigenic drift is a key determinant of viral evolution across epidemic seasons, the evolutionary processes shaping influenza virus diversity within seasons are less clear. Here we show with a phylogenetic analysis of 413 complete genomes of human H3N2 influenza A viruses collected between 1997 and 2005 from New York State, United States, that genetic diversity is both abundant and largely generated through the seasonal importation of multiple divergent clades of the same subtype. These clades cocirculated within New York State, allowing frequent reassortment and generating genome-wide diversity. However, relatively low levels of positive selection and genetic diversity were observed at amino acid sites considered important in antigenic drift. These results indicate that adaptive evolution occurs only sporadically in influenza A virus; rather, the stochastic processes of viral migration and clade reassortment play a vital role in shaping short-term evolutionary dynamics. Thus, predicting future patterns of influenza virus evolution for vaccine strain selection is inherently complex and requires intensive surveillance, whole-genome sequencing, and phenotypic analysis.

Antigenic Variation↗

PubMed2006

Reactivation of ancestral strains of HIV-1 in the gp120 V3 env region in patients failing antiretroviral therapy and subjected to structured treatment interruption.

We analyzed gp120V3 HIV-1 env region genetic diversity of 27 patients failing antiretrovirals and subjected to 12-week structured treatment interruption (STI). Based on heteroduplex mobility assays, eight patients presented low pre- and post-STI genetic diversity (G1); five presented high pre-STI but low post-STI diversity (G2); five presented low pre-STI and high post-STI diversity (G3); and nine, high pre- and post-STI diversity (G4). One patient from G1, two from G2 and two from G3 were subjected to proviral DNA end-point PCR and sequencing. In three patients, the dramatic disturbance caused by STI resulted in ancestral viral progeny activation, which repopulated the cell reservoir. In two patients presenting highly homogeneous sequences and low immune selective pressure (dN/dS ratio <1), this phenomenon was not observed. The mechanisms involved in viral evolution, in which antiretroviral therapy also applies selective pressure, sometimes affects coreceptor usage of circulating viruses, leading to the suppression of x4 strains.

Amino Acid Sequence↗

PubMed2004

Long-term suppression of plasma viremia with highly active antiretroviral therapy despite virus evolution and very limited selection of drug-resistant genotypes.

HIV-1 evolution and the possible emergence of mutations associated with resistance to antiretroviral inhibitors have been evaluated in a cohort of sixty-three patients successfully treated with highly active antiretroviral therapy (HAART). The patients under effective HAART were recruited in three different hospitals in Spain, and none of them had been treated (naïve) before entering this study. HIV-1 RNA levels, CD4+, and CD8+ T-cell counts were determined, and nucleotide sequences of proviral regions encoding protease and reverse transcriptase (RT) were obtained for longitudinal blood samples spanning a mean follow-up period of 88 weeks. Phylogenetic reconstructions and calculations of genetic distances among the different sequences of each patient were performed. All except one of the patients under study showed an early and sustained decrease in plasma HIV-1 RNA to levels that were below 200 copies/ml. The plasma viral decline paralleled a significant increase in the CD4+ T-lymphocyte counts. Amino acid sequence analyses revealed the occurrence of mutations associated with antiretroviral resistance in nine patients (14.3%) during HAART treatment, that in some cases could be attributed to excess G to A transitions. In six of the nine patients, the mutations conferred resistance to inhibitors administered in the treatment regime, although the mutations did not result in treatment failure. Sequence comparisons revealed viral evolution during the period of treatment in 47.5% of the patients. The results indicate successful suppression of HIV-1 under HAART for extended time periods, indistinguishable for patients in which evidence of virus evolution could or could not be documented.

Adult↗

PubMed2026

Epistasis and the changing fitness landscapes of SARS-CoV-2.

Since its emergence in late 2019, millions of SARS-CoV-2 genomes have been generated as part of global efforts to monitor the evolution and spread of the virus. This unprecedented volume of data provides a unique opportunity to study viral evolution at unparalleled resolution. In particular, individual genomic sites can be observed to have mutated independently thousands of times. These mutation counts have been used to estimate site-specific mutation rates and fitness effects for most mutations across the viral genome. Here, we use these data to investigate how the landscape of mutational fitness costs has changed over the course of the pandemic. SARS-CoV-2 evolution over the past 6 years has been characterized by the emergence of distinct variants separated by long branches corresponding to evolutionary saltations involving up to 50 mutations. We compare inferred fitness landscapes of the Spike protein across these variants and find that shifts in the estimated effects of non-synonymous mutations are linked to genetic differences between them. Sites with altered fitness costs are enriched near positions where the genetic backgrounds differ. To explain the observed changes, we introduce a model with pairwise epistatic interactions between mutations and residues that differ between variants. This model is able to explain about half of the variance in the shifts of fitness effects and suggests that each mismatch between variants substantially alters mutation effects at typically 1 to 3 additional positions.

SARS-CoV-2↗

PubMed2004

High-resolution phylogenetic analysis of hepatitis C virus adaptation and its relationship to disease progression.

Hepatitis C virus (HCV) persists in the majority of those infected despite host immune responses. Evidence has accrued that selectively fixed mutations in the envelope genes (E1 and E2) are associated with viral persistence, particularly those that occur within the first hypervariable region of E2 (HVR1). However, the individual amino acid residues under selection have not been identified, nor have their selection pressures been measured, despite the importance of this information for understanding disease pathogenesis and for vaccine design. We performed a high-resolution analysis of published gene sequence data from individuals undergoing acute HCV infection, employing two phylogenetic methods to determine site-specific selection pressures. Strikingly, we found a statistically significant association between the number of sites selected and disease outcome, with the fewest selected sites in fulminant HCV cases and the greatest number of selected sites in rapid progressors, reflecting the duration and intensity of the arms race between host and virus. Moreover, sites outside the HVR1 appear to play a major role in viral evolution and pathogenesis, although there was no association between viral persistence and specific mutations in E1 and E2. Our analysis therefore allows fine dissection of immune selection pressures, which may be more diverse than previously thought. Such analyses could play a similarly informative role in studies of other persistent virus infections, such as human immunodeficiency virus.

Acute Disease↗

PubMed2003

Characterization of DNAbeta associated with begomoviruses in China and evidence for co-evolution with their cognate viral DNA-A.

Eighteen samples of begomoviruses isolated from tobacco, tomato and weed species in Yunnan, China were found to be associated with DNAbeta molecules, for which the complete nucleotide sequences were found to contain 1333-1355 nt. The 18 DNAbeta molecules identified consist of three main types, each associated with a different begomovirus species: 72-99 % nucleotide identity was found within one type, but only 39-57 % identity was found between types. All the DNAbeta molecules reported here and elsewhere contain a 115 nt conserved region that has 93-100 % identity with a consensus sequence, and have a common ORF encoding 118 amino acids on the complementary strand (designated C1). Co-agroinoculation of the DNA-A component of Tomato yellow leaf curl China virus tobacco isolate Y10, with its associated DNAbeta (Y10beta), shows this DNAbeta to be involved in symptom induction in tobacco and tomato. The in-frame ATG mutation of C1 of Y10beta caused much milder symptoms as compared with wild Y10beta, indicating a functional role for this ORF. Pairwise nucleotide sequence identity comparisons of DNAbeta molecules and their cognate viral DNA-A molecules indicate that DNAbeta molecules have co-evolved with their cognate helper viruses. Recombination between DNAbeta molecules is documented and a DNAbeta species concept is proposed and discussed.

Base Sequence↗

PubMed2006

Understanding human immunodeficiency virus type 1 and hepatitis C virus coinfection.

In recent years, there has been an alarming increase in the number of cases of coinfection with the human immunodeficiency virus type 1 (HIV-1) and the hepatitis C virus (HCV). It is now known that coinfection of HIV-1 patients by HCV can complicate the treatment of these patients with highly active antiretroviral therapy and the interactions between anti-HIV-1 and anti-HCV medications can also affect treatment efficacy and efficiency. Equally concerning, the bidirectional interferences between the two viruses are complex and can modify the natural history of both infections. This review aims to summarize the findings of numerous scientific investigations in the area of HIV/HCV coinfection. These investigations can be broadly classified into 3 groups; (a) immune evasion mechanisms (b) viral evolution and quasispecies diversity and (c) functions of viral proteins and their interactions with host factors. Our cumulative knowledge in this area and future research on the interplay between these two viruses will be important to the development of better antiviral therapeutics.

Anti-HIV Agents↗

PubMed2002

Modeling viral genome fitness evolution associated with serial bottleneck events: evidence of stationary states of fitness.

Evolution of fitness values upon replication of viral populations is strongly influenced by the size of the virus population that participates in the infections. While large population passages often result in fitness gains, repeated plaque-to-plaque transfers result in average fitness losses. Here we develop a numerical model that describes fitness evolution of viral clones subjected to serial bottleneck events. The model predicts a biphasic evolution of fitness values in that a period of exponential decrease is followed by a stationary state in which fitness values display large fluctuations around an average constant value. This biphasic evolution is in agreement with experimental results of serial plaque-to-plaque transfers carried out with foot-and-mouth disease virus (FMDV) in cell culture. The existence of a stationary phase of fitness values has been further documented by serial plaque-to-plaque transfers of FMDV clones that had reached very low relative fitness values. The statistical properties of the stationary state depend on several parameters of the model, such as the probability of advantageous versus deleterious mutations, initial fitness, and the number of replication rounds. In particular, the size of the bottleneck is critical for determining the trend of fitness evolution.

Animals↗

PubMed2000

How can human and simian immunodeficiency viruses utilize chemokine receptors as their coreceptors?

Several chemokine receptors (CKRs) act as coreceptors of human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2) and simian immunodeficiency virus (SIV). These CKRs interact with the V3 domain of the envelope (env) protein of HIV/SIV. In this study, we found that the amino acid sequences of two chemokines (SDF-1beta and RANTES), whose receptors (CXCR4 and CCR5) act as major coreceptors for HIV-1, HIV-2 or SIV, showed statistically significant similarity to those of the region containing the third variable (V3) and the third conserved (C3) domains (the V3--C3 domain) of the env protein of HIV-1 and HIV-2. We made a multiple alignment of amino acid sequences for 24 chemokines and the region encompassing the second conserved (C2), V3 and C3 domains (the C2--V3--C3 region) of 10 strains of HIV/SIV. Surprisingly, the hydropathic profile and several important amino acids for protein conformation, such as cysteine and tryptophan, are remarkably conserved between chemokines and the V3--C3 region of HIV/SIV. Moreover, hydrophobic amino acids, such as leucine, isoleucine and valine, are found to be clustered both in the amino-terminal region of chemokines and the C2 domain of HIV/SIV. Thus, chemokines have significantly similar profiles of amino acid properties to those of the C2--V3--C3 region of the env protein of HIV/SIV. These findings raise a hypothesis that chemokines and the C2--V3--C3 region have a common origin. Namely, the HIV/SIV ancestor incorporated a chemokine gene into its env gene. The captured chemokine gene has rapidly diverged by frequent mutations specific to the retroviral genome, and thereby obtained the ability to interact with various CKRs in a short period of time. This paper proposes that the capture of a ligand gene of the host cells into the viral genome may be one of the important mechanisms of viral evolution to expand its host range and generate new viral species.

Amino Acid Sequence↗

PubMed2006

An aged host promotes the evolution of avirulent coxsackievirus into a virulent strain.

The emergence of new, more pathogenic viruses necessitates elucidation of factors that promote viral evolution. Aging, a potential factor, is associated with increased susceptibility to viral infections. We used the enterovirus coxsackievirus B3 (CVB3) to investigate the effects of host age on pathogenicity and viral gene sequence. Old mice infected with a normally amyocarditic strain of CVB3, CVB3/0, had significantly higher mean heart viral titers compared with CVB3/0-infected adult mice. To determine whether a change in the CVB3/0 viral population could contribute to the higher titers observed in the old infected mice, CVB3/0 was passed once through an old or adult host and the changes in pathogenicity and viral genome were examined after subsequent infection of old or adult mice. Adult mice infected with CVB3/0 that was passed through an old host (CVB3/0(Old)) exhibited significantly higher heart viral titers, pathology, and weight loss than adult mice infected with either stock CVB3/0 or CVB3/0 passed through an adult host (CVB3/0(Adult)). Sequence analysis of virus isolated from CVB3/0(Old)-infected mice revealed 13 specific and reproducible nucleotide changes. These changes result in a sequence that matches the virulent CVB3/20 strain and are associated with promoting cardiovirulence. In contrast, we observed only one nucleotide change, low heart viral titers, and no heart and liver pathology in adult mice infected with CVB3/0(Adult). These results demonstrate that the aged host promotes rapid selection of a pathogenic variant of CVB3 from an avirulent strain and introduces a host-virus paradigm for studies of viral infection in the aged.

Aging↗

PubMed2006

Epochal evolution shapes the phylodynamics of interpandemic influenza A (H3N2) in humans.

Human influenza A (subtype H3N2) is characterized genetically by the limited standing diversity of its hemagglutinin and antigenically by clusters that emerge and replace each other within 2 to 8 years. By introducing an epidemiological model that allows for differences between the genetic and antigenic properties of the virus's hemagglutinin, we show that these patterns can arise from cluster-specific immunity alone. Central to the formulation is a genotype-to-phenotype mapping, based on neutral networks, with antigenic phenotypes, not genotypes, determining the degree of strain cross-immunity. The model parsimoniously explains well-known, as well as previously unremarked, features of interpandemic influenza dynamics and evolution. It captures the observed boom-and-bust pattern of viral evolution, with periods of antigenic stasis during which genetic diversity grows, and with episodic contraction of this diversity during cluster transitions.

Amino Acid Substitution↗

PubMed1996

Genome rearrangements of rotaviruses.

Rotaviruses (and other members of the Reoviridae family) undergo rearrangements of their genomes. This review describes evidence of rearranged genomes in rotaviruses. Their structure and functions are reviewed. Possible mechanisms of their emergence are discussed, and the significance of genome rearrangements for viral evolution is considered.

Animals↗

PubMed1998

Chemokine coreceptor usage by diverse primary isolates of human immunodeficiency virus type 1.

We tested chemokine receptor subset usage by diverse, well-characterized primary viruses isolated from peripheral blood by monitoring viral replication with CCR1, CCR2b, CCR3, CCR5, and CXCR4 U87MG.CD4 transformed cell lines and STRL33/BONZO/TYMSTR and GPR15/BOB HOS.CD4 transformed cell lines. Primary viruses were isolated from 79 men with confirmed human immunodeficiency virus type 1 (HIV-1) infection from the Chicago component of the Multicenter AIDS Cohort Study at interval time points. Thirty-five additional well-characterized primary viruses representing HIV-1 group M subtypes A, B, C, D, and E and group O and three primary simian immunodeficiency virus (SIV) isolates were also used for these studies. The restricted use of the CCR5 chemokine receptor for viral entry was associated with infection by a virus having a non-syncytium-inducing phenotype and correlated with a reduced rate of disease progression and a prolonged disease-free interval. Conversely, broadening chemokine receptor usage from CCR5 to both CCR5 and CXCR4 was associated with infection by a virus having a syncytium-inducing phenotype and correlated with a faster rate of CD4 T-cell decline and progression of disease. We also observed a greater tendency for infection with a virus having a syncytium-inducing phenotype in men heterozygous for the defective CCR5 Delta32 allele (25%) than in those men homozygous for the wild-type CCR5 allele (6%) (P = 0.03). The propensity for infection with a virus having a syncytium-inducing phenotype provides a partial explanation for the rapid disease progression among some men heterozygous for the defective CCR5 Delta32 allele. Furthermore, we did not identify any primary viruses that used CCR3 as an entry cofactor, despite this CC chemokine receptor being expressed on the cell surface at a level commensurate with or higher than that observed for primary peripheral blood mononuclear cells. Whereas isolates of primary viruses of SIV also used STRL33/BONZO/TYMSTR and GPR15/BOB, no primary isolates of HIV-1 used these particular chemokine receptor-like orphan molecules as entry cofactors, suggesting a limited contribution of these other chemokine receptors to viral evolution. Thus, despite the number of chemokine receptors implicated in viral entry, CCR5 and CXCR4 are likely to be the physiologically relevant chemokine receptors used as entry cofactors in vivo by diverse strains of primary viruses isolated from blood.

Animals↗

PubMed2003

Acute hepatitis C in a chronically HIV-infected patient: evolution of different viral genomic regions.

AIM: To analyze the molecular evolution of different viral genomic regions of HCV in an acute HCV infected patient chronically infected with HIV through a 42-month follow-up. METHODS: Serum samples of a chronically HIV infected patient that seroconverted to anti HCV antibodies were sequenced, from the event of superinfection through a period of 17 months and in a late sample (42nd month). Hypervariable genomic regions of HIV (V3 loop of the gp120) and HCV (HVR-1 on the E2 glycoprotein gene) were studied. In order to analyze genomic regions involved in different biological functions and with the cellular immune response, HCV core and NS5A were also chosen to be sequenced. Amplification of the different regions was done by RT-PCR and directly sequenced. Confirmation of sequences was done on reamplified material. Nucleotide sequences of the different time points were aligned with CLUSTAL W 1.5, and the corresponding amino acid ones were deduced. RESULTS: Hypervariable genomic regions of both viruses (HVR1 and gp120 V3 loop) presented several nonsynonymous changes but, while in the gp120 V3 loop mutations were detected in the sample obtained right after HCV superinfection and maintained throughout, they occurred following a sequential and cumulative pattern in the HVR1. In the NS5A region of HCV, two amino acid changes were detected during the follow-up period, whereas the core region presented several amino acid replacements, once the HCV chronic infection had been established. CONCLUSION: During the HIV-HCV superinfection, each genomic region analyzed shows a different evolutionary pattern. Most of the nucleotide substitutions observed are non-synonymous and clustered in previously described epitopes, thus suggesting an immune-driven evolutionary process.

Acute Disease↗