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Earlier this summer, two dozen scientists gathered here to take another crack at the question of viral origins and evolution. Fresh evidence that viruses have existed for billions of years suggests that they were on hand when the first cells arose. That has scientists wondering what role these stripped-down microbes played in the evolution of life.
OBJECTIVE: To investigate the effect of pulse cyclophosphamide treatment on hepatitis C virus (HCV) kinetics and quasispecies in interferon alpha (IFNalpha) resistant HCV related cryoglobulinaemic vasculitis. METHODS: Reports on two patients with severe manifestations of HCV related cryoglobulinaemia who failed to respond to interferon alpha are given. Both patients were treated with pulse cyclophosphamide (750-1000 mg/month for six and 11 months, respectively). HCV RNA was quantified and HCV quasispecies determined in cryoprecipitates and supernatants before and during treatment. RESULTS: Cryocrit and complement activation decreased in both patients with rebound of cryocrit in one case during continuing pulse cyclophosphamide treatment. Vasculitic symptoms improved. Alanine aminotransferase (ALT) levels and HCV viral load (0.2-0.4 log) increased slightly and reached pretreatment levels after cyclophosphamide was stopped. A highly heterogeneous quasispecies was found in the cryoprecipitate and supernatant of one patient, whereas the viral population was homogeneous in the other patient. After six cycles of cyclophosphamide, viral distances decreased non-significantly. However, phylogenetic analysis showed the evolution of distinct viral strains in one patient and replacement of the main viral population by another population in the second patient. CONCLUSIONS: Immunosuppressive treatment with pulse cyclophosphamide has a temporary limited effect on HCV associated cryoglobulinaemia and leads to a reversible increase of ALT levels and HCV viral load. Short term immunosuppression does not affect the viral heterogeneity as measured by amino acid and nucleotide distances in the hypervariable region 1 of HCV. A change of quasispecies was observed, but further studies are needed to evaluate if this does affect the outcome of IFNalpha treatment in such patients.
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A study of 164 consecutive patients (97 males, 67 females; aged 3-11 years) with acute hepatitis was done. Hepatitis A was the most frequent etiologic type. It occurred in 82.7% of the 3-5-year age group, and in 72.2% and 57.2% of the 6-8- and 9-11-year age groups, respectively. Non-A, non-B hepatitis was rather infrequent (4.3%). Hepatitis B occurred in 13.7% of the 3-5-year age group and reached 39.6% in the 9-11-year age group. While all hepatitis A and non-A, non-B cases recovered within a relatively short time, hepatitis B patients recovered more slowly; two cases recovered 1 year after the onset of symptoms. Chronicity was demonstrated in 23.8% of hepatitis B patients 2 years after the onset of the disease. HBsAg clearance was slower in children than in adults. At 4 months, only 59% of patients had serum converted, and a chronic carrier state occurred in 13 of 42 subjects followed for up to 2 years (three healthy carriers and 10 with chronic hepatitis of various types). Our data show that persistence of HBeAg positivity does not always lead to chronicity in children. Of the eight patients HBeAg-positive 1 year after the onset of symptoms, two recovered.
Influenza viruses are the etiological agents of influenza. Although vaccines and drugs are available for the prophylaxis and treatment of influenza virus infections, the generation of escape mutants has been reported. To develop vaccines and drugs that are less susceptible to the generation of escape mutants, it is important to understand the evolutionary mechanisms of the viruses. Here natural selection operating on all the proteins encoded by the H3N2 human influenza A virus genome was inferred by comparing the numbers of synonymous (d(S) [D(S)]) and nonsynonymous (d(N) [D(N)]) substitutions per site. Natural selection was also inferred for the groups of functional amino acid sites involved in B-cell epitopes (BCEs), T-cell epitopes (TCEs), drug resistance, and growth in eggs. The entire region of PB1-F2 was positively selected, and positive selection also appeared to operate on BCEs, TCEs, and growth in eggs. The frequency of escape mutant generation appeared to be positively correlated with the d(N)/d(S) (D(N)/D(S)) values for the targets of vaccines and drugs, suggesting that the amino acid sites under strong functional constraint are suitable targets. In particular, TCEs may represent candidate targets because the d(N)/d(S) (D(N)/D(S)) values were small and negative selection was inferred for many of them.
Approximately 60% of the genome of an adenovirus isolated from a corn snake (Elaphe guttata) was cloned and sequenced. The results of homology searches showed that the genes of the corn snake adenovirus (SnAdV-1) were closest to their counterparts in members of the recently proposed new genus ATADENOVIRUS: In phylogenetic analyses of the complete hexon and protease genes, SnAdV-1 indeed clustered together with the atadenoviruses. The characteristic features in the genome organization of SnAdV-1 included the presence of a gene homologous to that for protein p32K, the lack of structural proteins V and IX and the absence of homologues of the E1A and E3 regions. These characteristics are in accordance with the genus-defining markers of atadenoviruses. Comparison of the cleavage sites of the viral protease in core protein pVII also confirmed SnAdV-1 as a candidate member of the genus ATADENOVIRUS: Thus, the hypothesis on the possible reptilian origin of atadenoviruses (Harrach, Acta Veterinaria Hungarica 48, 484-490, 2000) seems to be supported. However, the base composition of DNA sequence (>18 kb) determined from the SnAdV-1 genome showed an equilibrated GC content of 51%, which is unusual for an atadenovirus.
We characterized 1,534 rotavirus (RV) strains collected in Bangladesh from 1992 to 1997 to assess temporal changes in G type and to study the most common G and P types using reverse transcription-PCR, oligonucleotide probe hybridization, and monoclonal antibody-based enzyme immunoassay. Results from this study combined with our previous findings from 1987 to 1991 (F. Bingnan et al., J. Clin. Microbiol. 29:862-868, 1991, and L. E. Unicomb et al., Arch. Virol. 132:201-208, 1993) (n = 2,515 fecal specimens) demonstrated that the distribution of the four major G types varied from year to year, types G1 to G4 constituted 51% of all strains tested (n = 1,364), and type G4 was the most prevalent type (22%), followed by type G2 (17%). Of 351 strains tested for both G and P types, three globally common types, type P[8], G1, type P[4], G2, and type P[8], G4, comprised 45% (n = 159) of the strains, although eight other strains were circulating during the study period. Mixed G and/or P types were found in 23% (n = 79) of the samples tested. Type G9 RVs that were genotype P[6] and P[8] with both long and short electrophoretic patterns emerged in 1995. The finding of five different genotypes among G9 strains, of which three were frequently detected, suggests that they may have an unusual propensity for reassortment that exceeds that found among the common G types. We also detected antigenic changes in serotypes G2 and G4 over time, as indicated by the loss of reactivity with standard typing monoclonal antibodies. Our data suggest that a vaccine must provide protection against type G9 RVs as well as against the four major G types because G9 strains constituted 16% (n = 56) of the typeable RV strains and have predominated since 1996.
Human influenza A viruses evolve more rapidly than influenza B viruses. To clarify the cause of this difference, we have evaluated the mutation rate of the nonstructural gene as revealed by the genetic diversity observed during the growth of individual plaques in MDCK cells. Six plaques were studied, representing two strains each of type A and B viruses. A total of 813,663 nucleotides were sequenced, giving rates of 2.0 x 10(-6) and 0.6 x 10(-6) mutations per site per infectious cycle, which, when extended to 1 year, agree well with the published annual evolutionary rates.
This is a report about 177 patients suffering acute viral hepatitis type B; 135 (76%) men and 42 (24%) women. Sequential monitoring was carried out of HBe Ag, HBs Ag and their corresponding antibodies until negativitation or positivitation. Even though the immune response was adequate, there were three kinds of response: a) Simultaneous, disappearance of antigens and appearance of antibodies at the same time; 46% for antigen e and 39% for s. b) Late the elimination of antigens preceded the appearance of the antibodies; 37% for antigen e and 34% for antigen s. c) Early, the antibodies anticipated negativitation of antibodies which enables both markers to be detected simultaneously; 17% for antigen e and 27% for antigen s.
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All polynucleotide polymerases have a similar structure and mechanism of catalysis, consistent with their evolution from one progenitor polymerase. Viral RNA-dependent RNA polymerases (RdRp) are expected to have properties comparable to those from this progenitor and therefore may offer insight into the commonalities of all classes of polymerases. We examined RNA synthesis by the brome mosaic virus RdRp on DNA, RNA, and hybrid templates and found that precise initiation of RNA synthesis can take place from all of these templates. Furthermore, initiation can take place from either internal or penultimate initiation sites. Using a template competition assay, we found that the BMV RdRp interacts with DNA only three- to fourfold less well than it interacts with RNA. Moreover, a DNA molecule with a ribonucleotide at position -11 relative to the initiation nucleotide was able to interact with RdRp at levels comparable to that observed with RNA. These results suggest that relatively few conditions were needed for an ancestral RdRp to replicate DNA genomes.
A minority of flies in natural populations of Drosophila melanogaster are endemically infected by a rhabdovirus, sigma. The virus is vertically transmitted through male and female gametes. Two alleles of a fly locus, the ref(2)P locus, are present as a polymorphism in all populations: O permissive, and P restrictive for viral multiplication and transmission. Two viral types are known, Type I, which is very sensitive to the P allele, and Type II, which is more resistant. Previous observations have shown that, in presence of the P allele, viral Type II is selected for, in both natural and experimental populations. The aim of the present study was to determine whether, in the absence of P, Type I is selected for, or whether the two types are equivalent. For this purpose, experimental populations deprived of the P allele and differing in the initial proportions of the two viral types were established. After several generations, and despite a possible bias toward Type I, the frequencies of Type I and Type II clones differed in the various populations, depending on their initial values. These findings do not rule out selective advantage of viral Type I in the absence of P, but suggest that, if any, this advantage is in no way comparable to that displayed by viral Type II in the presence of P.
Developing a non-viral gene delivery system that functions in vivo raises the challenge of finding solutions to efficiently deliver DNA to the cell surface that are also compatible with the efficient release of DNA into the cytosol. The stability, particle size and charge of DNA polyplexes and lipoplexes may be optimized to mediate efficient in vitro transfection only to find that different properties are necessary for successful in vivo transfection. Despite their versatility and improved safety, non-viral gene vectors still lack appreciable in vivo transfection efficiency compared to viral vectors. An emerging theme in recent studies is the use of cross-linking to achieve balance between the stability of polyplexes and lipoplexes in the blood and the controlled release of DNA in the cytosol. This review evaluates the evolution of cross-linking strategies aimed at transiently stabilizing non-viral gene delivery systems.
OBJECTIVES: To evaluate survival, morbidity, and CD4 and viral load (VL) evolution in HIV-infected adults receiving antiretroviral therapy (ART) in Côte d'Ivoire. METHODS: Since 1996, 723 HIV-infected adults have been followed up in the ANRS 1203 cohort study in Abidjan. For those patients who received ART, we describe data between ART initiation and August 2002. RESULTS: One-hundred-and-one adults (61% women) were followed up under ART for a median of 17 months. At ART initiation, median age, CD4 count and VL were 36 years, 135/mm3 and 5.3 log10 copies/ml, respectively. Initial ART regimens were two nucleoside reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor in 74 patients, two NRTIs plus one non-nucleoside reverse transcriptase inhibitor in 16, and two NRTIs in 11. No patient was lost to follow-up. The most frequent causes of severe morbidity were bacterial infections [11.6/100 person-years (PY), 95% CI: 7.2-18.7], drug-related events (6.5/100 PY, 3.5-12.0), tuberculosis (3.1/100 PY, 1.3-7.4) and malaria (3.1/100 PY, 1.3-7.4). The incidence of death was 3.0/100 PY (1.1-8.0) in patients with baseline CD4 > or = 50/mm3 and 16.1/100 PY (7.2-35.9) in patients with CD4 < 50/mm3. Fifty percent of causes of death were active infections pre-existing ART initiation, mainly atypical mycobacteriosis. After 1 year, 51% of patients had undetectable VL, 28% had detectable VL reduced by more than 0.5 log10 copies/ml since ART initiation, and the median gain in CD4 was +115/mm3. CONCLUSION: Medium-term survival under ART may be as good in Africa as in industrialized countries, provided that patients benefit from access to care for opportunistic infections, including bacterial diseases, tuberculosis and malaria.
Adeno-associated viral vectors are highly safe and efficient gene delivery vehicles. However, numerous challenges in vector design remain, including neutralizing antibody responses, tissue transport and infection of resistant cell types. Changes must be made to the viral capsid to overcome these problems; however, very often insufficient information is available for rational design of improvements. We therefore applied a directed evolution approach involving the generation of large mutant capsid libraries and selection of adeno-associated virus (AAV) 2 variants with enhanced properties. High-throughput selection processes were designed to isolate mutants within the library with altered affinities for heparin or the ability to evade antibody neutralization and deliver genes more efficiently than wild-type capsid in the presence of anti-AAV serum. This approach, which can be extended to additional gene delivery challenges and serotypes, directs viral evolution to generate 'designer' gene delivery vectors with specified, enhanced properties.