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PubMed2003

Genetic evolution of human immunodeficiency virus type 1 in two spouses responding successfully to highly active antiretroviral therapy.

The current case study provided an unusual setting to track the evolution of HIV-1 envelope gene over a maximum period of 6 years in two asymptomatic spouses undergoing suppressive highly active antiretroviral therapy. For this purpose, proviral DNA samples taken from uncultured peripheral blood mononuclear cells and spanning the C2-V5 regions of env were analyzed at three sampling points per subject. Two distinct topological patterns were observed in the phylogenetic reconstructions of the genetically linked sequences of the couple: an intermingled pattern and a sequentially shifting pattern in the virus populations of the male index case and his spouse, respectively. Application of three evolutionary models for the amino acid-encoded sites, using the maximum likelihood approach, indicated the operation of positive selection in the region only at the second time point in the woman, before receiving therapy. These findings reinforce the evidence of a crucial role for host-selective constraints on HIV-1 env evolution in vivo.

Antiretroviral Therapy, Highly Active↗
PubMed1999

Timing of human immunodeficiency virus type 1 (HIV-1) transmission from mother to child: bayesian estimation using a mixture.

The timing of mother-to-child HIV transmission is not directly observable but influences the infected child's viral and immune status in the neonatal period. A hierarchical model was developed in a Bayesian framework to 'back-calculate' the timing of HIV-1 transmission from mother to child from the virological and immunological kinetics in the infected infant. Joint evolution of viral markers and immune response was modelled as a continuous time Markov process. The modelling of the period from infection to birth was based on a mixture of three distributions taking into account the various mother-to-child transmission pathways: In utero (early or late in gestation) and intrapartum (during the delivery process), integrating the fact that transmission is a continuum during the pregnancy. Gibbs sampling was used to estimate the marginal posterior distributions of the transition intensities between stages of HIV infection and those of the individual times from infection to birth. We applied our model to data on 135 perinatally HIV-1-infected children included in the French Prospective Study on Pediatric HIV infection. The model suggested that transmission occurred late in utero during the last month of pregnancy and that the day of delivery was a particularly critical time in HIV-1 transmission from mother to child. The paper ends with a discussion of model assumptions and a comparison with results obtained using a non-parametric method.

Antibodies, Viral↗
PubMed1997

Complete coding sequence of hepatitis C virus genotype 6a.

Hepatitis C virus (HCV) genotype 6a is found in a restricted part of South East Asia, including Hong Kong, Macau and Vietnam. We determined the full length coding sequence of a type 6a isolate (EUHK2) obtained from a Hong Kong blood donor. The sequence of EUHK2 contained a single open reading frame coding for a polyprotein of 3018 amino acids, within the range of 3008 to 3037 for other HCV genotypes. The full length sequence of EUHK2 showed 30.3%-32.9% nucleotide (24.3%-29.4% amino acid) sequence divergence from genotypes 1-4, but only 27.7% (20.7% amino acid) divergence from JK046 ("type 11a"). These similarity values were intermediate between those of other HCV genotypes (minimum 28.4%) and between subtypes (maximum 25%). The close evolutionary relationship of EUHK2 with JK046 was further indicated by their grouping together by phylogenetic analysis.

Cloning, Molecular↗
PubMed2003

Impact of clade diversity on HIV-1 virulence, antiretroviral drug sensitivity and drug resistance.

HIV-1 infection is characterized by genetic diversity wherein distinct viral subtypes (clades A, B, C, D, E, F, G, K and O) are expanding in different geographical regions. This article deals with the topic of HIV-1 subtype diversity in the context of sensitivity to antiretroviral drugs, drug resistance and viral fitness. Increasing evidence suggests that all clades of HIV probably display similar sensitivity to antiviral drugs. However, viruses from some subtypes and/or geographical regions may have a greater propensity to develop resistance against certain drugs than do other viral variants. In addition, differences in regard to replication capacity or fitness may exist among various HIV subtypes and differences in this regard may potentially become magnified under conditions of drug resistance. Immunological pressures may also play an important role in the evolution of viral subtypes that may impact on ultimate drug resistance profiles.

Animals↗
PubMed2004

Evolution of the fish rhabdovirus viral haemorrhagic septicaemia virus.

Viral haemorrhagic septicaemia (VHS) caused by the rhabdovirus VHSV is economically the most important viral disease in European rainbow trout farming. Until 1989, this virus was mainly isolated from freshwater salmonids but in the last decade, it has also been isolated from an increasing number of free-living marine fish species. To study the genetic evolution of VHSV, the entire G gene from 74 isolates was analysed. VHSV from wild marine species caught in the Baltic Sea, Skagerrak, Kattegat, North Sea, and English Channel and European freshwater isolates, appeared to share a recent common ancestor. Based on the estimated nucleotide substitution rate, the ancestor of the European fresh water isolates was dated some 50 years ago. This finding fits with the initial reports in the 1950s on clinical observations of VHS in Danish freshwater rainbow trout farms. The study also indicates that European marine VHSV and the North American marine line separated approx. 500 years ago. The codon substitution rate among the freshwater VHSV isolates was found to be 2.5 times faster than among marine isolates. The data support the hypothesis of the marine environment being the original reservoir of VHSV and that the change in host range (to include rainbow trout) may have occurred several times. Virus from the marine environment will therefore continue to represent a threat to the trout aquaculture industry.

Animals↗
PubMed2003

Epidemiology, genetic diversity, and evolution of endemic feline immunodeficiency virus in a population of wild cougars.

Within the large body of research on retroviruses, the distribution and evolution of endemic retroviruses in natural host populations have so far received little attention. In this study, the epidemiology, genetic diversity, and molecular evolution of feline immunodeficiency virus specific to cougars (FIVpco) was examined using blood samples collected over several years from a free-ranging cougar population in the western United States. The virus prevalence was 58% in this population (n = 52) and increased significantly with host age. Based on phylogenetic analysis of fragments of envelope (env) and polymerase (pol) genes, two genetically distinct lineages of FIVpco were found to cooccur in the population but not in the same individuals. Within each of the virus lineages, geographically nearby isolates formed monophyletic clusters of closely related viruses. Sequence diversity for env within a host rarely exceeded 1%, and the evolution of this gene was dominated by purifying selection. For both pol and env, our data indicate mean rates of molecular evolution of 1 to 3% per 10 years. These results support the premise that FIVpco is well adapted to its cougar host and provide a basis for comparing lentivirus evolution in endemic and epidemic infections in natural hosts.

Animals↗
PubMed2005

Simian immunodeficiency virus (SIV) envelope quasispecies transmission and evolution in infant rhesus macaques after oral challenge with uncloned SIVmac251: increased diversity is associated with neutralizing antibodies and improved survival in previously immunized animals.

BACKGROUND: Oral infection of infant macaques with simian immunodeficiency virus (SIV) is a useful animal model to test interventions to reduce postnatal HIV transmission via breast-feeding. We previously demonstrated that immunization of infant rhesus macaques with either modified vaccinia virus Ankara (MVA) expressing SIV Gag, Pol and Env, or live-attenuated SIVmac1A11 resulted in lower viremia and longer survival compared to unimmunized controls after oral challenge with virulent SIVmac251 (Van Rompay et al., J. Virology 77:179-190, 2003). Here we evaluate the impact of these vaccines on oral transmission and evolution of SIV envelope variants. RESULTS: Limiting dilution analysis of SIV RNA followed by heteroduplex mobility assays of the V1-V2 envelope (env) region revealed two major env variants in the uncloned SIVmac251 inoculum. Plasma sampled from all infants 1 week after challenge contained heterogeneous SIV env populations including one or both of the most common env variants in the virus inoculum; no consistent differences in patterns of env variants were found between vaccinated and unvaccinated infants. However, SIV env variant populations diverged in most vaccinated monkeys 3 to 5 months after challenge, in association with the development of neutralizing antibodies. CONCLUSIONS: These patterns of viral envelope diversity, immune responses and disease course in SIV-infected infant macaques are similar to observations in HIV-infected children, and underscore the relevance of this pediatric animal model. The results also support the concept that neonatal immunization with HIV vaccines might modulate disease progression in infants infected with HIV by breast-feeding.

Animals↗
PubMed2001

Follow-up study of intrahost HIV type 2 variability reveals discontinuous evolution of C2V3 sequences.

Sequence change dynamics in the highly polymorphic C2V3 region of the envelope glycoprotein gp105 coding sequence of HIV-2 was studied for two HIV-2 seropositive Guinean individuals over a 5-year period. Proviral DNA was amplified by PCR from uncultured peripheral blood mononuclear cells (PBMC), cloned, and sequenced. Amino acid sequence alignment and phylogenetic analysis showed distinct viral populations for the three collected samples (1992, 1995, and 1997) for both individuals. A discontinuous replacement of sequences suggests activation of latent viruses present in reservoirs, a process that has been documented for the HIV-1 infection but unreported so far for HIV-2. The nucleotide sequences presented in this work have been assigned accession numbers AJ400276 to AJ400319.

Amino Acid Sequence↗
PubMed2004

The origin and evolution of geminivirus-related DNA sequences in Nicotiana.

A horizontal transmission of a geminiviral DNA sequence, into the germ line of an ancestral Nicotiana, gave rise to multiple repeats of geminivirus-related DNA, GRD, in the genome. We follow GRD evolution in Nicotiana tabacum (tobacco), an allotetraploid, and its diploid relatives, and show GRDs are derived from begomoviruses. GRDs occur in two families: the GRD5 family's ancestor integrated into the common ancestor of three diploid species, Nicotiana kawakamii, Nicotiana tomentosa and Nicotiana tomentosiformis, on homeologous group 4 chromosomes. The GRD3 family was acquired more recently on chromosome 2 in a lineage of N. tomentosiformis, the paternal ancestor of tobacco. Both GRD families include individual members that are methylated and diverged. Using relative rates of synonymous and nonsynonymous nucleotide substitutions, we tested for evidence of selection on GRD units and found none within the GRD3 and GRD5 families. However, the substitutions between GRD3 and GRD5 do show a significant excess of synonymous changes, suggesting purifying selection and hence a period of autonomous evolution between GRD3 and GRD5 integration. We observe in the GRD3 family, features of Helitrons, a major new class of putative rolling-circle replicating eukaryotic transposon, not found in the GRD5 family or geminiviruses. We speculate that the second integration event, resulting in the GRD3 family, involved a free-living geminivirus, a Helitron and perhaps also GRD5. Thus our data point towards recurrent dynamic interplay between geminivirus and plant DNA in evolution.

Base Sequence↗
PubMed2003

[Observational study on the efficacy of the application of two classical regimens of triple antiretroviral therapy].

BACKGROUND: To compare the temporal evolution of viral load and CD4 parameters in two cohorts of HIV infected patients enrolled in classical triple antiretroviral regimens. METHODS: Retrospective, observational, descriptive study of the proportions of patients reaching undetectable levels of viral load (VL) as well as the time necessary to get it. The two cohorts were as follows: 91 HIV patients on triple therapy with zidovudine plus lamivudine and indinavir (cohort A) versus 80 HIV patients with Stavudine plus Didanosine and Indinavir (cohort B). RESULTS: The evolution of the patients in terms of percentages who reach undetectable VL was similar in the two therapeutic cohorts (75.8%for cohort A vs 73.8% for cohort B) along the duration of the study (four years). However, the mean time period needed to reach undetectable VL was different, 209 days (IC 95% 175-243 days) for patients in zidovudine plus lamivudine and indinavir and 330 days (IC 95% 263-396 days) for stavudine plus didanosine and indinavir regimen. The immunological status observed in the patients when reaching his first undetectable VL was significantly different. The proportion of patients with CD4 cells counts >200/mm3 in cohort A was 83.1% while for patients from cohort B was 65.4% (p=0.032). CONCLUSIONS: This observational study from clinical settings seems demonstrate similar efficacy to reach undetectable VL with both classical triple antiretroviral therapies evaluated but a shorter delay of time to reach that virological situation for zidovudine plus lamivudine and indinavir regimen is reported.

Anti-HIV Agents↗
PubMed2005

Differential evolution of cell-associated virus in blood and genital tract of HIV-infected females undergoing HAART.

PBMC and vaginal cell (VC) viruses were studied from 5 HIV-infected females for the presence of drug-resistance and non-drug resistance associated mutations. A 1318-bp fragment of polymerase gene was amplified from PBMC and VC proviral DNA. Four of the 5 PBMC viruses exhibited drug resistance-associated mutations in reverse transcriptase and protease genes, whereas only 2 VC viruses contained drug resistance-associated mutations. However, all 5 females showed non-drug resistance-associated mutations both in PBMC and VC virus suggesting continuous evolution of the virus in these compartments. The emergence of drug resistance was slower in PBMC and VC viruses than that observed in the cell-free plasma (P) and vaginal secretion (VS) viruses. Phylogenetic analysis revealed that VC virus was closer to PBMC virus than either cell-free viruses (P and VS) suggesting comparable evolution among cell-associated viruses.

Adult↗
PubMed1999

Identification, sequence analysis and characterisation of equine herpesvirus 5 glycoprotein B.

The complete nucleotide sequence of the gammaherpesvirus equine herpesvirus 5 (EHV5) glycoprotein B (gB) was determined and the deduced amino acid sequence compared with that of the second equine gammaherpesvirus EHV2. EHV5 gB is an 870 amino acid protein and is 79% similar and 66% identical with EHV2 gB at the amino acid level. EHV5 gB like EHV2 gB is a disulphide linked heterodimer with subunits of 92 and 68 kDa. EHV5 gB is an integral membrane glycoprotein containing only N-linked oligosaccharides and contains a putative endoproteolytic cleavages site at amino acids 422-485. The EHV5 gB amino acid sequence showed greatest homology with other members of the Rhadinovirus genus of the subfamily Gammaherpesvirinae. Alignment of EHV5 gB sequence with the gB sequence of seven other gammaherpesviruses showed conservation of 10 cysteine residues as well as conservation of three predicted sites of N-linked glycosylation; the highest degree of conservation of the predicted sites of N-linked glycosylation was observed between EHV5 and the other members of the Rhadinovirus genus. Phylogenetic analysis confirmed EHV2 and EHV5 were most closely related to each other and equally distant from other members of the Rhadinovirus genus included in the analysis.

Amino Acid Sequence↗
PubMed2002

Differential selection of specific human immunodeficiency virus type 1/JC499 variants after mucosal and parenteral inoculation of chimpanzees.

Regardless of the route of transmission, it is generally accepted that the human immunodeficiency virus type 1 (HIV-1) quasispecies transmitted from an infected individual to an uninfected individual is genetically homogeneous. This finding and the observation that HIV-1 genotypes in recipients are minor variants in the donors suggest strongly that selection for specific variants occurs. However, most analyses have been limited to the V3 region of env. In addition, the exact time at which most new infections occurred was not known, making it almost impossible to analyze virus populations present in donor-recipient pairs at the time of HIV-1 transmission. To circumvent this problem, three chimpanzees were inoculated with a genetically defined stock of cell-free HIV-1/JC499 by one of three routes: intravenously or via the cervical or penile mucosa. PCR products of the C2-to-V5 region of env were amplified from both proviral DNA and virion RNA in blood samples collected soon after infection and were screened by heteroduplex analysis (HDA). Those PCR products with distinct HDA banding patterns were cloned and sequenced. In all three animals, transmitted variants encoded one of two V3-loop populations identified in the inoculum, indicating relative homogeneity in this region. However, different virus populations, defined by combinations of specific V4 and V5 sequences, were found when variants in the animal inoculated intravenously (at least 13 V4-plus-V5 combinations) were compared with those in the two animals inoculated by the mucosal routes (limited to only four V4-plus-V5 combinations). The only V4-plus-V5 population in variants found in all three chimpanzees was the major population in the inoculum, which contained viruses with more than 30 different V4-plus-V5 combinations. That the majority of the V4-plus-V5 genotypes in variants transmitted to all three animals were minor populations in the inoculum indicated that selective transmission defined by the V4-plus-V5 regions had occurred but that distinct populations were transmitted by parenteral versus mucosal routes. These results indicate that the putative homogeneity of HIV-1 variants in a newly infected individual might be an artifact of the region of the env gene evaluated and that regions other than V3 might play a major role in selective transmission.

Amino Acid Sequence↗
PubMed1989

RNA virus evolution and the control of viral disease.

RNA viruses and other RNA genetic elements must be viewed as organized distributions of sequences termed quasi-species. This means that the viral genome is statistically defined but individually indeterminate. Stable distributions may be maintained for extremely long time periods under conditions of population equilibrium. Perturbation of equilibrium results in rapid distribution shifts. This genomic organization has many implications for viral pathogenesis and disease control. This review has emphasized the problem of selection of viral mutants resistant to antiviral drugs and the current difficulties encountered in the design of novel synthetic vaccines. Possible strategies for antiviral therapy and vaccine development have been discussed.

Animals↗
PubMed2004

Phylogenetic relationships in the Lymphocryptovirus genus of the Gammaherpesvirinae.

Complete DNA sequences were determined for the glycoprotein B (gB) genes of four viruses from the genus Lymphocryptovirus, whose hosts had been assigned as baboon, orangutan, chimpanzee and gorilla. Together with published sequences for the gB genes of three lymphocryptoviruses, namely the human pathogen Epstein-Barr virus (EBV), a rhesus monkey virus and a marmoset virus, the sequences were used to investigate evolutionary relationships in the genus. The chimpanzee and orangutan viruses' sequences were found to be so close that it is unlikely both represent natural infections in these hosts. Phylogenetic analyses showed that the New World marmoset virus lineage formed a sister clade to that of the Old World viruses, consistent with a cospeciational separation. Within the Old World virus group, resolution of branching pattern was incomplete, and suggestive of a complex history. In particular, it was inferred that separation of the EBV lineage from that of the gorilla virus plus the chimpanzee/orangutan virus may have predated separation of the present day host species.

Animals↗
PubMed2003

Analysis of NCp7-dependent activation of HIV-1 cDNA integration and its conservation among retroviral nucleocapsid proteins.

HIV-1 nucleocapsid protein NCp7 is a small basic protein with two zinc fingers, found in the virion core where several hundred molecules coat the genomic RNA. NCp7 has nucleic acid chaperone properties that guide reverse transcriptase (RT) to synthesize the proviral DNA flanked by the long terminal repeats (LTR). In vitro, NCp7 can strongly activate magnesium-dependent LTR-DNA strand transfer by integrase (IN). Here we show that IN activation relies on both the basic residues and the zinc fingers of NCp7. NCp7 lacking the zinc fingers binds DNA but moderately stimulates strand transfer by IN. The NCp7 zinc-finger domain binds DNA poorly and does not efficiently stimulate IN activity. However, the NC zinc-finger domain can complement DNA binding to restore full activation of strand transfer by IN. We propose that the basic residues and the zinc fingers function together to stabilize IN at the LTR ends and promote the formation of a nucleoprotein complex competent for integration. We also show that these properties of HIV-1 NCp7 are remarkably conserved among nucleocapsid proteins of retrotransposon and retrovirus origins.

Amino Acid Sequence↗
PubMed1999

Characterization of V3 sequence heterogeneity in subtype C human immunodeficiency virus type 1 isolates from Malawi: underrepresentation of X4 variants.

We have examined the nature of V3 sequence variability among subtype C human immunodeficiency virus type 1 (HIV-1) sequences from plasma-derived viral RNA present in infected men from Malawi. Sequence variability was assessed by direct sequence analysis of the V3 reverse transcription-PCR products, examination of virus populations by a subtype C V3-specific heteroduplex tracking assay (V3-HTA), and selected sequence analysis of molecular clones derived from the PCR products. Sequence variability in V3 among the subtype C viruses was not associated with the presence of basic amino acid substitutions. This observation is in contrast to that for subtype B HIV-1, where sequence variability is associated with such substitutions, and these substitutions are determinants of altered coreceptor usage. Evolutionary variants in subtype C V3 sequences, as defined by the V3-HTA, were not correlated with the CD4 level in the infected person, while such a correlation was found with subtype B V3 sequences. Viruses were isolated from a subset of the subjects; all isolates used CCR5 and not CXCR4 as a coreceptor, and none was able to grow in MT-2 cells, a hallmark of the syncytium-inducing phenotype that is correlated with CXCR4 usage. The overall sequence variability of the subtype C V3 region was no greater than that of the conserved regions of gp120. This limited sequence variability was also a feature of subtype B V3 sequences that do not carry the basic amino acid substitutions associated with altered coreceptor usage. Our results indicate that altered coreceptor usage is rare in subtype C HIV-1 isolates in sub-Saharan Africa and that sequence variability is not a feature of the V3 region of env in the absence of altered coreceptor usage.

Base Sequence↗
PubMed1997

Viral phenotype, antiretroviral resistance and clinical evolution in human immunodeficiency virus-infected children.

BACKGROUND: The syncytium-inducing (SI) viral phenotype and the emergence of viral strains resistant to zidovudine have been described in persons infected with HIV, and in some cases they have been associated with poor prognosis. METHODS: HIV isolates obtained from 37 HIV-infected children were analyzed to determine whether the SI viral phenotype and the mutation on the 215 position of the reverse transcriptase (M215) could be used as markers of disease progression. We performed peripheral blood coculture mononuclear cells, and we analyzed the induction of syncytia using the MT-2 cell line. The emergence of mutations on the 215 position was determined by PCR. RESULTS: We found a statistically significant association (P < 0.05) between SI viral phenotype and (1) recurrent serious bacterial infections, (2) absolute CD4+ cell counts <2 SD, (3) progression to AIDS and (4) death. Sixty percent of the children treated with zidovudine developed 215 mutant viral strains without statistically significant association with clinical or immunologic findings. The SI viral phenotype was statistically associated with the presence of the 215 mutation (P < 0.05). CONCLUSIONS: SI viral phenotype is a marker associated with a poor clinical and immunologic progression of the disease and it may facilitate the emergence of mutant strains in children treated with zidovudine.

Adolescent↗