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PubMed1998

mtDNA analysis of a prehistoric Oneota population: implications for the peopling of the New World.

mtDNA was successfully extracted from 108 individuals from the Norris Farms Oneota, a prehistoric Native American population, to compare the mtDNA diversity from a pre-Columbian population with contemporary Native American and Asian mtDNA lineages and to examine hypotheses about the peopling of the New World. Haplogroup and hypervariable region I sequence data indicate that the lineages from haplogroups A, B, C, and D are the most common among Native Americans but that they were not the only lineages brought into the New World from Asia. The mtDNA evidence does not support the three-wave hypothesis of migration into the New World but rather suggests a single "wave" of people with considerable mtDNA diversity that exhibits a signature of expansion 23,000-37,000 years ago.

DNA, Mitochondrial↗

PubMed2000

mtDNA affinities of the peoples of North-Central Mexico.

mtDNA haplotypes of representatives of the cosmopolitan peoples of north-central Mexico were studied. Two hundred twenty-three samples from individuals residing in vicinities of two localities in north-central Mexico were analyzed. A combination of strategies was employed to identify the origin of each haplotype, including length variation analysis of the COII and tRNALYS intergenic region, nucleotide sequence analysis of control region hypervariable segment 1, and RFLP analysis of PCR products spanning diagnostic sites. Analysis of these data revealed that the majority of the mtDNA haplotypes were of Native American origin, belonging to one of four primary Native American haplogroups. Others were of European or African origin, and the frequency of African haplotypes was equivalent to that of haplotypes of European derivation. These results provide diagnostic, discrete character, molecular genetic evidence that, together with results of previous studies of classical genetic systems, is informative with regard to both the magnitude of African admixture and the relative maternal contribution of African, European, and Native American peoples to the genetic heritage of Mexico. Phylogenetic analysis revealed that African sequences formed a basal, paraphyletic group.

Africa↗

PubMed2000

Longitudinal analysis of hepatitis C virus replication and liver fibrosis progression in renal transplant recipients.

The pathogenesis of hepatitis C virus (HCV) infection was investigated by analysis of changes in viral and histologic parameters in 36 renal transplant recipients who were infected with HCV before transplantation. Each patient was classified according to development of liver fibrosis as assessed by 2 liver biopsies done 45 and 81 months after transplantation: 13 had progressing liver fibrosis (fibrosers) and 23 did not (nonfibrosers). All developed high-titer posttransplant viremia with a significant increase of 1.2 log RNA copies/mL. There were no significant differences in the increases in serum HCV RNA or genotype distributions in fibrosers and nonfibrosers. The hypervariable region (HVR)-1 of the HCV genome was analyzed by cloning and sequencing 20 clones per sample from 5 fibrosers and 5 nonfibrosers. Comparison of samples revealed that liver fibrosis progression was significantly associated with slower HVR-1 quasispecies diversification, suggesting the selection of more aggressive variants in fibrosers.

Adult↗

PubMed2002

Association of symptomatic acute human parvovirus B19 infection with human leukocyte antigen class I and II alleles.

To determine the effect of the major histocompatibility complex on the development of symptoms during acute human parvovirus B19 infection, we compared human leukocyte antigen (HLA) class I and II alleles in 36 patients with symptomatic acute B19 infection with those in >900 control subjects from northwestern England. The frequency of each of HLA-DRB1*01 (P=.016), DRB1*04 (P=.007), and DRB1*07 (P<.0001) alleles was significantly higher in parvovirus B19 patients than in control subjects. In the parvovirus group, 63.9% carried the rheumatoid arthritis-associated shared epitope sequence, compared with 45% of control subjects (odds ratio [OR], 2.2; 95% confidence interval [CI], 0.97-4.8; P=.04), and carriage was associated with fatigue during the acute phase (OR, 4.2; 95% CI, 0.8-23.9; P=.047). All symptomatic parvovirus-associated HLA-DRB1 molecules carry a neutrally charged glutamine at position 10 and a positively charged lysine at position 12 of the first hypervariable region. HLA-B49 was associated with parvovirus infection independently of HLA-DRB1*01, DRB1*04, and DRB1*07.

Acute Disease↗

PubMed2002

Distribution patterns of postmortem damage in human mitochondrial DNA.

The distribution of postmortem damage in mitochondrial DNA retrieved from 37 ancient human DNA samples was analyzed by cloning and was compared with a selection of published animal data. A relative rate of damage (rho(v)) was calculated for nucleotide positions within the human hypervariable region 1 (HVR1) and cytochrome oxidase subunit III genes. A comparison of damaged sites within and between the regions reveals that damage hotspots exist and that, in the HVR1, these correlate with sites known to have high in vivo mutation rates. Conversely, HVR1 subregions with known structural function, such as MT5, have lower in vivo mutation rates and lower postmortem-damage rates. The postmortem data also identify a possible functional subregion of the HVR1, termed "low-diversity 1," through the lack of sequence damage. The amount of postmortem damage observed in mitochondrial coding regions was significantly lower than in the HVR1, and, although hotspots were noted, these did not correlate with codon position. Finally, a simple method for the identification of incorrect archaeological haplogroup designations is introduced, on the basis of the observed spectrum of postmortem damage.

Animals↗

PubMed2003

Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection.

The existence of extrahepatic sites of hepatitis C virus (HCV) replication has been proposed as a mechanism responsible for the poor antiviral immune response found in chronic infection. Dendritic cells (DCs), as unique antigen-presenting cells able to induce a primary immune response, are prime targets of persistent viruses. From 24 blood samples obtained from HCV-seropositive patients, peripheral blood DCs (PBDCs) were purified. HCV genomic sequences were specifically detected by reverse-transcription polymerase chain reaction in 6 of 24 PBDC pellets, and replicative-strand RNA also was found in 3 of 24 cell purifications. Analysis of the HCV quasi-species distribution in the PBDC population of 1 patient showed the presence of a dominant variant different from that found in plasma with respect to the primary amino-acid sequence and physicochemical profile of the hypervariable region 1 of glycoprotein E2. These data strongly suggest that PBDCs constitute a reservoir in which HCV replication takes place during natural infection.

Adult↗

PubMed2004

Complexity and diversity of hepatitis C virus RNA in african americans and whites: analysis of the envelope-coding domain.

African Americans infected with hepatitis C virus (HCV) are less responsive than whites to interferon-based therapy. HCV quasi species have been implicated. Quasi-species complexity and diversity were evaluated in matched African American and white individuals. Complexity and diversity in the first hypervariable region were similar in the 2 groups. Both the frequency of nonsynonymous amino acid substitutions and the mean ratio of nonsynonymous mutations to synonymous mutations were greater in clones derived from white patients. Racial differences in amino acid usage at otherwise conserved positions were observed. Differences in amino acid representation at key positions are suggestive of immunologic and functional selection along racial lines.

Adult↗

PubMed2005

Reemergence of hepatitis C virus after 8.5 years in a patient with hypogammaglobulinemia: evidence for an occult viral reservoir.

The question of whether viruses persist after apparent clearance of infection remains unanswered. Here, we describe a patient with hypogammaglobulinemia whose acute hepatitis C virus (HCV) infection appeared to resolve after receipt of interferon therapy, relapse immediately, and then clear spontaneously--only to relapse after receipt of corticosteroid therapy, and clear again, 8.5 years later. Sequencing indicated that the viruses detected during each relapse were virtually identical, with the hypervariable region 1 of E2 appearing to be monoclonal, which is typical of patients with hypogammaglobulinemia. Nonstructural 5A sequences exhibited quasispecies diversity initially but, after 8.5 years, had become monoclonal. The prolonged period of negativity for HCV RNA followed by relapse suggests that HCV may persist in apparent sustained viral responders.

Adrenal Cortex Hormones↗

PubMed2001

Rapid molecular typing of methicillin-resistant Staphylococcus aureus by PCR-RFLP.

OBJECTIVE: To establish a new, rapid, and reliable genotypic fingerprinting technique for methicillin-resistant Staphylococcus aureus (MRSA) typing in routine epidemiological surveillance. DESIGN: The method is based on polymerase chain reaction (PCR) restriction fragment-length polymorphism (RFLP) following HaeII digestion of simultaneously amplified parts of the protein A gene, the coagulase gene, and the hypervariable region adjacent to mecA. A total of 46 MRSA initial isolates were analyzed, including 14 isolates from five countries; the six German epidemic strains; 16 isolates from the Frankfurt metropolitan area, which were known to be heterogeneous by pulsed-field gel electrophoresis (PFGE); and 10 isolates obtained during three epidemics, all of which displayed an identical genotype. RESULTS: Restriction analysis by PCR-RFLP permitted discrimination of 10 of 14 international isolates, all six German epidemic strains, and 15 of 16 national isolates. It also confirmed the homogeneous character of the 10 outbreak isolates. CONCLUSIONS: This new and rapid PCR-RFLP typing method is an attractive tool in routine epidemiological surveillance. Its impressive characteristics are ease of performance and interpretation, while at the same time guaranteeing good discriminatory power, reproducibility, and typeability.

Bacterial Typing Techniques↗

PubMed2002

An epidemiologic survey of methicillin-resistant Staphylococcus aureus by combined use of mec-HVR genotyping and toxin genotyping in a university hospital in Japan.

OBJECTIVE: To evaluate the usefulness of an assay using two polymerase chain reaction-based genotyping methods in the practical surveillance of methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Nosocomial infection and colonization were surveyed monthly in a university hospital in Japan for 20 months. Genotyping with mec-HVR is based on the size of the mec-associated hypervariable region amplified by polymerase chain reaction. Toxin genotyping uses a multiplex polymerase chain reaction method to amplify eight staphylococcal toxin genes. RESULTS: Eight hundred nine MRSA isolates were classified into 49 genotypes. We observed differing prevalences of genotypes for different hospital wards, and could rapidly demonstrate the similarity of genotype for outbreak isolates. The incidence of genotype D: SEC/TSST1 was significantly higher in isolates causing nosocomial infections (49.5%; 48 of 97) than in nasal isolates (31.4%; 54 of 172) (P = .004), suggesting that this genotype may represent the nosocomial strains. CONCLUSION: The combined use of these two genotyping methods resulted in improved discriminatory ability and should be further investigated.

Bacterial Toxins↗

PubMed2006

HIV infection and antiretroviral therapy: effect on hepatitis C virus quasispecies variability.

BACKGROUND: Hepatitis C virus (HCV) quasispecies variability has been associated with liver disease progression. The effects of human immunodeficiency virus (HIV) coinfection and highly active antiretroviral therapy (HAART) on HCV quasispecies variability have not been firmly established. METHODS: We determined HCV quasispecies complexity and diversity in 69 subjects, 28 of whom were HIV infected, using clonal frequency analysis via heteroduplex mobility analysis of the second envelope gene hypervariable region. Nucleotide sequencing was performed for a small subset of subjects. RESULTS: HIV-positive, HAART-naive subjects had significantly lower HCV quasispecies complexity and diversity than did both HIV-negative and HIV-positive HAART-treated subjects. In multivariate analysis, HIV infection predicted decreased complexity (P < .0001) and diversity (P = .001) of HCV quasispecies, whereas HAART predicted increased complexity (P = .013) and diversity (P = .026). For 4 of 6 patients, sequence analysis yielded data supporting the model that positive host pressure drives HCV quasispecies heterogeneity, although data favoring the hypothesis of selective outgrowth of the most fit variants were also observed. CONCLUSION: HIV coinfection is associated with decreased HCV quasispecies variability, which appears to be reversed by effective HAART. Although HIV- and HAART-related effects on host immune pressure are likely to play a role in the observed differences in HCV genetic heterogeneity, other mechanisms may be operative.

Adult↗

PubMed2006

Selective transmission of hepatitis C virus quasi species through a needlestick accident in acute resolving hepatitis.

BACKGROUND: Little is known about the transmission of variant hepatitis C virus (HCV) genome through needlestick injuries. METHODS: To demonstrate how HCV quasi species are transmitted and adapt to the new host in acute resolving infection, we analyzed the nucleotide and deduced amino acid sequences of the hypervariable region 1 (HVR-1) in the E2 domain of HCV in both the source of the virus ("donor") and the person who received the virus through a needlestick accident ("recipient"). In addition, we also performed phylogenetic analysis of HCV quasi species in these patients to document the viral transmission. RESULTS: We obtained a total of 33 clones at different time points by using polymerase chain reaction amplification and cloning and sequencing of HVR-1. A predominant HVR-1 variant (in 4 of 10 isolates) in the donor was not present in the recipient 6 and 14 weeks after the accident. In contrast, a minor variant (in 1 of 10 isolates) in the donor became the predominant strain in the recipient 6 weeks (in 10 of 12 isolates) and 14 weeks (in 6 of 11 isolates) after the accident. Additional phylogenetic analysis showed high homology of nucleotide sequences between isolates obtained from the donor and isolates obtained from the recipient. In addition, the variants in the recipient's virus showed substantial genetic preservation in the course of acute resolving hepatitis. CONCLUSIONS: These data suggested that a minor HCV variant from a donor was transmitted to the recipient through a needlestick injury and that it prevailed as the dominant species. The preserved genetic homogeneity of the transmitted viral variants in patients with acute HCV infection may account for their clinical outcomes of resolving hepatitis.

Adult↗

PubMed1997

Assessment of hepatitis C virus quasispecies heterogeneity by gel shift analysis: correlation with response to interferon therapy.

Hepatitis C virus (HCV) quasispecies heterogeneity was assessed in pretreatment sera of 22 patients treated with interferon (IFN). Quasispecies heterogeneity was quantitated by analysis of 490 hypervariable region 1 (HVR1) clones using gel shift analysis (GSA), which allowed determination of two components of HCV quasispecies heterogeneity: genetic complexity (number of variants) and genetic diversity (mean genetic distance between variants). HCV genotype and pretreatment RNA titer were similar between responders (n = 12) and nonresponders (n = 10). GSA correlated well with nucleotide sequencing for estimating HCV genetic diversity (R = .952; P < .001). A positive correlation of .666 (P < .001) was observed between genetic diversity and complexity, suggesting that these components of quasispecies heterogeneity were related. However, while there were no significant differences in pretreatment complexity or genetic diversity among response groups, higher pretreatment genetic diversity was predictive of response failure (P = .041). Assessment of HVR1 heterogeneity by GSA revealed important relationships between quasispecies genetic diversity, complexity, and response to IFN therapy and suggested a need for analysis of other HCV genes.

Cloning, Molecular↗

PubMed1997

The 30-bp deletion variant of Epstein-Barr virus-encoded latent membrane protein-1 prevails in acute infectious mononucleosis.

To assess the frequency of malignancy-associated 30-bp deletion variants of the latent membrane protein 1 (LMP-1) in benign conditions, a comparative sequence analysis was done using samples from 20 American children with acute infectious mononucleosis and 16 Swiss children with chronic tonsillar hyperplasia. The 30-bp deletion variant (LMP-1-del) was present in 66% of patients (12/20 with infectious mononucleosis and 12/16 with tonsillar hyperplasia). Two additional patients had a 3-bp deletion and an inframe insertion of 18 nucleotides, respectively. All but 1 isolate had numerous nonsilent point mutations. These data identify a hypervariable region within the C-terminus of LMP-1, in a domain required for maximal stimulation of NF-kappaB activity. These data demonstrate that LMP-1-del variants are frequent in acute infectious mononucleosis and tonsillar hyperplasia and identical to those observed in Epstein-Barr virus-associated AIDS-related lymphoma.

Acute Disease↗

PubMed1991

Induction of HIV-specific CTL and antibody responses in mice using retroviral vector-transduced cells.

Recombinant retroviral vectors can efficiently transduce and express foreign genes in mammalian cells. We have examined the utility of retroviral vector-mediated gene transfer to deliver genes which encode human immunodeficiency virus type I (HIV) antigens capable of stimulating specific immune responses. Murine fibroblast cell lines were transduced with a nonreplicating murine retroviral vector carrying the gene encoding the HIV-IIIB envelope protein and were shown to express the gp160/120 protein. Mice immunized with syngeneic vector-transduced cells developed CD8+, class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) specific for targets expressing the HIV envelope protein. The CTL also exhibited lytic activity on target cells coated with synthetic peptides derived from the gp120 V3 hypervariable region of both the HIV-IIIB and HIV(MN) isolates. Following adoptive transfer in a murine tumor model, these CTL were shown to be effective in vivo by their ability to eliminate established tumor cells expressing the HIV protein. Vector-transduced syngeneic cells were also capable of eliciting HIV envelope-specific antibody responses in immunized mice. Sera obtained from these mice were found to bind to the HIV-IIIB gp160 protein as well as a peptide-defined neutralizing antibody epitope contained within the V3 domain of gp120. These sera exhibited virus-neutralizing activity in that they markedly reduced the ability of HIV to infect and form syncytia of a human T-cell line. This is the first demonstration that cells transduced with a retroviral vector encoding the HIV-IIIB envelope protein are capable of inducing effective HIV-specific cellular and humoral immune responses in mice.

Amino Acid Sequence↗

PubMed1991

In vivo sequence variation of the human immunodeficiency virus type 1 env gene: evidence for recombination among variants found in a single individual.

To assess in vivo sequence heterogeneity of the human immunodeficiency virus type 1 (HIV-1) env gene, we used the polymerase chain reaction to amplify proviral sequences present in peripheral blood mononuclear cell DNA of a patient with acquired immunodeficiency syndrome (AIDS). The amplified env gene fragment (575 bp) contains the first hypervariable region and part of the first conserved region. Eleven and twelve clones were sequenced, respectively, from specimens collected two months apart. Notable heterogeneity was observed among sequences recovered from both specimens. Also, the proviral population recovered from the first specimen varied significantly from that found in the second specimen. Both specimens contained forms with and without an 18 bp duplication. The presence or absence of this duplication, in addition to several point mutations, appear to define two molecular groups evolving in parallel within this patient. Several genotypes which had sequences characteristic of both groups occurred primarily in the second specimen; these can best be explained by multiple recombinational events between representatives of the two groups during reverse transcription. This study demonstrates that recombination may contribute significantly to the generation of diversity among HIV variants within a single individual.

Adult↗

PubMed1992

Genetic variation of simian immunodeficiency viruses in nonhuman primates.

The generation of biologically active proviral DNA clones of simian immunodeficiency virus (SIV) that give rise to infectious virions has allowed the detailed examination of genetic variation in experimentally inoculated monkeys. Studies of nucleotide sequences derived directly from circulating leukocytes of infected monkeys show that the SIV genome undergoes rapid and dramatic variation during the course of infection. The env gene is a major site for variation, and within the Env protein, hypervariable regions analogous to those previously defined for the human immunodeficiency virus type 1 (HIV-1) env gene are apparent. A major exception is the region corresponding to the V3 domain in HIV-1, which has been highly conserved in all SIV studies to date. These data notwithstanding, the role of SIV genetic variation in the pathogenesis of AIDS in monkeys remains unclear. Genetic variation within the env gene does not appear to be sufficient for the development of AIDS since significant variation is observed in both pathogenic and nonpathogenic SIV infections. Furthermore, although it generally is believed that env gene variation might allow HIV and SIV to avoid recognition and elimination by host immune responses, this premise has not been rigorously proven. The use of molecularly cloned SIV in monkey models has provided important quantitative and qualitative information on in vivo sequence variation, and these data, in turn, have laid the groundwork for addressing the undoubtedly complex functional significance of this variation.

Amino Acid Sequence↗

PubMed1993

Diversification of HIV-1 strains after infection from a unique source.

In 1990, 7 hemophilia B patients were infected with human immunodeficiency virus type 1 (HIV-1) after exposure to a single common lot of clotting factor. The hypervariable regions V1 and V2 of the proviral env gene from the patients shared a homology between 97.5% and 100% at the time of seroconversion. To determine the in vivo diversification of these epidemiologically closely related virus strains, the patients were followed up in the early phase of HIV infection. Direct sequencing of the V1/V2 region in the env gene still revealed a very high degree of homology (96.5%-100%). In the case of the patient who showed the highest decrease of CD4+ cells, moderate genetic diversification of the virus was associated with a biological differentiation. The strain originally presenting two expressed substitutions displayed three more deviations 9 months after the first investigation (including one reversion to the consensus sequence). In addition, the virus that originally could not be cultivated could now be isolated as a low cytopathogenic agent. This study provides evidence that the high genetic homogeneity of HIV-1 observed at the time of seroconversion is maintained as a predominant consensus sequence in the following so-called latent phase of infection.

Amino Acid Sequence↗