• The epidemic behavior of the hepatitis C virus.

    3 July 2018

    Hepatitis C virus (HCV) is a leading worldwide cause of liver disease. Here, we use a new model of HCV spread to investigate the epidemic behavior of the virus and to estimate its basic reproductive number from gene sequence data. We find significant differences in epidemic behavior among HCV subtypes and suggest that these differences are largely the result of subtype-specific transmission patterns. Our model builds a bridge between the disciplines of population genetics and mathematical epidemiology by using pathogen gene sequences to infer the population dynamic history of an infectious disease.

  • Genetic analysis reveals the complex structure of HIV-1 transmission within defined risk groups.

    3 July 2018

    We explored the epidemic history of HIV-1 subtype B in the United Kingdom by using statistical methods that infer the population history of pathogens from sampled gene sequence data. Phylogenetic analysis of HIV-1 pol gene sequences from Britain showed at least six large transmission chains, indicating a genetically variable, but epidemiologically homogeneous, epidemic among men having sex with men. Through coalescent-based analysis, we showed that these chains arose through separate introductions of subtype B strains into the United Kingdom in the early to mid-1980s. After an initial period of exponential growth, the rate of spread generally slowed in the early 1990s, which is more likely to correlate with behavior change than with reduced infectiousness resulting from highly active antiretroviral therapy. Our results provide insights into the complexity of HIV-1 epidemics that must be considered when developing HIV monitoring and prevention initiatives.

  • Evolutionary and Phylogenetic Analysis of the Hepaciviruses and Pegiviruses.

    3 July 2018

    The known genetic diversity of the hepaciviruses and pegiviruses has increased greatly in recent years through the discovery of viruses related to hepatitis C virus and human pegivirus in bats, bovines, equines, primates, and rodents. Analysis of these new species is important for research into animal models of hepatitis C virus infection and into the zoonotic origins of human viruses. Here, we provide the first systematic phylogenetic and evolutionary analysis of these two genera at the whole-genome level. Phylogenies confirmed that hepatitis C virus is most closely related to viruses from horses whereas human pegiviruses clustered with viruses from African primates. Within each genus, several well-supported lineages were identified and viral diversity was structured by both host species and location of sampling. Recombination analyses provided evidence of interspecific recombination in hepaciviruses, but none in the pegiviruses. Putative mosaic genome structures were identified in NS5B gene region and were supported by multiple tests. The identification of interspecific recombination in the hepaciviruses represents an important evolutionary event that could be clarified by future sampling of novel viruses. We also identified parallel amino acid changes shared by distantly related lineages that infect similar types of host. Notable parallel changes were clustered in the NS3 and NS4B genes and provide a useful starting point for experimental studies of the evolution of Hepacivirus host-virus interactions.

  • Tracing the origin of Brazilian HTLV-1 as determined by analysis of host and viral genes.

    3 July 2018

    We compared the genetic diversity of the Brazilian human T-cell lymphotropic virus type 1 isolates with those found in KwaZulu-Natal (KZN), South Africa, and with the genetic background of the hosts. The seroprevalence rate in KZN was 1.7%. All sequences belonged to the A subgroup. The presence of South African sequences in two different clusters from Brazil, and the finding of the beta-globin haplotype in infected hosts are consistent with the transmission of this virus from southern Africa to Brazil.

  • B-cell depletion reveals a role for antibodies in the control of chronic HIV-1 infection

    3 July 2018

    HIV can be partially contained by host immunity and understanding the basis of this may inform vaccine design. The importance of B-cell function in long-term control is poorly understood. One method of investigating this is in vivo cellular depletion. In this study, we take advantage of a unique opportunity to investigate the role of B cells in an HIV-infected patient. The HIV-1+patient studied here was not taking antiretroviral drugs and was treated for pre-existing low-grade lymphoplasmacytoid lymphoma by depletion of CD20+ B cells using rituximab. We demonstrate that B-cell depletion results in a decline in autologous neutralizing antibody (NAb) responses and a 1.7 log10rise in HIV-1 plasma viral load (pVL). The recovery of NAbs results in a decline in pVL. The HIV-1 sequences diversify and NAb-resistant mutants are subsequently selected. These data suggest that B-cell function can contribute to the long-term control of pVL, and that NAbs may be more important in controlling chronic HIV-1 infection than previously suspected. © 2010 Macmillan Publishers Limited. All rights reserved.

  • Disease-associated XMRV sequences are consistent with laboratory contamination.

    3 July 2018

    Xenotropic murine leukaemia viruses (MLV-X) are endogenous gammaretroviruses that infect cells from many species, including humans. Xenotropic murine leukaemia virus-related virus (XMRV) is a retrovirus that has been the subject of intense debate since its detection in samples from humans with prostate cancer (PC) and chronic fatigue syndrome (CFS). Controversy has arisen from the failure of some studies to detect XMRV in PC or CFS patients and from inconsistent detection of XMRV in healthy controls.Here we demonstrate that Taqman PCR primers previously described as XMRV-specific can amplify common murine endogenous viral sequences from mouse suggesting that mouse DNA can contaminate patient samples and confound specific XMRV detection. To consider the provenance of XMRV we sequenced XMRV from the cell line 22Rv1, which is infected with an MLV-X that is indistinguishable from patient derived XMRV. Bayesian phylogenies clearly show that XMRV sequences reportedly derived from unlinked patients form a monophyletic clade with interspersed 22Rv1 clones (posterior probability >0.99). The cell line-derived sequences are ancestral to the patient-derived sequences (posterior probability >0.99). Furthermore, pol sequences apparently amplified from PC patient material (VP29 and VP184) are recombinants of XMRV and Moloney MLV (MoMLV) a virus with an envelope that lacks tropism for human cells. Considering the diversity of XMRV we show that the mean pairwise genetic distance among env and pol 22Rv1-derived sequences exceeds that of patient-associated sequences (Wilcoxon rank sum test: p = 0.005 and p < 0.001 for pol and env, respectively). Thus XMRV sequences acquire diversity in a cell line but not in patient samples. These observations are difficult to reconcile with the hypothesis that published XMRV sequences are related by a process of infectious transmission.We provide several independent lines of evidence that XMRV detected by sensitive PCR methods in patient samples is the likely result of PCR contamination with mouse DNA and that the described clones of XMRV arose from the tumour cell line 22Rv1, which was probably infected with XMRV during xenografting in mice. We propose that XMRV might not be a genuine human pathogen.

  • Tracing the HIV-1 subtype B mobility in Europe: a phylogeographic approach.

    3 July 2018

    BACKGROUND: The prevalence and the origin of HIV-1 subtype B, the most prevalent circulating clade among the long-term residents in Europe, have been studied extensively. However the spatial diffusion of the epidemic from the perspective of the virus has not previously been traced. RESULTS: In the current study we inferred the migration history of HIV-1 subtype B by way of a phylogeography of viral sequences sampled from 16 European countries and Israel. Migration events were inferred from viral phylogenies by character reconstruction using parsimony. With regard to the spatial dispersal of the HIV subtype B sequences across viral phylogenies, in most of the countries in Europe the epidemic was introduced by multiple sources and subsequently spread within local networks. Poland provides an exception where most of the infections were the result of a single point introduction. According to the significant migratory pathways, we show that there are considerable differences across Europe. Specifically, Greece, Portugal, Serbia and Spain, provide sources shedding HIV-1; Austria, Belgium and Luxembourg, on the other hand, are migratory targets, while for Denmark, Germany, Italy, Israel, Norway, the Netherlands, Sweden, Switzerland and the UK we inferred significant bidirectional migration. For Poland no significant migratory pathways were inferred. CONCLUSION: Subtype B phylogeographies provide a new insight about the geographical distribution of viral lineages, as well as the significant pathways of virus dispersal across Europe, suggesting that intervention strategies should also address tourists, travellers and migrants.

  • B-cell depletion reveals a role for antibodies in the control of chronic HIV-1 infection.

    3 July 2018

    HIV can be partially contained by host immunity and understanding the basis of this may inform vaccine design. The importance of B-cell function in long-term control is poorly understood. One method of investigating this is in vivo cellular depletion. In this study, we take advantage of a unique opportunity to investigate the role of B cells in an HIV-infected patient. The HIV-1(+) patient studied here was not taking antiretroviral drugs and was treated for pre-existing low-grade lymphoplasmacytoid lymphoma by depletion of CD20+ B cells using rituximab. We demonstrate that B-cell depletion results in a decline in autologous neutralizing antibody (NAb) responses and a 1.7 log(10) rise in HIV-1 plasma viral load (pVL). The recovery of NAbs results in a decline in pVL. The HIV-1 sequences diversify and NAb-resistant mutants are subsequently selected. These data suggest that B-cell function can contribute to the long-term control of pVL, and that NAbs may be more important in controlling chronic HIV-1 infection than previously suspected.

  • Evolutionary analysis of hepatitis C virus gene sequences from 1953

    3 July 2018

    Reconstructing the transmission history of infectious diseases in the absence of medical or epidemiological records often relies on the evolutionary analysis of pathogen genetic sequences. The precision of evolutionary estimates of epidemic history can be increased by the inclusion of sequences derived from 'archived' samples that are genetically distinct from contemporary strains. Historical sequences are especially valuable for viral pathogens that circulated for many years before being formally identified, including HIV and the hepatitis C virus (HCV). However, surprisingly few HCV isolates sampled before discovery of the virus in 1989 are currently available. Here,we report and analyse two HCV subgenomic sequences obtained from infected individuals in 1953, which represent the oldest genetic evidence of HCV infection. The pairwise genetic diversity between the two sequences indicates a substantial period of HCV transmission prior to the 1950s, and their inclusion in evolutionary analyses provides new estimates of the common ancestor of HCV in the USA. To explore and validate the evolutionary information provided by these sequences, we used a new phylogenetic molecular clock method to estimate the date of sampling of the archived strains, plus the dates of four more contemporary reference genomes. Despite the short fragments available, we conclude that the archived sequences are consistent with a proposed sampling date of 1953, although statistical uncertainty is large. Our cross-validation analyses suggest that the bias and low statistical power observed here likely arise from a combination of high evolutionary rate heterogeneity and an unstructured, star-like phylogeny.We expect that attempts to date other historical viruses under similar circumstances will meet similar problems. © 2013 The Author(s) Published by the Royal Society. All rights reserved.