No abstract

Previous data have indicated that the development of resistance to amprenavir, an inhibitor of the human immunodeficiency virus type 1 protease, is associated with the substitution of valine for isoleucine at residue 50 (I50V) in the viral protease. We present further findings from retrospective genotypic and phenotypic analyses of plasma samples from protease inhibitor-naïve and nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients who experienced virological failure while participating in a clinical trial where they had been randomized to receive either amprenavir or indinavir in combination with NRTIs. Paired baseline and on-therapy isolates from 31 of 48 (65%) amprenavir-treated patients analyzed demonstrated the selection of protease mutations. These mutations fell into four distinct categories, characterized by the presence of either I50V, I54L/I54M, I84V, or V32I؉I47V and often included accessory mutations, commonly M46I/L. The I50V and I84V genotypes displayed the greatest reductions in susceptibility to amprenavir, although each of the amprenavir-selected genotypes conferred little or no cross-resistance to other protease inhibitors. There was a significant association, for both amprenavir and indinavir, between preexisting baseline resistance to NRTIs subsequently received during the study and development of protease mutations (P ‫؍‬ 0.014 and P ‫؍‬ 0.031, respectively). Our data provide a comprehensive analysis of the mechanisms by which amprenavir resistance develops during clinical use and present evidence that resistance to concomitant agents in the treatment regimen predisposes to the development of mutations associated with protease inhibitor resistance and treatment failure.

The unique poly(U/UC) tract, the middle part of the tripartite 3h non-coding region (3hNCR) of hepatitis C virus (HCV) genomic RNA, may represent a recognition signal for the HCV replicase complex. In this study, several proteins binding specifically to immobilized ribooligonucleotide r(U) 25 mimicking this structure were identified using cytosolic extracts from HCV-negative or -positive liver explants, and a prominent 36 kDa protein was studied further. Competition experiments including homoribopolymers revealed binding affinities in the order : oligo/poly(U) S (A) S (C) S (G). The protein was identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a multifunctional protein known to bind RNA. GAPDH bound efficiently to the full-length HCV RNA and binding to various 3hNCR constructs revealed critical dependence upon the presence of the middle part of the 3hNCR. Polypyrimidine tract-binding protein, described previously to bind the 3hNCR, did not bind efficiently to the middle part of 3hNCR and was captured from liver extracts in considerably smaller quantities.The mechanisms underlying the development of chronic hepatitis following hepatitis C virus (HCV) infection remain unclear, with little known about replication of the 9n4 kb pluspolarity HCV RNA genome. The lack of a robust in vitro HCV replication system is one reason for this lack of clarity. HCV encodes three or four structural and six or seven non-structural (NS) proteins, which may interact with viral RNA (e.g. core protein ; non-structural protein NS3 with protease, NTPase

Background-A novel flavivirus has been described recently and designated hepatitis G virus (HGV). The virus is transmitted by the parenteral route but it is uncertain whether it is associated with chronic liver disease because liver biopsy is diYcult to justify in this group. Aims-To examine histological features of liver biopsy in patients infected with hepatitis C virus (HCV) according to the presence or absence of HCV and HGV RNA. Methods-One hundred and thirty one consecutive HCV carriers undergoing staging liver biopsy were studied retrospectively. In each, HCV RNA and HGV RNA were detected by reverse transcription polymerase chain reaction on serum samples collected at the time of biopsy. The presence of each RNA was correlated with histological features blind to the RNA results; individual histological features of inflammation or fibrosis were scored separately. Results-Nineteen patients were positive for both HGV and HCV RNA in serum, 91 were positive for HCV RNA alone, two were positive for HGV RNA alone, and 19 were negative for both RNA species. Neither age nor sex diVered between the groups; a greater proportion of intravenous drug users were HGV RNA positive, but this was not statistically significant. There was no eVect of HGV coinfection on the stage of fibrosis or any other histological parameter except steatosis; patients with HCV and HGV RNA had a higher mean score for fat than those patients with HCV RNA alone (p<0.05). Conclusions-HGV coinfection has no important eVects on histological features in chronic HCV carriers. It is unlikely that HGV infection causes chronic liver disease. (Gut 1998;42:103-106)

Hypervariable region 1 (HVR1) sequences of 96 clones at six time-points representing 27 variants in two major and one minor group were identified in a patient with chronic hepatitis C virus (HCV) infection over 3 years. Major and selected minor variants were used to design synthetic peptides corresponding to the HVR1 C terminus. Peptide ELISA reactivity with IgG was plotted against the corresponding clone frequency, and three patterns emerged : (1) three peptides were unreactive ; (2) antibodies against two peptides followed emergence of the corresponding variant, suggesting isolate-specificity ; (3) antibodies against four peptides preceded the appearance of the corresponding variant, indicating cross-reactivity or previous exposure. Cross-reactivity was investigated further : sera from six time-points were tested against 11 unrelated HVR1 peptides, seven of which (63n6 %) showed cross-reactivity at all time-points. Cross-reactivity of nine patientspecific peptides tested against a panel of 45 heterologous sera from chronic HCV carriers ranged between 0 and 20 %. Only three of 27 variants appeared at more than one time-point and in two cases specific and/or cross-reactive HVR1 antibodies coexisted with the corresponding variant, consistent with emergence of escape mutants. In addition, analysis of HVR1 IgG reactivity within a group of closely related patient-specific peptides revealed a loss of reactivity in one peptide attributable to a single amino acid substitution. Interferon-α treatment considerably reduced viral RNA but, paradoxically, heterogeneity increased.

This article’s subject is the theory and practice of ‘regional survey’, the method of social and environmental study associated with Scottish thinker Patrick Geddes (1854–1932). Despite being overlooked or dismissed in most accounts of early 20th-century social science, regional survey had a wide influence on the development of the nascent disciplines of anthropology, sociology, and human geography. Emerging from late 19th-century field biology, the regional survey came to typify a methodological moment in the natural and social sciences that favoured the holistic analysis of geographically delimited areas. By the interwar period, the kinds of projects that went under its name can clearly be seen as forerunners of the post-Second World War tradition of community studies. Additionally, in its self-presentation as a civic, participatory exercise, the regional survey can be read as a form of popular autoethnography that contrasts with other, more familiar social-scientific ventures in the first half of the 20th century, and defies the dichotomy between ‘gentlemanly’ and ‘technical’ modes of social science. As a result, this article argues, the regional survey provides an alternative point of departure for thinking about the origins and development of the modern social sciences in Britain.