Absence of viral transmission in injecting drug users in Russia.
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Adolescent↗
Biomedical subjects
J N Weber
Publications and source records attributed to J N Weber.
Impact of baseline polymorphisms in RT and protease on outcome of highly active antiretroviral therapy in HIV-1-infected African patients.
OBJECTIVE: To assess the therapeutic response and investigate the significance of polymorphic codons in African patients receiving highly-active antiretroviral therapy (HAART). DESIGN AND METHODS: African patients were identified from the St Mary's Hospital HIV-1 database. Clinical outcome was assessed by viral load and CD4 cell count. Pre- and post-therapy sequences of RT and protease were analysed. The impact of subtype and individual polymorphic codons on therapeutic outcome was assessed statistically (Fishers exact and chi2 tests) and phylogenetically (Jukes and Cantor). RESULTS: Of 79 drug-naive African patients who were prescribed HAART, 60 remained undetectable for 1 year, with no differences detected in the clinical response to non-nucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor (PI)-containing regimes. Country of origin, sex and viral subtype had no impact on outcome of HAART. A total of 133 polymorphisms were identified in pol (37 in protease and 96 in RT), with a mean of 9.0 in protease and 22.3 in RT per patient. There was no significant difference in the overall numbers of polymorphisms per patient, and no single polymorphism had any impact on clinical outcome. Sequences from 'failing' patients experiencing viral rebound produced few mutations known to be associated with drug resistance, suggesting minimal drug pressure. CONCLUSIONS: The response of patients infected with African subtypes of HIV-1 to HAART appears to be independent of regime, HIV-1 clade and baseline polymorphisms. Non-B subtypes are fully sensitive to HAART and, accordingly, therapy should not be withheld from African patients for reasons of viral diversity.
Africa↗
High production of interferon gamma but not interleukin-2 by human T-lymphotropic virus type I-infected peripheral blood mononuclear cells.
The transactivator protein of human T-lymphotropic virus I (HTLV-I), Tax, has been associated with the up-regulation of several host cell genes, including interleukin 2 (IL-2), the IL-2 receptor-alpha (IL-2Ralpha) chain (CD25), interferon gamma (IFN-gamma), and tumor necrosis factor (TNF). It has been proposed that an IL-2/CD25 autocrine loop plays a part in maintaining the very high proviral loads often found in HTLV-I infection. Furthermore, abnormal production of inflammatory cytokines might contribute to the pathogenesis of the inflammatory diseases associated with HTLV-I infection. However, there has been no study of the expression of these genes in freshly isolated peripheral blood mononuclear cells (PBMCs) naturally infected with HTLV-I. In the present study, flow cytometry was used to determine which cytokines are produced by freshly isolated PBMCs that spontaneously express the HTLV-I Tax protein. Surprisingly, the results show that intracellular Tax expression is associated with rapid up-regulation of IFN-gamma but not TNF or IL-2. A proportion of HTLV-I-infected cells express both IFN-gamma and the surface markers of effector memory cells. Such cells are capable of migration through peripheral tissues and could therefore contribute to the inflammation seen in diseases such as HTLV-I-associated myelopathy/tropical spastic paraparesis. (Blood. 2001;98:721-726)
Cytokines↗
Direct ex vivo analysis reveals distinct phenotypic patterns of HIV-specific CD8(+) T lymphocyte activation in response to therapeutic manipulation of virus load.
Therapeutic intervention with antiretroviral therapy (ART) enables the modulation of HIV virus load and hence provides a unique opportunity to study the consequences of varying antigen load on the phenotype of virus-specific CD8(+) T lymphocytes in a persistent human viral infection. The recent advent of tetrameric peptide / HLA class I complexes has enabled the direct phenotypic characterization of antigen-specific T cell populations ex vivo. Here, we use this technology to examine directly ex vivo the consequences of therapeutic manipulation of HIV virus load on the phenotype of HIV-specific CTL. Our observations show that: (1) distinct sequential activation patterns of CD8(+) T cells are associated with increasing virus load; (2) T cell receptor (TCR) down-regulation without apoptosis represents an early event during the generation of a T cell response in a natural infection and precedes the emergence of two distinct antigen-specific CD8(+) T cell populations which differ in TCR and CD8 expression levels. Clear differences in surface Annexin V staining were observed between these populations. The observation that CTL activation, demonstrated by TCR and CD8 down-regulation, in response to rising levels of virus load, co-segregates with apoptosis only during later stages of the response indicates that antigen-associated cell death is restricted to distinct subpopulations of CTL.
Annexin A5↗
Variable fate of virus-specific CD4(+) T cells during primary HIV-1 infection.
Impairment of CD4(+) T lymphocyte responses to human immunodeficiency virus (HIV)-derived antigens is the classic immunological defect observed during the chronic phase of HIV-1 infection. Early intervention with potent antiretroviral therapy (ART) can preserve HIV-specific CD4(+) T lymphocyte reactivity, providing indirect evidence that such responses are mounted during primary infection and subsequently lost in the majority of infected individuals. Here, we demonstrate early and dramatic expansions of functional HIV-specific CD4(+) T lymphocyte frequencies directly ex vivo. These responses are initially of broad specificity, and can disappear rapidly during the natural course of primary infection. This process of loss is variable, such that the rapidity and extent of functional compromise differs between individuals. Institution of ART during these early phases of HIV-1 infection preserves patterns of functional reactivity within the HIV-specific CD4(+) T lymphocyte population. However, there was no evidence for the restoration of deleted responses. These findings indicate that, in some individuals at least, ART must be administered within a narrow window of opportunity during primary HIV-1 infection to effect substantial immune preservation.
Acquired Immunodeficiency Syndrome↗
Simple detection of point mutations associated with HIV-1 drug resistance.
A novel assay is described for the detection of HIV-1 drug resistance that is simple, cheap and sensitive. HIV-1 drug resistance in B and non-B HIV-1 subtypes was investigated using Mutagenically-Separated PCR (MS--PCR) --- a competitive semi-nested PCR which uses mutagenic primers. The assay was assessed for sensitivity, specificity and its ability to detect mutant virus within a mixed mutant--wild-type population. Gene sequencing was carried out simultaneously for comparison. MS--PCR detected five copies of HIV-1 RNA from laboratory isolates and 50 copies from patient samples. We demonstrate 100% specificity of detection for wild type or mutant virus for clades A, B, C, D and E. For mixed populations of virus, MS--PCR can detect at least a 10% mix of wild type:mutant, or vice-versa. When applied to African patient samples MS--PCR detected 91.6% of the codons tested. Concordance with sequencing data was 88.8% for protease and 97.2% for RT. MS--PCR is sensitive and specific for the detection of mutations in HIV-1, and can be adapted easily to test for resistance at any codon of interest.
Africa↗
A phase I/II study of the safety and activity of a microsphere formulation of KNI-272 in patients with HIV-1 infection.
Eighteen patients with symptomatic HIV disease were enrolled into a phase I/II study of a microsphere formulation of the HIV protease inhibitor KNI-272, with doses escalated up to a maximum dose of 60 mg/kg/day. One patient developed reversible elevation in hepatic transaminase. The plasma half-life of the drug was very short, varying between 0.25 and 1.1 h. No consistent effect on plasma HIV RNA levels or CD4(+) lymphocyte counts was seen.
Adult↗
The development of novel vaginal microbicides: from the bench to the clinic.
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Administration, Intravaginal↗
In vivo selection of T-cell receptor junctional region sequences by HLA-A2 human T-cell lymphotropic virus type 1 Tax11-19 peptide complexes.
Using HLA-peptide tetrameric complexes, we isolated human T-cell lymphotrophic virus type 1 Tax peptide-specific CD8(+) T cells ex vivo. Antigen-specific amino acid motifs were identified in the T-cell receptor Vbeta CDR3 region of clonally expanded CD8(+) T cells. This result directly confirms the importance of the CDR3 region in determining the antigen specificity in vivo.
Amino Acid Motifs↗
Serological approaches to subtyping of HIV-1 in injecting drug users in Russia: evidence of subtype homogeneity at the main sites of the epidemic.
The aim of this study was to develop and evaluate a simple V3 peptide-based enzyme immunoassay (PEIA) for large-scale serotyping of HIV-1 specimens derived from injecting drug users (IDUs) in the Russian Federation. Two synthetic peptides were evaluated, named P1 (RKSIHIGPGRAFYATGD) and P2 (RTSVRIGPGQVFYKTGD), in an PEIA on 63 HIV-1 IDUs sera for which genotypes had been determined by heteroduplex mobility assay (HMA) and sequencing. The sensitivities of P1 (subtype B) and P2 (subtype A) were 87% and 75% respectively. Specificity of the assay was 100% for both peptides, with 100% predictive values of a monoreactive positive test for both peptides. Using the PEIA with peptides P1 and P2, we have serotyped 375 of 477 serum samples derived from IDUs in 4 main sites of the HIV-1 epidemic in Russia. The results demonstrated a high level of subtype homogeneity in all regions studied. In 3 of 4 territories, Tver' (n=345), and Rostov-on-Don (n=61) regions, and Krasnodar Kray (n=27), 100% of typable sera were found to belong to env subtype A. On the other hand, all specimens serotyped in the Kaliningrad region (n=38) belonged to env subtype B, and there is strong evidence that the recombinant gagAenvB virus which has caused the largest outbreak of HIV-1 in Russia is located in this region. At the present time another parental strain with gagBenvB genotype is of minor importance in the IDUs HIV-1 epidemic in Russia.
Amino Acid Sequence↗
A prospective social and molecular investigation of gonococcal transmission.
BACKGROUND: Gonorrhoea is a common infectious disease, poorly controlled despite effective treatments. Tracing chains of transmission is difficult, because sexual partners are commonly difficult or impossible to identify. We assess the use of gonococcal opa-typing in identifying transmission links not revealed through interview. METHODS: Epidemiological data and gonococcal isolates were collected prospectively from patients at two UK clinics in London and Sheffield. Social and epidemiological data were combined with molecular typing of gonococcal isolates by a new methodology based on the polymorphisms of the opa gene. FINDINGS: In London, interview data and opa-typing on samples from 215 cases showed a diverse population with few links. In Sheffield, interview data identified links between 51 (43%) of 120 cases, whereas opa-typing suggested a more connected population: 95 (79%) of cases had shared profiles. There was a highly significant correlation between the two distributions with epidemiological clusters appearing as a subset of the opa clusters. Two large opa clusters, of 18 and 43 cases, accounted for 50% of local cases of gonorrhoea. Discordance between epidemiological and opa-typing data was observed at highly connected points in the sexual network. INTERPRETATION: Opa-typing is a more powerful tool for epidemiological investigation of gonorrhoea transmission than earlier methods. Opa-typing can link infections that would otherwise remain unlinked, and may aid interventions to control endemic disease.
Adolescent↗
High frequency of viral protein expression in human T cell lymphotropic virus type 1-infected peripheral blood mononuclear cells.
Most human T cell lymphotropic virus type (HTLV)-1-infected individuals mount a strong and persistently activated cytotoxic T lymphocyte (CTL) response to the virus, which implies that there is abundant chronic transcription of HTLV-1 genes. On the other hand, several observations suggest that HTLV-1 might be latent in vivo and therefore not detectable by CTLs. To clarify these discrepancies, we quantified the frequency of provirus-positive peripheral blood mononuclear cells (PBMCs) that were capable of expressing the HTLV-1 Tax protein, which is known to be the immunodominant target antigen recognized by HTLV-1-specific CTLs. The analysis showed that a significant proportion of HTLV-1-infected cells (from 14 to 100%) starts to express the Tax protein within a few hours of culture ex vivo. Phenotypic analysis confirmed that the main cell subpopulation expressing the Tax protein is CD4 positive. Frequent Tax expression in CD4(+) T lymphocytes in vivo might account for the chronic activation of the cytotoxic immune response observed in the majority of HTLV-1-infected patients and might contribute to the pathogenesis of HTLV-1-associated diseases.
CD4-Positive T-Lymphocytes↗
HIV-1 resistance genotyping by sequencing produces inconsistent results for mixed viral populations.
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Anti-HIV Agents↗
Serotype, parental country of birth, and ethnic status in unlinked anonymous neonatal HIV seroprevalence surveys.
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Africa, Central↗
Human T cell leukaemia/lymphoma virus infection in pregnant women in the United Kingdom: population study.
OBJECTIVE: To assess the prevalence of human T cell leukaemia/lymphoma virus (HTLV) infection in pregnant women in the United Kingdom. DESIGN: Population study. SUBJECTS: Guthrie card samples from babies born in 1997-8. Samples were linked to data on mother's age and ethnic status and parents' country of birth and then anonymised. SETTING: North Thames Regional Health Authority. MAIN OUTCOME MEASURES: Presence of antibodies against HTLV in eluates tested by gelatin particle agglutination assay and results confirmed by immunoblot. RESULTS: Of 126 010 samples tested, 67 had confirmed antibodies to HTLV (59 HTLV-I, 2 HTLV-II, 6 untyped) and six had indeterminate results. Seroprevalence was 17.0 per 1000 (95% confidence interval 9.2 to 28.3) in infants whose mothers were born in the Caribbean, 3.2/1000 (1.5 to 5.9) with mothers born in west and central Africa, and 6.8/1000 (3.1 to 12.9) in infants of black Caribbean mothers born in non-endemic regions. In infants with no known risk (both parents born in non-endemic regions and mother not black Caribbean) seroprevalence was 0.06-0.12 per 1000. Mother's country of birth, father's country of birth, and mother's ethnic status were all independently associated with neonatal seroprevalence. An estimated 223 (95% confidence interval 110 to 350) of the 720 000 pregnant women each year in the United Kingdom are infected with HTLV. CONCLUSIONS: The prevalence of HTLV and HIV infections in pregnant women in the United Kingdom are comparable. The cost effectiveness of antenatal HTLV screening should be evaluated, and screening of blood donations should be considered.
Adult↗
Abundant tax protein expression in CD4+ T cells infected with human T-cell lymphotropic virus type I (HTLV-I) is prevented by cytotoxic T lymphocytes.
The role of the cellular immune response in human T-cell leukemia virus type I (HTLV-I) infection is not fully understood. A persistently activated cytotoxic T lymphocyte (CTL) response to HTLV-I is found in the majority of infected individuals. However, it remains unclear whether this CTL response is protective or causes tissue damage. In addition, several observations paradoxically suggest that HTLV-I is transcriptionally silent in most infected cells and, therefore, not detectable by virus-specific CTLs. With the use of a new flow cytometric procedure, we show here that a high proportion of naturally infected CD4+ peripheral blood mononuclear cells (PBMC) (between 10% and 80%) are capable of expressing Tax, the immunodominant target antigen recognized by virus-specific CTLs. Furthermore, we provide direct evidence that autologous CD8+ T cells rapidly kill CD4+ cells naturally infected with HTLV-I and expressing Tax in vitro by a perforin-dependent mechanism. Consistent with these observations, we observed a significant negative correlation between the frequency of Tax(11-19)-specific CD8+ T cells and the percentage of CD4+ T cells in peripheral blood of patients infected with HTLV-I. Those results are in accordance with the view that virus-specific CTLs participate in a highly efficient immune surveillance mechanism that persistently destroys Tax-expressing HTLV-I-infected CD4+ T cells in vivo. (Blood. 2000;95:1386-1392)
Anti-Bacterial Agents↗
Silent mutation in the V3 region characteristic of HIV type 1 env subtype B strains from injecting drug users in the former Soviet Union.
New independent states of the former Soviet Union are facing a rapidly growing epidemic of HIV-1 among injecting drug users (IDUs). This epidemic is caused by three HIV-1 populations, one belonging to HIV-1 subtype A (IDU-A), another to subtype B (IDU-B), and the third being a recombinant of the IDU-A and IDU-B viruses (IDU-A/B, gagA/envB). Each of these populations is characterized by a high level of genetic homogeneity. We identified a unique synonymous nucleotide substitution in the first isoleucine codon at the IHIGPGR motif (ATT), which was observed in the env subtype B V3 sequences derived from IDUs in Russia and the Ukraine. This substitution was observed in none of 179 sequences obtained from IDUs in western Europe, northern America, and Asia. Molecular epidemiological analysis of HIV-1 strains based on this sequence pattern could be useful for tracing the origin and spread of the IDU-B viruses to other countries and risk groups.
Base Sequence↗
Comparative quantification of diverse serotypes of HIV-1 in plasma from a diverse population of patients.
HIV-1 is characterised by extensive genetic variability encompassing at least 10 different phylogenetically related clades within the major group of HIV-1 subtypes. Most commercially available HIV-1 RNA plasma viral load assays have been optimised with clade B viruses and may yield misleadingly low RNA levels for nonclade B viruses that are increasingly found in Europe. In this study we compare the most recent versions of the Roche Amplicor HIV Monitor and the Chiron Quantiplex for ability to detect viraemia in a population of patients infected with a range of HIV-1 subtypes. EDTA-treated plasma was obtained from 206 patients. The Amplicor and Quantiplex assays were carried out in accordance with manufacturers' instructions. Results from 53/206 (25.7%) samples differed by >0.4 log between Amplicor 1.5 and Quantiplex 3.0. A >0.5 log and 1.0 log difference was detected between Amplicor 1.5 and Quantiplex 3.0 in 37/206 (17.9%) and 7/206 (3.4%) of samples, respectively. Overall, Amplicor 1.5 gave a median value of 0.22 log higher than Quantiplex 3.0. Discordant results were detected in 53 out of 206 (25.7%) samples. Of these 22 out of 123 (17.9%) samples were of UK origin, 18 out of 43 (41.9%) African, 1 out of 8 (12.5%) South American, 1 out of 6 (16.7%) North American, 4 out of 9 (44.4%) North European, 3 out of 11 (23.7%) South European and 3 out of 7 (42.3%) Asian samples, respectively. Serotyping revealed that discordant viral load results between Amplicor 1.5 and Quantiplex 3.0 occurred within samples from all subtypes (A-E). Despite the improvements made to both the Roche Amplicor and the Chiron Quantiplex assays discordant results were detected between the two assays in 25.7% of cases. In a substantial minority of patients there were major discrepancies between the two assays that were not explained by HIV subtype differences.
HIV Infections↗