Publications
321 results found
Gall A, Kaye S, Hue S, et al., 2013, Restriction of V3 region sequence divergence in the HIV-1 envelope gene during antiretroviral treatment in a cohort of recent seroconverters, Retrovirology, Vol: 10, ISSN: 1742-4690
Background: Dynamic changes in Human Immunodeficiency Virus 1 (HIV-1) sequence diversity and divergence areassociated with immune control during primary infection and progression to AIDS. Consensus sequencing or singlegenome amplification sequencing of the HIV-1 envelope (env) gene, in particular the variable (V) regions, is used asa marker for HIV-1 genome diversity, but population diversity is only minimally, or semi-quantitatively sampledusing these methods.Results: Here we use second generation deep sequencing to determine inter-and intra-patient sequenceheterogeneity and to quantify minor variants in a cohort of individuals either receiving or not receivingantiretroviral treatment following seroconversion; the SPARTAC trial. We show, through a cross-sectional study ofsequence diversity of the env V3 in 30 antiretroviral-naive patients during primary infection that considerablepopulation structure diversity exists, with some individuals exhibiting highly constrained plasma virus diversity.Diversity was independent of clinical markers (viral load, time from seroconversion, CD4 cell count) of infection.Serial sampling over 60 weeks of non-treated individuals that define three initially different diversity profiles showedthat complex patterns of continuing HIV-1 sequence diversification and divergence could be readily detected.Evidence for minor sequence turnover, emergence of new variants and re-emergence of archived variants could beinferred from this analysis. Analysis of viral divergence over the same time period in patients who received short(12 weeks, ART12) or long course antiretroviral therapy (48 weeks, ART48) and a non-treated control group revealedthat ART48 successfully suppressed viral divergence while ART12 did not have a significant effect.Conclusions: Deep sequencing is a sensitive and reliable method for investigating the diversity of the env V3 as animportant component of HIV-1 genome diversity. Detailed insights into the complex early intra-patie
Fidler S, Porter K, Ewings F, et al., 2013, Short-Course Antiretroviral Therapy in Primary HIV Infection, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 368, Pages: 207-217, ISSN: 0028-4793
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- Citations: 163
McKay PF, Cope AV, Swales J, et al., 2012, Antigen-specific T lymphocyte responses elicited by a DNA - MVA HIV CN54gp140 immunization regime are significantly altered by the TLR4 adjuvant GLA, Publisher: BIOMED CENTRAL LTD, ISSN: 1742-4690
Jentsch U, Lunga P, Lacey C, et al., 2012, The implementation and appraisal of a novel confirmatory HIV-1 testing algorithm in the microbicides development programme 301 trial (MDP301), PLOS One, Vol: 7, ISSN: 1932-6203
We describe the application of a novel HIV confirmatory testing algorithm to determine the primary efficacy endpoint in alarge Phase III microbicide trial. 9385 women were enrolled between 2005 and 2009. Of these women, 537 (6%) had at leastone positive HIV rapid test after enrolment. This triggered the use of the algorithm which made use of archived serum andBuffy Coat samples. The overall sample set was.95% complete. 419 (78%) of the rapid test positive samples wereconfirmed as primary endpoints using a combination of assays for the detection of HIV-specific antibodies (EIA’s andWestern Blot), and for components of the virus itself (PCR for the detection of nucleic acids and EIA for p24 antigen). 63(12%) cases were confirmed as being HIV-positive at screening or enrolment and 55 (10%) were confirmed as HIV negative.The testing algorithm confirmed the endpoint at the same visit as that of the first positive rapid test in 90% of cases and atthe time of the preceding visit in 10% of cases. Of the 63 cases which were subsequently confirmed to be HIV-1 positive ator before enrolment, 54 specimens contained no detectable HIV antibodies at screening or enrolment. However, 43 werepositive using an EIA which detects both HIV antigen and antibody and also had a positive p24 antigen or HIV PCR test,which was highly suggestive of acute infection. There were 6 unusual cases which had undetectable HIV-1 DNA or RNA. In 4of the 6 cases the presence of HIV-1-specific antibodies was confirmed by Western Blot. One of these cases with anindeterminate Western Blot was a previous vaccine trial participant. The algorithm served the objectives of the study welland can be recommended for use in determining HIV as an endpoint in clinical trials.
Hamlyn E, Ewings FM, Porter K, et al., 2012, Plasma HIV Viral Rebound following Protocol-Indicated Cessation of ART Commenced in Primary and Chronic HIV Infection, PLoS ONE, Vol: 7, ISSN: 1932-6203
Objectives: The magnitude of HIV viral rebound following ART cessation has consequences for clinical outcome and onwardtransmission. We compared plasma viral load (pVL) rebound after stopping ART initiated in primary (PHI) and chronic HIVinfection (CHI).Design: Two populations with protocol-indicated ART cessation from SPARTAC (PHI, n = 182) and SMART (CHI, n = 1450)trials.Methods: Time for pVL to reach pre-ART levels after stopping ART was assessed in PHI using survival analysis. Differences inpVL between PHI and CHI populations 4 weeks after stopping ART were examined using linear and logistic regression.Differences in pVL slopes up to 48 weeks were examined using linear mixed models and viral burden was estimatedthrough a time-averaged area-under-pVL curve. CHI participants were categorised by nadir CD4 at ART stop.Results: Of 171 PHI participants, 71 (41.5%) rebounded to pre-ART pVL levels, at a median of 50 (95% CI 48–51) weeks afterstopping ART. Four weeks after stopping treatment, although the proportion with pVL$400 copies/ml was similar (78% PHIversus 79% CHI), levels were 0.45 (95% CI 0.26–0.64) log10 copies/ml lower for PHI versus CHI, and remained lower up to 48weeks. Lower CD4 nadir in CHI was associated with higher pVL after ART stop. Rebound for CHI participants with CD4 nadir.500 cells/mm3 was comparable to that experienced by PHI participants.Conclusions: Stopping ART initiated in PHI and CHI was associated with viral rebound to levels conferring increasedtransmission risk, although the level of rebound was significantly lower and sustained in PHI compared to CHI.
Weber J, 2012, AIDS: reflections on 1987-1992, AIDS, Vol: 26, Pages: 1193-1193, ISSN: 0269-9370
Martin F, Castro H, Gabriel C, et al., 2012, Ciclosporin A Proof of Concept Study in Patients with Active, Progressive HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis, PLOS NEGLECTED TROPICAL DISEASES, Vol: 6, ISSN: 1935-2735
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- Citations: 22
Schmidt C, Smith C, Barin B, et al., 2012, Background morbidity in HIV vaccine trial participants from various geographic regions as assessed by unsolicited adverse events, HUMAN VACCINES & IMMUNOTHERAPEUTICS, Vol: 8, Pages: 630-638, ISSN: 2164-5515
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- Citations: 4
Barber TJ, Harrison L, Asboe D, et al., 2012, Frequency and patterns of protease gene resistance mutations in HIV-infected patients treated with lopinavir/ritonavir as their first protease inhibitor, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 67, Pages: 995-1000, ISSN: 0305-7453
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- Citations: 22
Fox J, White PJ, Weber J, et al., 2011, Could we, should we? Yes, AIDS, Vol: 25, Pages: 1801-1801, ISSN: 0269-9370
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- Citations: 1
Erlwein O, Robinson MJ, Dustan S, et al., 2011, DNA extraction columns contaminated with murine sequences, PLOS One, Vol: 6, ISSN: 1932-6203
Sequences of the novel gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV) have been described in human prostate cancer tissue, although the amounts of DNA are low. Furthermore, XMRV sequences and polytropic (p) murine leukemia viruses (MLVs) have been reported in patients with chronic fatigue syndrome (CFS). In assessing the prevalence of XMRV in prostate cancer tissue samples we discovered that eluates from naïve DNA purification columns, when subjected to PCR with primers designed to detect genomic mouse DNA contamination, occasionally gave rise to amplification products. Further PCR analysis, using primers to detect XMRV, revealed sequences derived from XMRV and pMLVs from mouse and human DNA and DNA of unspecified origin. Thus, DNA purification columns can present problems when used to detect minute amounts of DNA targets by highly sensitive amplification techniques.
English S, Katzourakis A, Bonsall D, et al., 2011, Phylogenetic analysis consistent with a clinical history of sexual transmission of HIV-1 from a single donor reveals transmission of highly distinct variants, Retrovirology, Vol: 8, ISSN: 1742-4690
Background: To combat the pandemic of human immunodeficiency virus 1 (HIV-1), a successful vaccine will needto cope with the variability of transmissible viruses. Human hosts infected with HIV-1 potentially harbour many viralvariants but very little is known about viruses that are likely to be transmitted, or even if there are viralcharacteristics that predict enhanced transmission in vivo. We show for the first time that genetic divergenceconsistent with a single transmission event in vivo can represent several years of pre-transmission evolution.Results: We describe a highly unusual case consistent with a single donor transmitting highly related but distinctHIV-1 variants to two individuals on the same evening. We confirm that the clustering of viral genetic sequences,present within each recipient, is consistent with the history of a single donor across the viral env, gag and polgenes by maximum likelihood and Bayesian Markov Chain Monte Carlo based phylogenetic analyses. Based on anuncorrelated, lognormal relaxed clock of env gene evolution calibrated with other datasets, the time since themost recent common ancestor is estimated as 2.86 years prior to transmission (95% confidence interval 1.28 to4.54 years).Conclusion: Our results show that an effective design for a preventative vaccine will need to anticipate extensiveHIV-1 diversity within an individual donor as well as diversity at the population level.
White P, Fox J, MacDonald N, et al., 2011, HOW MANY INFECTIONS ARE AVERTED BY BEHAVIOUR CHANGE AFTER EARLY HIV DIAGNOSIS & COUNSELLING OF MSM? ESTIMATES FROM A STOCHASTIC INDIVIDUAL-BASED MODEL, SEXUALLY TRANSMITTED INFECTIONS, Vol: 87, Pages: A51-A52, ISSN: 1368-4973
Thomson EC, Fleming VM, Main J, et al., 2011, Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men, GUT, Vol: 60, Pages: 837-845, ISSN: 0017-5749
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- Citations: 133
Fox J, White PJ, Weber J, et al., 2011, Quantifying sexual exposure to HIV within an HIV-serodiscordant relationship: development of an algorithm., AIDS, Vol: 25, Pages: 1065-1082
The risk of acquiring HIV from a single sexual contact varies enormously reflecting biological and behavioural characteristics of both infected and uninfected partners. Accurate information on HIV transmission risk is required to construct evidence-based risk reduction practices for individuals, to direct the provision of prevention strategies at the population level, and enable the definition, quantification and comparison of true exposure in individuals termed 'exposed uninfected' within clinical trials.
Guimaraes-Walker A, Mackie N, McCormack S, et al., 2011, Lessons from IAVI-006, a Phase I clinical trial to evaluate the safety and immunogenicity of the pTHr.HIVA DNA and MVA.HIVA vaccines in a prime-boost strategy to induce HIV-1 specific T-cell responses in healthy volunteers (vol 26, pg 6671, 2008), VACCINE, Vol: 29, Pages: 3511-3511, ISSN: 0264-410X
Erlwein O, Robinson MJ, Kaye S, et al., 2011, Investigation into the presence of and serological response to XMRV in CFS patients, PLOS One, Vol: 6, ISSN: 1932-6203
The novel human gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV), originally described in prostate cancer, has also been implicated in chronic fatigue syndrome (CFS). When later reports failed to confirm the link to CFS, they were often criticised for not using the conditions described in the original study. Here, we revisit our patient cohort to investigate the XMRV status in those patients by means of the original PCR protocol which linked the virus to CFS. In addition, sera from our CFS patients were assayed for the presence of xenotropic virus envelope protein, as well as a serological response to it. The results further strengthen our contention that there is no evidence for an association of XMRV with CFS, at least in the UK.
McKay PF, Cope A, Swales J, et al., 2011, HIV CN54gp140 +GLA Significantly Enhances VaccineAntigen-Specific T and B Cell Immune Responses After Priming with DNA and MVA, AIDS Vaccine 2011, Publisher: Mary Ann Liebert, Inc.
Robinson M, Erlwien O, Kaye S, et al., 2010, Mouse DNA contamination in human tissue tested for XMRV, Retrovirology, Vol: 7, ISSN: 1742-4690
BackgroundWe used a PCR-based approach to study the prevalence of genetic sequences related to a gammaretrovirus, xenotropic murine leukemia virus-related virus, XMRV, in human prostate cancer. This virus has been identified in the US in prostate cancer patients and in those with chronic fatigue syndrome. However, with the exception of two patients in Germany, XMRV has not been identified in prostate cancer tissue in Europe. Most putative associations of new or old human retroviruses with diseases have turned out to be due to contamination. We have looked for XMRV sequences in DNA extracted from formalin-fixed paraffin- embedded prostate tissues. To control for contamination, PCR assays to detect either mouse mitochondrial DNA (mtDNA) or intracisternal A particle (IAP) long terminal repeat DNA were run on all samples, owing to their very high copy number in mouse cells.ResultsIn general agreement with the US prevalence, XMRV-like sequences were found in 4.8% of prostate cancers. However, these were also positive, as were 21.5% of XMRV-negative cases, for IAP sequences, and many, but not all were positive for mtDNA sequences.ConclusionsThese results show that contamination with mouse DNA is widespread and detectable by the highly sensitive IAP assay, but not always with less sensitive assays, such as murine mtDNA PCR. This study highlights the ubiquitous presence of mouse DNA in laboratory specimens and offers a means of rigorous validation for future studies of murine retroviruses in human disease.
Huang K-HG, Bonsall D, Katzourakis A, et al., 2010, B-cell depletion reveals a role for antibodies in the control of chronic HIV-1 infection, Nature Communications, Vol: 7
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 log10 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.
Barnes E, Flanagan P, Brown A, et al., 2010, Failure to Detect Xenotropic Murine Leukemia Virus-Related Virus in Blood of Individuals at High Risk of Blood-Borne Viral Infections, JOURNAL OF INFECTIOUS DISEASES, Vol: 202, Pages: 1482-1485, ISSN: 0022-1899
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- Citations: 38
McCormack S, Ramjee G, Kamali A, et al., 2010, PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial, LANCET, Vol: 376, Pages: 1329-1337, ISSN: 0140-6736
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- Citations: 262
Huang KH, Bonsall D, Katzourakis A, et al., 2010, B-cell depletion reveals a role for antibodies in the control of chronic HIV-1 infection., Nat Commun, Vol: 1, ISSN: 2041-1723
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.
Weber J, Tatoud R, Fidler S, 2010, Postexposure prophylaxis, preexposure prophylaxis or universal test and treat: the strategic use of antiretroviral drugs to prevent HIV acquisition and transmission, AIDS, Vol: 24, Pages: S27-S39, ISSN: 0269-9370
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- Citations: 25
Levy Y, Ellefsen K, Stoeehr W, et al., 2010, Optimal priming of poxvirus vector (NYVAC)-based HIV vaccine regimens requires 3 DNA injections. Results of the EV03/ANRS Vac20 Phase I/II Trial, AIDS Vaccine 2010, Publisher: MARY ANN LIEBERT INC, Pages: A10-A10, ISSN: 0889-2229
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- Citations: 1
Fox J, Castro H, Kaye S, et al., 2010, Epidemiology of non-B clade forms of HIV-1 in men who have sex with men in the UK, AIDS, Vol: 24, Pages: 2397-2401, ISSN: 0269-9370
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- Citations: 31
Erlwein O, Kaye S, McClure MO, et al., 2010, Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome, PLOS One, Vol: 5, ISSN: 1932-6203
BackgroundIn October 2009 it was reported that 68 of 101 patients with chronic fatigue syndrome (CFS) in the US were infected with a novel gamma retrovirus, xenotropic murine leukaemia virus-related virus (XMRV), a virus previously linked to prostate cancer. This finding, if confirmed, would have a profound effect on the understanding and treatment of an incapacitating disease affecting millions worldwide. We have investigated CFS sufferers in the UK to determine if they are carriers of XMRV.MethodologyPatients in our CFS cohort had undergone medical screening to exclude detectable organic illness and met the CDC criteria for CFS. DNA extracted from blood samples of 186 CFS patients were screened for XMRV provirus and for the closely related murine leukaemia virus by nested PCR using specific oligonucleotide primers. To control for the integrity of the DNA, the cellular beta-globin gene was amplified. Negative controls (water) and a positive control (XMRV infectious molecular clone DNA) were included. While the beta-globin gene was amplified in all 186 samples, neither XMRV nor MLV sequences were detected.ConclusionXMRV or MLV sequences were not amplified from DNA originating from CFS patients in the UK. Although we found no evidence that XMRV is associated with CFS in the UK, this may be a result of population differences between North America and Europe regarding the general prevalence of XMRV infection, and might also explain the fact that two US groups found XMRV in prostate cancer tissue, while two European studies did not.
Wallis CL, Viana R, St John EP, et al., 2010, Presence of low abundance drug-resistant mutations in recently infected HIV-1 subtype C patients from South Africa, International HIV and Hepatitis Virus Drug Resistance and Curative Strategies Workshop, Publisher: INT MEDICAL PRESS LTD, Pages: A35-A35, ISSN: 1359-6535
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- Citations: 2
Wallis CL, Viana R, St John EP, et al., 2010, Presence of low abundance drug-resistant mutations in recently infected HIV-1 subtype C patients from South Africa, Workshop on International HIV and Hepatitis Virus Drug Resistance and Curative Strategies, Publisher: INT MEDICAL PRESS LTD, Pages: A35-A35, ISSN: 1359-6535
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- Citations: 2
Thomson EC, Main J, Weber JN, et al., 2009, PREDICTING CLEARANCE OF ACUTE HCV IN HIV-POSITIVE PATIENTS, 60th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases, Publisher: JOHN WILEY & SONS INC, Pages: 343A-343A, ISSN: 0270-9139
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