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SCIENTIFIC AMERICAN 2000年第5期282卷 96-105页

作者： Ezzell, C

Photographs by Karin Relief, Trace Images/The Image WorksIn Zimbabwe-where AIDS is prematurely killing a generation of adults-counselors and researchers struggle against social customs, viral resourcefulness, and desp... 详细信息

关键词：获得性免疫缺陷综合征/死亡率获得性免疫缺陷综合征/预防和控制获得性免疫缺陷综合征/传播获得性免疫缺陷综合征/病毒学非洲/流行病学避孕套文化 HIV/生理学 HIV血清阳性卫生保健费用健康教育病人教育(主题) 性行为性伴侣津巴布韦/流行病学青少年成年人儿童女(雌)性人类男(雄)性

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Meta-analysis of antiretroviral effects on HIV-1 RNA, CD4 cell count and progression to AIDS or death

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ANTIVIRAL THERAPY 1998年第3期3卷 139-145页

作者： Hill, AM DeMasi, R Dawson, D GlaxoWellcome Antiviral Clin Res Greenford UB6 0HE Middx England GlaxoWellcome Inc Res Triangle Pk NC USA

There is uncertainty as to how the effects of antiretroviral treatments on human immunodeficiency Virus type 1 (HIV-I) RNA levels and CD4 cell counts can predict reductions in clinical progression to AIDS or death. A meta-analysis war conducted for 27 pairwise comparisons of antiretroviral treatments in 15 randomized trials of antiretroviral treatments, For each trial. three measures of treatment effect were used: (i) 16 week change from baseline in HIV-I RNA;(ii) 16 week change from baseline in CD4 cell count;and (iii) rate of clinical progression. Treatments which caused greater increases in CD4 cell count and greater reductions in HIV-1 RNA were move effective at reducing the rate of clinical progression (P<0.05 for each comparison). However. there was variability in the consistency of this correlation between different trials and treatments. The results support the use of both CD4 count and HIV-I RNA levels as the primary markers of the efficacy of antiretroviral treatment.

关键词：获得性免疫缺陷综合征/药物疗法获得性免疫缺陷综合征/免疫学获得性免疫缺陷综合征/病毒学抗HIV药/治疗应用 CD4淋巴细胞计数 HIV-1/药物作用 HIV-1/遗传学 RNA 病毒/分析人类

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Observations of HIV-1 genotypic drug resistance in a trial of four reverse transcriptase inhibitors (Quattro Trial)

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ANTIVIRAL THERAPY 2002年第1期7卷 11-20页

作者： Kaye, S Dunn, DT Babiker, AG Darbyshire, JH Hooker, MH Nesarantnam, S Newberry, A Weber, J Breckenridge, A Babiker, A Back, D Blatchford, N Darbyshire, JH Gazzard, B Gartland, M Hooker, M Jeffries, D Johnson, M Plummer, K Wills, B Kitchen, V Loveday, C Tedder, R Weber, J Weller, IVD Withnall, R Chelsea & Westminster Hosp London England Kings Coll Hosp London London England Royal Free Hosp London NW3 2QG England St Bartholomews Hosp London England Univ London St Georges Hosp London SW17 0RE England St Marys Hosp London England St Thomas Hosp London England UCL Sch Med London W1N 8AA England Dept Virol London England Royal London Sch Med & Dent London England Imperial Coll Sch Med St Marys London England Royal Free & Univ Coll Med Sch Dept Virol London England MRC Clin Trials Unit London W1N 4AL England Quattro Steering Comm London England

The Quattro Trial compared the use of four HIV-1 reverse transcriptase (RT) inhibitors (zidovudine, lamivudine, loviride and zalcitabine), given either as four-drug combination therapy or monotherapy, with 8-week cycles of each drug, with zidovudine/lamivudine dual therapy. Observations of resistance associated and other mutations in the RT gene were made to determine whether therapy failure could be explained by acquisition of these mutations and whether novel mutation patterns developed. As in the intent-to-treat analysis, the use of cyclical monotherapy gave a smaller reduction in plasma virus load at 64 weeks (0.4 log(10) copies/ml below baseline) than the quadruple or dual therapy arms (1.3 and 0.8 log(10) copies/ml below baseline). Cyclical therapy appeared to generate less genotypic resistance to zidovudine, loviride or zalcitabine than the other arms. Resistance to lamivudine (mutation M184V) developed rapidly in all three arms. Resistance to zidovudine was acquired by a larger proportion of subjects on dual therapy than on quadruple therapy. Resistance to loviride or zalcitabine was rarely observed. During lamivudine monotherapy the M184V mutation was rapidly acquired and viral load rebounded. Zalcitabine monotherapy initially selected M184V mutants, but these were lost as therapy continued. Novel mutations that may have been associated with combination or cyclical quadruple therapy were observed infrequently. There was no clear correlation between changes in response to therapy and the development of previously described resistance mutations or with novel mutations in the RT gene.

关键词：乙酰胺类/投药和剂量苯乙酮类/投药和剂量获得性免疫缺陷综合征/药物疗法获得性免疫缺陷综合征/病毒学抗药性病毒/遗传学药物疗法联合基因型 HIV-1/分类 HIV-1/遗传学拉米夫定/投药和剂量突变逆转录酶抑制剂/治疗应用病毒载量扎昔他宾/投药和剂量齐多夫定/投药和剂量人类

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Timing the ancestor of the HIV-1 pandemic strains

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SCIENCE 2000年第5472期288卷 1789-1796页

作者： Korber, B Muldoon, M Theiler, J Gao, F Gupta, R Lapedes, A Hahn, BH Wolinsky, S Bhattacharya, T Los Alamos Natl Lab Los Alamos NM 87545 USA Santa Fe Inst Santa Fe NM 87501 USA Univ Manchester Inst Sci & Technol Dept Math Manchester M60 1QD Lancs England Univ Alabama Birmingham Dept Med & Microbiol Birmingham AL 35294 USA Northwestern Univ Dept Med Div Infect Dis Chicago IL 60611 USA

HIV-1 sequences were analyzed to estimate the timing of the ancestral sequence of the main group of HIV-1, the strains responsible for the AIDS pandemic. Using parallel supercomputers and assuming a constant rate of evolution, we applied maximum-likelihood phylogenetic methods to unprecedented amounts of data for this calculation. We validated our approach by correctly estimating the timing of two historically documented points. Using a comprehensive full-length envelope sequence alignment, we estimated the date of the Last common ancestor of the main group of HIV-1 to be 1931 (1915-41). Analysis of a gag gene alignment, subregions of envelope including additional sequences, and a method that relaxed the assumption of a strict molecular clock also supported these results.

关键词：获得性免疫缺陷综合征/流行病学获得性免疫缺陷综合征/传播获得性免疫缺陷综合征/病毒学非洲/流行病学置信区间共有序列疾病暴发流行欧洲/流行病学进化分子基因 env HIV包膜蛋白质gp160/遗传学 HIV-1/分类 HIV-1/遗传学海地/流行病学似然函数黑猩猩属种系发生猴获得性免疫缺陷综合征/传播猴获得性免疫缺陷综合征/病毒学猴免疫缺陷病毒/遗传学时间因素美国/流行病学动物传染病动物人类

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Genealogical evidence for positive selection in the nef gene of HIV-1

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GENETICS 1999年第3期153卷 1077-1089页

作者： Zanotto, PMD Kallas, EG de Souza, RF Holmes, EC Univ Sao Paulo Escola Paulista Med Bioinformat & Retrovirol Lab BR-05508900 Sao Paulo Brazil Univ Sao Paulo Escola Paulista Med Immunol Lab DIPA BR-05508900 Sao Paulo Brazil Univ Oxford Dept Zool Wellcome Trust Ctr Epidemiol Infect Dis Oxford OX1 3PS England

The pattern and process of evolution in the nef gene of HIV-1 was analyzed within and among patients. Using a maximum likelihood method that allows for variable intensity of selection pressure among codons, strong positive selection was detected in a hemophiliac patient over 30 mo of infection. By reconstructing the process of allele substitution in this patient using parsimony, the synapomorphic amino acid changes separating each time point were found to have high probabilities of being under positive selection, with selective coefficients of at least 3.6%. Positive selection was also detected among 39 nef sequences from HIV-1 subtype B. Tn contrast, multiple pairwise comparisons of nonsynonymous and synonymous substitution rates provided no good evidence for positive selection and sliding window analyses failed to detect most positively selected sites. These findings demonstrate that positive selection is an important determinant of nef gene evolution and that genealogy-based methods outperform pairwise methods in the detection of adaptive evolution. Mapping the locations of positively selected sites may also be of use in identifying targets of the immune response and hence aid vaccine design.

关键词：获得性免疫缺陷综合征/病因学获得性免疫缺陷综合征/病毒学等位基因氨基酸序列密码子进化分子基因产物 nef/化学基因产物 nef/遗传学基因 nef HIV-1/遗传学血友病A/并发症似然函数分子序列数据种系发生选择(遗传学) 序列比对序列同源性氨基酸人类

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Effect of weekly adefovir (PMEA) infusions on HIV-1 virus load: results of a Phase I/II study

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ANTIVIRAL THERAPY 1999年第2期4卷 101-107页

作者： Kamp, W Schokker, J Cambridge, E De Jong, S Schuurman, R De Groot, T Boucher, CAB Fight Life Fdn Amsterdam Netherlands Univ Utrecht Hosp Eijkman Winkler Inst Dept Virol Utrecht Netherlands

The compound 9-(2-phosphonylmethoxyethyl)adenine (adefovir;PMEA) is a potent inhibitor of a number of viruses in vitro, such as human immunodeficiency virus (HIV) type 1 and 2, herpes simplex virus (HSV) type 1 and 2, human papillomavirus virus (HBV) and Epstein-Barr virus (EBV). Adefovir also proved to be effective in vivo against feline immunodeficiency virus (FIV) in cats and simian immunodeficiency virus (SIV) in rhesus monkeys. In an open, non-placebo-controlled trial the antiviral activity of weekly doses of adefovir in nine patients with AIDS or AIDS-related complex was studied for a period of 11 weeks. CD4 cell counts at baseline were between 10 and 450 cells/mm(3), HIV-1 RNA levels at baseline were between 24210 copies/ml and 406197 copies/ml. The drug was administered intravenously at a dose of 1000 mg every week and plasma viral load was assessed at multiple points during the study. Administration of adefovir was tolerated well and no severe side effects were seen. The response to adefovir treatment differed widely between patients. The increase in CD4 cell count at end point ranged from -40 to 120 cell/mm(3). The lowest HIV RNA levels were measured after 3-5 days, showing an increase thereafter. The nadir in viral load was achieved after 2 weeks, with a mean viral load decline of 0.7 from baseline. The decrease of the HIV RNA level at end point ranged from -0.3 log(10) to 1.8 log(10), with a mean decrease of 0.4 log(10). Our results indicate that adefovir given intravenously once weekly has a short-lasting initial antiviral effect. The effect of more frequent dosing requires further evaluation. If adefovir is to be useful clinically, it needs to be combined with other antiviral agents.

关键词：获得性免疫缺陷综合征/药物疗法获得性免疫缺陷综合征/病毒学腺嘌呤/投药和剂量腺嘌呤/类似物和衍生物抗病毒药/投药和剂量 CD4淋巴细胞计数 HIV-1/遗传学 HIV-1/分离和提纯 RNA 病毒/血液成年人人类男(雄)性中年人

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Rapid progression to AIDS in HIV⁺ individuals with a structural variant of the chemokine receptor CX₃CR1

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SCIENCE 2000年第5461期287卷 2274-2277页

作者： Faure, S Meyer, L Costagliola, D Vaneensberghe, C Genin, E Autran, B Delfraissy, JF McDermott, DH Murphy, PM Debré, P Théodorou, I Combadière, C Hop La Pitie Salpetriere Lab Immunol Cellulaire & Tissulaire CNRS UMR 7627 Paris France Hop Bicetre Fac Med Dept Epidemiol INSERMU292 Le Kremlin Bicetre France Univ Paris 06 INSERM SC4 Paris France Hop Bicetre INSERM U155 Le Kremlin Bicetre France Hop Bicetre Serv Med Interne Le Kremlin Bicetre France NIAID Host Def Lab NIH Bethesda MD 20892 USA CHU Bichat INSERM U479 Paris France

Human immunodeficiency virus (HIV) enters cells in vitro via CD4 and a coreceptor. Which of 15 known coreceptors are important in vivo is poorly defined but may be inferred from disease-modifying mutations, as for CCR5, Here two single nucleotide polymorphisms are described in Caucasians in CX(3)CR1, an HIV coreceptor and leukocyte chemotactic/adhesion receptor for the chemokine fractalkine. HIV-infected patients homozygous for CX(3)CR1-1249 M280, a variant haplotype affecting two amino acids (isoleucine-249 and methionine-280), progressed to AIDS more rapidly than those with other haplotypes. Functional CX(3)CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Thus, CX(3)CR1-1249 M280 is a recessive genetic risk factor in HIV/AIDS.

关键词：获得性免疫缺陷综合征/遗传学获得性免疫缺陷综合征/病理生理学获得性免疫缺陷综合征/病毒学病例对照研究趋化因子CX3CL1 趋化因子 CX3C 趋化因子 CXC/代谢染色体人 3对队列研究疾病恶化欧洲大陆世系人群/遗传学遗传变异基因型 HIV/生理学 HIV感染/遗传学 HIV感染/病理生理学 HIV感染/病毒学单倍型纯合子白细胞单核/代谢连锁不平衡膜蛋白质类/代谢突变多态性限制性片段长度多态性单核苷酸多态现象单链构象受体细胞因子/遗传学受体细胞因子/生理学受体 HIV/遗传学受体 HIV/生理学存活率分析人类

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Small amino acid changes in the V3 loop of human immunodeficiency virus type 2 determines the coreceptor usage for CXCR4 and CCR5

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VIROLOGY 1999年第1期264卷 237-243页

作者： Isaka, Y Sato, A Miki, S Kawauchi, S Sakaida, H Hori, T Uchiyama, T Adachi, A Hayami, M Fujiwara, T Yoshie, O Shionogi Inst Med Sci Osaka 5660022 Japan Kyoto Univ Inst Virus Res Kyoto 606 Japan Univ Tokushima Sch Med Dept Virol Tokushima 770 Japan Kinki Univ Sch Med Dept Bacteriol Osaka 5898511 Japan

HIV-2 GH-1 is a molecular clone derived from an AIDS patient from Ghana. In contrast to the prototypic molecular clone ROD, GH-1 exhibits a narrow range of target cell specificity. By an infectious assay using HeLa-CD4 cells stably transfected with an HIV-1 LTR-beta-galactosidase reporter gene and transiently expressing various cloned chemokine receptors, we have examined the coreceptor usage of GH-1. In contrast to ROD, which uses principally CXCR4, GH-1 was found to use mainly if not exclusively CCR5 but not CXCR4. The distinct coreceptor usage of these two molecular clones allowed us to further map the region of gp120 that is important for the coreceptor specificity. By constructing a series of chimeric viruses between GH-1 and ROD, we have demonstrated that the C-terminal half of the V3 loop region of gp120 determines the differential coreceptor usage between GH-1 and ROD, and only a few amino acid differences in this region appear to be able to shift the specificity between CCR5 and CXCR4. Notably, the shift in the coreceptor usage from CCR5 to CXCR4 is associated with an increase in the net positive charge in the V3 region. (C) 1999 Academic Press.

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AIDS as a Zoonosis: Scientific and public health implications

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Science 2000年第5453期287卷 607-614页

作者： Hahn, Beatrice H. Shaw, George M. De, Cock, Kevin M. Sharp, Paul M. Depts. of Medicine and Microbiology University of Alabama at Birmingham Birmingham AL 35294 United States Howard Hughes Medical Institute University of Alabama at Birmingham Birmingham AL 35294 United States Div. HIV/AIDS Prev.-Survlnc. E. Natl. Ctr. HIV STD and TB Prev. Centers for Dis. Contr. and Prev. Atlanta GA 30333 United States Institute of Genetics University of Nottingham Queens Medical Centre Nottingham NH7 2UH United Kingdom

Evidence of simian immunodeficiency virus (SIV) infection has been reported for 26 different species of African nonhuman primates. Two of these viruses, SIVcpz from chimpanzees and SIVsm from sooty mangabeys, are the cause of acquired immunodeficiency syndrome (AIDS) in humans. Together, they have been transmitted to humans on at least seven occasions. The implications of human infection by a diverse set of SIVs and of exposure to a plethora of additional human immunodeficiency virus-related viruses are discussed.

关键词：获得性免疫缺陷综合征/流行病学获得性免疫缺陷综合征/传播获得性免疫缺陷综合征/病毒学非洲西部/流行病学氨基酸序列疾病暴发流行疾病贮主 HIV-1/遗传学 HIV-2/遗传学直鼻猴亚目/病毒学分子序列数据种系发生公共卫生猴获得性免疫缺陷综合征/病毒学猴免疫缺陷病毒/分类猴免疫缺陷病毒/遗传学猴免疫缺陷病毒/生理学种特异性动物传染病/传播动物人类

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Prediction of HIV-1 RNA suppression and its durability during treatment with zidovudine/lamivudine

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ANTIVIRAL THERAPY 1998年第3期3卷 169-176页

作者： Opravil, M Hill, AM DeMasi, R Dawson, D Univ Zurich Hosp Dept Med Div Infect Dis & Hosp Epidemiol CH-8091 Zurich Switzerland Glaxo Wellcome Antiviral Clin Res Greenford Middx England Glaxo Wellcome Res Triangle Pk NC USA

To predict the probability of long-term viral suppression during treatment with zidovudine and lamivudine, human immunodeficiency virus type 1 (HIV-1) RNA values were retrospectively pooled for 1083 patients from six randomized, double-blind clinical trials. All analyses of HIV-1 RNA were obtained using the Roche Amplicor assay or its earlier prototype. Time to loss of response was evaluated by Kaplan-Meier analysis;Cox proportional hazards models were used to assess the influence of baseline variables. Among 523 patients with less than or equal to 6 months of prior zidovudine treatment, the probability of HIV-1 RNA suppression below 400 copies/ml at 48 weeks was 71% in those with baseline HIV-1 RNA <5000 copies/ml, but only 14% in those with HIV-I RNA between 50000 and 200000 copies/ml. Among 560 patients with less than or equal to 6 months of prior zidovudine treatment, the rates of sustained viral suppression were lower, but also significantly associated with the baseline HIV-1 RNA. Multivariate analyses showed no independent effect of CD4 cell count, age. sex, race. or CDC disease stage on the probability of sustained HIV-1 RNA suppression. When patients with less than or equal to 6 months of prior therapy were stratified based on the magnitude of HIV-1 RNA nadir achieved during treatment, those who reached a nadir of <400 copies/ml retained this response for significantly longer time periods than the ones who only achieved partial viral suppression. In conclusion, baseline HIV-I RNA levels and the duration of prior zidovudine therapy strongly predict the antiretroviral efficacy of zidovudine/lamivudine. The baseline parameters should influence the choice of the antiretroviral regimen.

关键词：获得性免疫缺陷综合征/药物疗法获得性免疫缺陷综合征/病毒学抗HIV药/投药和剂量 CD4淋巴细胞计数双盲法药物疗法联合 HIV-1/药物作用 HIV-1/遗传学拉米夫定/投药和剂量 RNA 病毒/血液回顾性研究齐多夫定/投药和剂量青少年成年人老年人女(雌)性人类男(雄)性中年人

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