抗病毒治疗人群HIV-1辅助受体利用及V3区基因预测研究
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摘要
研究背景
世界上抗病毒药物——第一个辅助受体拮抗剂于2007年在美国批准上市,该类药物是通过阻断HIV-1gp120与CCR5的结合,从而阻止HIV-1进入宿主细胞,此药将对于职业暴露紧急预防、治疗失败者替换治疗发挥重要作用,同时还会有更多辅助受体拮抗剂进入临床研究,然而,该药物应用临床之前必须对HIV辅助受体的利用有全面了解,才能更有效地发挥药物的作用。但是我国抗病毒治疗后HIV辅助受体利用如何,非辅助受体拮抗剂药物对辅助受体的利用是否有直接或间接的影响,还不是很清楚,抗病毒治疗后HIV-1V3区是否发生了变化,V3区能否用于预测辅助受体的利用还有待于研究。本文将通过未治疗人群和抗病毒治疗人群HIV-1辅助受体利用、V3区序列分析,旨在探讨抗病毒治疗对HIV辅助受体利用的影响及其影响因素,以及V3区对HIV毒株辅助受体预测的可行性。该研究将今后更合理的指导临床用药提供理论基础。
研究方法
从安徽、河南HIV-1感染者中选择治疗人群和未治疗人群,通过外周血单个核细胞(Peripheral blood mononuclear cell,PBMCs)共培养方法分离HIV-1毒株、利用P24抗原试剂盒监测病毒分离情况,利用Ghost细胞系(表达CD4并选择性表达CCR5或CXCR4辅助受体)检测HIV-1辅助受体利用,结合感染者基本特征分析抗病毒治疗对HIV-1辅助受体影响,通过V3基因扩增、测序分析V3的序列特征与辅助受体利用的关系,进一步利用网络预测工具WebPSSM和geno2pheno进行HIV-1辅助受体的预测,并与病毒表型相比较,分析网络预测的可行性。
研究结果
从抗病毒治疗人群中分离出45株HIV-1病毒,其中23(51%)株来自河南省,采用的治疗方案为AZT+DDI+NVP,22(49%)株来自安徽省,采用治疗方案为D4T+DDI+NVP。治疗时间平均为26(6-48)月,经过pol基因型分析所有毒株均为HIV-1 B'亚型,并且89%(40株)的病毒株为耐药株。从安徽省既往献血未经过抗捕局瘟迫巳褐蟹掷?09株HIV-1病毒,经过序列分析亦为B'亚型HIV-1毒株。
经过Ghost细胞系检验,从治疗人群中分离得到的45株病毒中,有22(48.89%)株利用CCR5辅助受体(R5毒株),21(46.67%)株利用X4/R5辅助受体(X4/R5毒株),2株(4.44%)利用CXCR4辅助受体(X4毒株)。从未治疗人群从分离得到的109株病毒中,96(88.07%)株利用CCR5辅助受体(R5毒株),13(11.93%)株利用CCR5/CXCR4辅助受体(X4/R5毒株),没有发现CXCR4毒株。
以CD4~+T细胞计数分组(CD4＜100为一组,100=＜CD4＜200为一组,CD4＞200为一组)进一步分析疾病进展与病毒辅助受体利用的关系,无论是治疗人群中还是未治疗人群中随着CD4~+T细胞数的降低,利用X4/R5的HIV-1毒株均逐步增加,说明即使抗病毒治疗后,病毒利用X4辅助受体仍然与病程进展有一定关系,并且在同一CD4~+T细胞水平下,治疗人群中X4/R5利用率均高于未治疗人群。
利用Logistic回归进行分析HIV抗病毒治疗中各因素对HIV辅助受体利用的影响发现:治疗相对于未治疗的OR为7.72((3.39-17.58)(p＜0.0001),而治疗时间、治疗方案、年龄、性别对辅助受体利用的影响都没有统计学意义。
治疗组R5毒株相对于标准株SF33感染率为6.63倍,未治疗人群R5株相对于标准株SF33感染率为4.68倍。对于双嗜性毒株,治疗组对Ghost-CXCR4细胞的感染率是SF33感染率的2.09倍,对Ghost-CCR5细胞的感染率是SF33的4.50倍,未治疗组Ghost-CXCR4细胞的感染率是SF33感染率的0.69倍,对Ghost-CCR5细胞的感染率是SF33的1.90倍,提示抗病毒治疗后HIV的感染性增强。
通过V3区净电荷研究发现,治疗人群中V3区净电荷为2-7之间(4.20±1.63);未治疗人群中V3净电荷在3-6之间(4.26±0.78)。利用11/25规则发现共有24(33.3%)株X4病毒,其中治疗人群中16株,未治疗人群中8株。通过配对四格表检验基因预测和病毒表型检测的一致性,发现在未治疗人群中两种结果不存关联性(X2=0.69,p=0.41),在治疗人群中两种结果存在关联性(X2=5.33,p=0.02),提示对治疗人群来说,11/25位点能够用于预测辅助受体的利用。利用WebPSSM预测出53(72.6%)株R5嗜性株,geno2pheno共预测出34(46.6%)株R5嗜性株,两种预测方法的一致率为50%。通过辅助受体表型检测与网络预测的一致性分析,发现WebPSSM预测CCR5嗜性毒株与Ghost细胞系检测结果一致性为89.5%,预测CXCR4嗜性株与Ghost细胞检测结果一致性为44.1%,geno2pheno预测出的CCR5嗜性毒株与Ghost细胞系检测结果一致性为50%,预测CXCR4嗜性株与Ghost细胞检测结果一致性为55.9%,WebPSSM对CCR5嗜性毒株的预测一致性要明显好于geno2pheno。
结论
1.本研究发现治疗人群中利用CXCR4辅助受体的HIV-1毒株明显高于未治疗人群,并且在同一CD4~+T计数水平下CXCR4的利用率也高于未治疗人群。提示目前在我国中部地区艾滋病抗病毒治疗失败后,对于辅助受体拮抗剂的选择必须慎重,同时提示这种高感染力的X4毒株有可能在人群中广泛传播。
2.经过抗病毒治疗的HIV-1V3区净电荷要高于未治疗的HIV-1,而经过抗病毒治疗后,V3区净电荷的仍然与X4毒株的使用有一定的相关性,11/25位阳电荷仍能够有效地预测HIV辅助受体利用。
3.对于未治疗人群,考虑使用辅助受体拮抗剂时建议WebPSSM方法,对于治疗人群失败人群,考虑用辅助受体拮抗剂替换治疗时也推荐使用WebPSSM方法。
Background
In 2007,the world's first co-receptor antagonist Maraviroc against HIV-1 was approved in the United States.Maraviroc,blocking HIV-1gp120 combination with CCR5, thereby prevents HIV-1 into the host cell.So,the drug will play an important role for occupational exposure to emergency prevention,and treatment failure.Meanwhile,there will be more co-receptor antagonist for clinical trial.In order to utilize the drugs rationally,it is necessary to know HIV-1 co-receptor usage before clinical application. However,we do not know what co-receptor HIV-1 strains use after anti-retroviral therapy. In this paper,in order to explore factors that influence HIV-1 co-receptor usage and analyze the feasibility that V3 region predicts HIV-1 co-receptor,HIV-1 co-receptor usage and V3 sequence were analyzed among anti-retroviral therapy and treatment-naive HIV-1 infection patients.And the study may provide information to help to design rational and effective treatment regimen for ART.
Methods
HIV-1 infected individuals who has experienced the anti-retroviral therapy were selected from Henan、Anhui province as treatment group,and unexperienced ART patients were from Anhui province taken as treatment-na(i|¨)ve group.HIV-1 strains were isolated form PBMCs of whole blood while HIV-1 p24 was quantified using a commercial enzyme-linked immunosorbent assay(ELISA) kit.Then HIV-1 co-receptor was identified using Ghost cell lines expressing CD4 and the chemokine receptor CCR5 or CXCR4.HIV-1 V3 region was amplified from HIV-1 strains and further was analyzed the relationship between the characteristics of V3 sequence and HIV co-receptor usage. Then V3 sequence was submitted into web-server(WebPSSM and geno2pheno) to predict HIV-1 co-receptor usage,and predicted result was compared with HIV phenotype based Ghost cell line.Furthmore,the feasibility of Web-server assay was analyzed.
Results
45 HIV-1 B' strains were isolated from antiretroviral-treatment patients in Henan or Anhui province,of which 23(51%) were from Henan,therapeutic regimen for the AZT+DDI+NVP,and of which 22(49%) were from Anhui,therapeutic regimen for D4T+DDI+NVP.And the average treatment time was 26(6-48) months.109 HIV-1 B' strains were isolated from treatment-na(i|¨)ve patients.All the strain was identified as HIV-1 B' subtype after pol sequence analysis.
Among 45 HIV strains from the treatment group,22(48.89%) strains used CCR5 as a co-receptor(R5 strain),21(46.67%) strains used CXCR4/CCR5 as a co-receptor(X4/R5 strain),and two(4.44%) used only CXCR4 as a co-receptor(X4 strain).In 109 strains from treatment-na(i|¨)ve group,96(88.07%) strains used CCR5 as a co-receptor(R5 strain), 13(11.93%) strains used CCR5/CXCR4 as a co-receptor use(X4/R5 strain).
In order to analyze relationship between disease progression and HIV co-receptor usage,first of all,CD4+T count was classed three groups as follow:CD4＜100, 100=＜CD4＜200,CD4＞200.Statistical analysis showed that HIV-1 X4/R5 strains gradually increased as CD4~+T count decreasing in both treatment and treatment-na(i|¨)ve group.Even in the same CD4~+T count,the HIV-1 X4/R5 utilization in treatment groups was remarkable higher than in treatment-na(i|¨)ve group.The resullt showed some correlation between HIV-1 X4/R5 utilization rate and CD4~+T count after antiretroviral-treatment.
Logistic regression analysis showed that the OR was 7.72(3.39-17.58)(p＜0.0001) between treatment and not,however treatment time,regimen,age and sex do not influence viral co-receptor usage,which statistical analysis was not significant difference(P＜0.05).
Infection possibility based on Ghost-CCR5 cells line assay showed:HIV-1 CCR5 strain isolated from treatment group was 6.63 times of infection possibility than SF33 strain;while HIV-1 CCR5 strain isolated from treatment-na(i|¨)ve was 4.68 times than SF33 strain.For the dual-tropic strains isolated from treatment group,the infection possibility on Ghost-CXCR4 cell was 2.09 times than SF33,while 4.50 times than SF33 on Ghost-CCR5.For the dual-tropic strains isolated from treatment-naive group,the infection possibility was 0.69 times than SF33 on Ghost-CXCR4 cells,while 1.90 times than SF33 on Ghost-CCR5 cells.
Among anti-retroviral therapy patients,V3 net charge was distributed from 2 to 7(4.20±1.63),while 3-6(4.26±0.78) in treatment-na(i|¨)ve population.There was no significant difference(p=0.38).The 11/25 rulle predicted 24(33.3%) X4 strains,16 strains form treatment group and 8 strains from treatment-na(i|¨)ve group.The fourfold table method was used to evaluate the agreement between phenotype based Ghost cell lines and predicted resullt based on 11/25 rulle.The result showed there was no relevance (X2=0.69,p=0.41) in the naive-treatment group.But in the treatment group,there was relevance(X2=5.33,p=0.02),suggesting 11/25 rule was adequate for predicting HIV-1 co-receptor usage after ART.As for Web-Server(WebPSSM and geno2pheno) for HIV-1 co-receptor prediction.WebPSSM predicted 53(72.6%) HIV-1 strain as CCRS-tropic, while geno2pheno predicted 34(46.6%) HIV-1 strain as CCR5-tropic.The concordance was 50%.
Compared with viral phenotype based on Ghost cell assay,the concordance of WebPSSM was significantly better than geno2pheno.For predicting CCR5-tropic strains, there was 89.5%concordance between WebPSSM and phenotype,while 50% concordance between geno2pheno and phenotype.But for predicting CXCR4 tropic strains,the concordance was 44.1%between WebPSSM and Ghost cell lines,while 55.9%between geno2pheno and phenotype.
Conclusion
1.The study found that the HIV-1 CXCR4 utilization among anti-retroviral therapy HIV-1 infected patients was higher than the treatment-na(i|¨)ve population,whatever CD4~+T was in differ level,implying that it should pay attention to the choice of co-receptor antagonists after the failure in the Chinese central region,Furthermore,suggesting X4 strains could spread in population.
2.V3 net charge was higher among anti-retroviral therapy patients than the treatment-na(i|¨)ve population,and there was still correlation between HIV-1 X4/R5 utilization and V3 net charge after antiretroviral-treatment,and 11/25 rule was adequate for predicting HIV-1 co-receptor usage after antiviral therapy.
3.For the treatment-na(i|¨)ve individual,if co-receptor antagonist is considered,WebPSSM is recommened to predict HIV-1 co-receptor usage.For the patients with onging treatment failure,if co-receptor antagonist is considered for replacement therapy,we also recommend WebPSSM.
世界上抗病毒药物——第一个辅助受体拮抗剂于2007年在美国批准上市,该类药物是通过阻断HIV-1gp120与CCR5的结合,从而阻止HIV-1进入宿主细胞,此药将对于职业暴露紧急预防、治疗失败者替换治疗发挥重要作用,同时还会有更多辅助受体拮抗剂进入临床研究,然而,该药物应用临床之前必须对HIV辅助受体的利用有全面了解,才能更有效地发挥药物的作用。但是我国抗病毒治疗后HIV辅助受体利用如何,非辅助受体拮抗剂药物对辅助受体的利用是否有直接或间接的影响,还不是很清楚,抗病毒治疗后HIV-1V3区是否发生了变化,V3区能否用于预测辅助受体的利用还有待于研究。本文将通过未治疗人群和抗病毒治疗人群HIV-1辅助受体利用、V3区序列分析,旨在探讨抗病毒治疗对HIV辅助受体利用的影响及其影响因素,以及V3区对HIV毒株辅助受体预测的可行性。该研究将今后更合理的指导临床用药提供理论基础。
研究方法
从安徽、河南HIV-1感染者中选择治疗人群和未治疗人群,通过外周血单个核细胞(Peripheral blood mononuclear cell,PBMCs)共培养方法分离HIV-1毒株、利用P24抗原试剂盒监测病毒分离情况,利用Ghost细胞系(表达CD4并选择性表达CCR5或CXCR4辅助受体)检测HIV-1辅助受体利用,结合感染者基本特征分析抗病毒治疗对HIV-1辅助受体影响,通过V3基因扩增、测序分析V3的序列特征与辅助受体利用的关系,进一步利用网络预测工具WebPSSM和geno2pheno进行HIV-1辅助受体的预测,并与病毒表型相比较,分析网络预测的可行性。
研究结果
从抗病毒治疗人群中分离出45株HIV-1病毒,其中23(51%)株来自河南省,采用的治疗方案为AZT+DDI+NVP,22(49%)株来自安徽省,采用治疗方案为D4T+DDI+NVP。治疗时间平均为26(6-48)月,经过pol基因型分析所有毒株均为HIV-1 B'亚型,并且89%(40株)的病毒株为耐药株。从安徽省既往献血未经过抗捕局瘟迫巳褐蟹掷?09株HIV-1病毒,经过序列分析亦为B'亚型HIV-1毒株。
经过Ghost细胞系检验,从治疗人群中分离得到的45株病毒中,有22(48.89%)株利用CCR5辅助受体(R5毒株),21(46.67%)株利用X4/R5辅助受体(X4/R5毒株),2株(4.44%)利用CXCR4辅助受体(X4毒株)。从未治疗人群从分离得到的109株病毒中,96(88.07%)株利用CCR5辅助受体(R5毒株),13(11.93%)株利用CCR5/CXCR4辅助受体(X4/R5毒株),没有发现CXCR4毒株。
以CD4~+T细胞计数分组(CD4＜100为一组,100=＜CD4＜200为一组,CD4＞200为一组)进一步分析疾病进展与病毒辅助受体利用的关系,无论是治疗人群中还是未治疗人群中随着CD4~+T细胞数的降低,利用X4/R5的HIV-1毒株均逐步增加,说明即使抗病毒治疗后,病毒利用X4辅助受体仍然与病程进展有一定关系,并且在同一CD4~+T细胞水平下,治疗人群中X4/R5利用率均高于未治疗人群。
利用Logistic回归进行分析HIV抗病毒治疗中各因素对HIV辅助受体利用的影响发现:治疗相对于未治疗的OR为7.72((3.39-17.58)(p＜0.0001),而治疗时间、治疗方案、年龄、性别对辅助受体利用的影响都没有统计学意义。
治疗组R5毒株相对于标准株SF33感染率为6.63倍,未治疗人群R5株相对于标准株SF33感染率为4.68倍。对于双嗜性毒株,治疗组对Ghost-CXCR4细胞的感染率是SF33感染率的2.09倍,对Ghost-CCR5细胞的感染率是SF33的4.50倍,未治疗组Ghost-CXCR4细胞的感染率是SF33感染率的0.69倍,对Ghost-CCR5细胞的感染率是SF33的1.90倍,提示抗病毒治疗后HIV的感染性增强。
通过V3区净电荷研究发现,治疗人群中V3区净电荷为2-7之间(4.20±1.63);未治疗人群中V3净电荷在3-6之间(4.26±0.78)。利用11/25规则发现共有24(33.3%)株X4病毒,其中治疗人群中16株,未治疗人群中8株。通过配对四格表检验基因预测和病毒表型检测的一致性,发现在未治疗人群中两种结果不存关联性(X2=0.69,p=0.41),在治疗人群中两种结果存在关联性(X2=5.33,p=0.02),提示对治疗人群来说,11/25位点能够用于预测辅助受体的利用。利用WebPSSM预测出53(72.6%)株R5嗜性株,geno2pheno共预测出34(46.6%)株R5嗜性株,两种预测方法的一致率为50%。通过辅助受体表型检测与网络预测的一致性分析,发现WebPSSM预测CCR5嗜性毒株与Ghost细胞系检测结果一致性为89.5%,预测CXCR4嗜性株与Ghost细胞检测结果一致性为44.1%,geno2pheno预测出的CCR5嗜性毒株与Ghost细胞系检测结果一致性为50%,预测CXCR4嗜性株与Ghost细胞检测结果一致性为55.9%,WebPSSM对CCR5嗜性毒株的预测一致性要明显好于geno2pheno。
结论
1.本研究发现治疗人群中利用CXCR4辅助受体的HIV-1毒株明显高于未治疗人群,并且在同一CD4~+T计数水平下CXCR4的利用率也高于未治疗人群。提示目前在我国中部地区艾滋病抗病毒治疗失败后,对于辅助受体拮抗剂的选择必须慎重,同时提示这种高感染力的X4毒株有可能在人群中广泛传播。
2.经过抗病毒治疗的HIV-1V3区净电荷要高于未治疗的HIV-1,而经过抗病毒治疗后,V3区净电荷的仍然与X4毒株的使用有一定的相关性,11/25位阳电荷仍能够有效地预测HIV辅助受体利用。
3.对于未治疗人群,考虑使用辅助受体拮抗剂时建议WebPSSM方法,对于治疗人群失败人群,考虑用辅助受体拮抗剂替换治疗时也推荐使用WebPSSM方法。
Background
In 2007,the world's first co-receptor antagonist Maraviroc against HIV-1 was approved in the United States.Maraviroc,blocking HIV-1gp120 combination with CCR5, thereby prevents HIV-1 into the host cell.So,the drug will play an important role for occupational exposure to emergency prevention,and treatment failure.Meanwhile,there will be more co-receptor antagonist for clinical trial.In order to utilize the drugs rationally,it is necessary to know HIV-1 co-receptor usage before clinical application. However,we do not know what co-receptor HIV-1 strains use after anti-retroviral therapy. In this paper,in order to explore factors that influence HIV-1 co-receptor usage and analyze the feasibility that V3 region predicts HIV-1 co-receptor,HIV-1 co-receptor usage and V3 sequence were analyzed among anti-retroviral therapy and treatment-naive HIV-1 infection patients.And the study may provide information to help to design rational and effective treatment regimen for ART.
Methods
HIV-1 infected individuals who has experienced the anti-retroviral therapy were selected from Henan、Anhui province as treatment group,and unexperienced ART patients were from Anhui province taken as treatment-na(i|¨)ve group.HIV-1 strains were isolated form PBMCs of whole blood while HIV-1 p24 was quantified using a commercial enzyme-linked immunosorbent assay(ELISA) kit.Then HIV-1 co-receptor was identified using Ghost cell lines expressing CD4 and the chemokine receptor CCR5 or CXCR4.HIV-1 V3 region was amplified from HIV-1 strains and further was analyzed the relationship between the characteristics of V3 sequence and HIV co-receptor usage. Then V3 sequence was submitted into web-server(WebPSSM and geno2pheno) to predict HIV-1 co-receptor usage,and predicted result was compared with HIV phenotype based Ghost cell line.Furthmore,the feasibility of Web-server assay was analyzed.
Results
45 HIV-1 B' strains were isolated from antiretroviral-treatment patients in Henan or Anhui province,of which 23(51%) were from Henan,therapeutic regimen for the AZT+DDI+NVP,and of which 22(49%) were from Anhui,therapeutic regimen for D4T+DDI+NVP.And the average treatment time was 26(6-48) months.109 HIV-1 B' strains were isolated from treatment-na(i|¨)ve patients.All the strain was identified as HIV-1 B' subtype after pol sequence analysis.
Among 45 HIV strains from the treatment group,22(48.89%) strains used CCR5 as a co-receptor(R5 strain),21(46.67%) strains used CXCR4/CCR5 as a co-receptor(X4/R5 strain),and two(4.44%) used only CXCR4 as a co-receptor(X4 strain).In 109 strains from treatment-na(i|¨)ve group,96(88.07%) strains used CCR5 as a co-receptor(R5 strain), 13(11.93%) strains used CCR5/CXCR4 as a co-receptor use(X4/R5 strain).
In order to analyze relationship between disease progression and HIV co-receptor usage,first of all,CD4+T count was classed three groups as follow:CD4＜100, 100=＜CD4＜200,CD4＞200.Statistical analysis showed that HIV-1 X4/R5 strains gradually increased as CD4~+T count decreasing in both treatment and treatment-na(i|¨)ve group.Even in the same CD4~+T count,the HIV-1 X4/R5 utilization in treatment groups was remarkable higher than in treatment-na(i|¨)ve group.The resullt showed some correlation between HIV-1 X4/R5 utilization rate and CD4~+T count after antiretroviral-treatment.
Logistic regression analysis showed that the OR was 7.72(3.39-17.58)(p＜0.0001) between treatment and not,however treatment time,regimen,age and sex do not influence viral co-receptor usage,which statistical analysis was not significant difference(P＜0.05).
Infection possibility based on Ghost-CCR5 cells line assay showed:HIV-1 CCR5 strain isolated from treatment group was 6.63 times of infection possibility than SF33 strain;while HIV-1 CCR5 strain isolated from treatment-na(i|¨)ve was 4.68 times than SF33 strain.For the dual-tropic strains isolated from treatment group,the infection possibility on Ghost-CXCR4 cell was 2.09 times than SF33,while 4.50 times than SF33 on Ghost-CCR5.For the dual-tropic strains isolated from treatment-naive group,the infection possibility was 0.69 times than SF33 on Ghost-CXCR4 cells,while 1.90 times than SF33 on Ghost-CCR5 cells.
Among anti-retroviral therapy patients,V3 net charge was distributed from 2 to 7(4.20±1.63),while 3-6(4.26±0.78) in treatment-na(i|¨)ve population.There was no significant difference(p=0.38).The 11/25 rulle predicted 24(33.3%) X4 strains,16 strains form treatment group and 8 strains from treatment-na(i|¨)ve group.The fourfold table method was used to evaluate the agreement between phenotype based Ghost cell lines and predicted resullt based on 11/25 rulle.The result showed there was no relevance (X2=0.69,p=0.41) in the naive-treatment group.But in the treatment group,there was relevance(X2=5.33,p=0.02),suggesting 11/25 rule was adequate for predicting HIV-1 co-receptor usage after ART.As for Web-Server(WebPSSM and geno2pheno) for HIV-1 co-receptor prediction.WebPSSM predicted 53(72.6%) HIV-1 strain as CCRS-tropic, while geno2pheno predicted 34(46.6%) HIV-1 strain as CCR5-tropic.The concordance was 50%.
Compared with viral phenotype based on Ghost cell assay,the concordance of WebPSSM was significantly better than geno2pheno.For predicting CCR5-tropic strains, there was 89.5%concordance between WebPSSM and phenotype,while 50% concordance between geno2pheno and phenotype.But for predicting CXCR4 tropic strains,the concordance was 44.1%between WebPSSM and Ghost cell lines,while 55.9%between geno2pheno and phenotype.
Conclusion
1.The study found that the HIV-1 CXCR4 utilization among anti-retroviral therapy HIV-1 infected patients was higher than the treatment-na(i|¨)ve population,whatever CD4~+T was in differ level,implying that it should pay attention to the choice of co-receptor antagonists after the failure in the Chinese central region,Furthermore,suggesting X4 strains could spread in population.
2.V3 net charge was higher among anti-retroviral therapy patients than the treatment-na(i|¨)ve population,and there was still correlation between HIV-1 X4/R5 utilization and V3 net charge after antiretroviral-treatment,and 11/25 rule was adequate for predicting HIV-1 co-receptor usage after antiviral therapy.
3.For the treatment-na(i|¨)ve individual,if co-receptor antagonist is considered,WebPSSM is recommened to predict HIV-1 co-receptor usage.For the patients with onging treatment failure,if co-receptor antagonist is considered for replacement therapy,we also recommend WebPSSM.
引文
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2.WHO,U.,Epidemiological Fact Sheet on HIV and AIDS.2008 Update.
3.JayA.Levy(美)著;邵一鸣[等]主译.艾滋病病毒与艾滋病的发病机制.2000,年科学出版社.
4.De Jong,J.J.,et al.,Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype:analysis by single amino acid substitution.J Virol,1992.66(11):p.6777-80.
5.20080146605A1,U.,Preparation and utility of CCR5 inhibitors.Uinted States Patent Application Publication,Jun.19,2008.
6.Fatkenheuer,G.,et al.,Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection N Engl J Med,2008.359(14):p.1442-55.
7.Giovannetti,A.,et al.,CCR5 and CXCR4 chemokine receptor expression and beta-chemokine production during early T cell repopulation induced by highly active anti-retroviral therapy.Clin Exp Immunol,1999.118(1):p.87-94.
8.Lambert,J.S.,et al.,Production of the HIV-suppressive chemokines CCL3/MIP-1alpha and CCL22/MDC is associated with more effective antiretroviral therapy in HIV-infected children.Pediatr Infect Dis J,2007.26(10):p.935-44.
9.Schuitemaker,H.,et al.,Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection:progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus popμlation.J Virol,1992.66(3):p.1354-60.
10.Liying Ma,Y.G.,Lin Yuan.et al.,Phenotypic and Genotypic Characterization of Human Immunodeficiency Virus Type 1 CRF07_BC Circulating in China.Retrovirology,2009.6(45).
11.Koot,M.,et al.,Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS.Ann Intern Med,1993.118(9):p.681-8.
12.Guo,Y.F.et al.,R5 to X4 coreceptor switch of human immunodeficiency virus type 1 B' and B'/C recombinant subtype isolates in China.Chin Med J(Engl),2007.120(6):p.522-5.
13.Trouplin,V.,et al.,Determination of coreceptor usage of human immunodeficiency virus type 1 from patient plasma samples by using a recombinant phenotypic assay.J Virol,2001.75(1):p.251-9.
14.Sing,T.,et al.,Predicting HIV coreceptor usage on the basis of genetic and clinical covariates.Antivir Ther,2007.12(7):p.1097-106.
15.Jensen,M.A.,et al.,Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences.J Virol,2003.77(24):p.13376-88.
16.Brumme,Z.L.,et al.,Clinical and immunological impact of HIV envelope V3 sequence variation after starting initial triple antiretroviral therapy.AIDS,2004.18(4):p.F1-9.
17.Mehandru,S.,et al.,Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract.J Exp Med,2004.200(6):p.761-70.
18.Brumme,Z.L.,et al.,Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naive individuals.J Infect Dis,2005.192(3):p.466-74.
19.李燕,徐慧芳,韩志刚等.广州市2004-2005年HIV-1毒株env基因V3区特征分析.华南预防医学,2008:34(1):26-29.
20.Morris,L.,et al.,CCR5 is the major coreceptor used by HIV-1 subtype C isolates from patients with active tuberculosis.AIDS Res Hum Retroviruses,2001.17(8):p.697-701.
21.Huang,W.,et al.,Coreceptor tropism in human immunodeficiency virus type 1 subtype D:high prevalence of CXCR4 tropism and heterogeneous composition of viral populations.J Virol,2007.81(15):p.7885-93.
22.Cocchi,F.,et al.,Identification of RANTES,MIP-1 alpha,and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ Tcells.Science,1995.270(5243):p.1811-5.
23.Bleul,C.C.,et al.,The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry.Nature,1996.382(6594):p.829-33.
24.Agrawal,L.,et al.,Anti-HIV therapy:Current and future directions.Curr Pharm Des,2006.12(16):p.2031-55.
25.Trkola,A.,et al.,HIV-1 escape from a small molecule,CCR5-specific entry inhibitor does not involve CXCR4 use.Proc Natl Acad Sci U S A,2002.99(1):p.395-400.
26.Moncunill,G.,et al.,Anti-HIV activity and resistance profile of the CXC chemokine receptor 4antagonist POL3026.Mol Pharmacol,2008.73(4):p.1264-73.
27.Walker,D.K.,et al.,Species differences in the disposition of the CCR5 antagonist,UK-427,857,a new potential treatment for HIV.Drug Metab Dispos,2005.33(4):p.587-95.
28.Strizki,J.M.,et al.,Discovery and characterization of vicriviroc(SCH 417690),a CCR5 antagonist with potent activity against human immunodeficiency virus type 1.Antimicrob Agents Chemother,2005.49(12):p.4911-9.
29.Rosenkilde,M.M.,et al.,Molecular mechanism of AMD3100 antagonism in the CXCR4 receptor:transfer of binding site to the CXCR3 receptor.J Biol Chem,2004.279(4):p.3033-41.
30.Lehmann,C.,et al.,Stable coreceptor usage of HIV in patients with ongoing treatment failure on HAART.J Clin Virol,2006.37(4):p.300-4.
31.Philpott,S.,et al.,Preferential suppression of CXCR4-specific strains of HIV-1 by antiviral therapy.J Clin Invest,2001.107(4):p.431-8.
32.Nicastri,E.,et al.,Replication capacity,biological phenotype,and drug resistance of HIV strains isolated from patients failing antiretroviral therapy.J Med Virol,2003.69(1):p.1-6.
33.Yuan,W.,et al.,CD4-induced T-20 binding to human immunodeficiency virus type 1 gp120 blocks interaction with the CXCR4 coreceptor.J Virol,2004.78(10):p.5448-57.
34.Trabaud,M.A.,et al.,Variants with different mutation patterns persist in the quasispecies of enfuvirtide-resistant HIV-1 population during and after treatment in vivo.J Acquir Immune Defic Syndr,2007.46(2):p.134-44.
35.张福杰,王玉,王建,等.国家免费艾滋病抗病毒药物治疗手册.2007年12月.人民卫生出版社.
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