中国经性途径感染的HIV/AIDS患者不同疾病进展特点及其影响因素研究
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摘要
[目的]：探讨中国经性途径感染HIV的CD4+T细胞≤350个/μl未治疗患者疾病进展特点,评价影响AIDS发病快慢的宿主遗传学、病毒学因素。
[方法1：筛选对象来自我国“十一五”HIV/AIDS抗病毒治疗队列一(即初治患者)以及协和医院门诊HIV/AIDS随访队列。入选标准：1)年龄18-65岁；2)ELISA检测HIV-1抗体阳性并通过免疫印迹法(Western Blot)法确认；3)经性途径感染；4)确诊HIV抗体阳性的时间明确；5)可能的HIV感染时间相对明确：6)CD4+T细胞均已下降至350个/μI以下；7)未接受过HAART治疗。排除标准：1)处于急性期；2)混合其他途径感染的可能。根据患者从HIV血清学转换至进展为AIDS发病的时间(T),将T≤5年,定义为快速进展者(Rapid progressors, RP); T>5年定义为非快速进展者(Non-rapid progressors, NRP)。评估影响AIDS不同疾病进展者的因素(包括性别、年龄、民族、性途径方式、基线CD4+T淋巴细胞计数、基线HIV病毒载量)。提取患者全血DNA基因组,进行聚合酶链反应-直接测序分型法(Polymerase Chain Reaction-sequence based typing, PCR-SBT)检测,分析HIV/AIDS患者HLA-A、HLA-B、HLA-C、HLA-DRB1位点等位基因。比较RP组和NRP组不同位点的等位基因分布频率差异,评价影响HIV/AIDS患者不同疾病进展的HLA多态性差异。按近似1：1比例从两个不同的疾病进展组中共选择35例有基线点冻存的血浆标本,提取血浆HIV-RNA,通过RT-PCR对ENV基因的V3-V4区、gag区、pol区进行扩增,序列测定。利用Contig Express软件、Bioedit 7.0软件、美国拉莫斯国家实验室Los Alamos网站上的HIV databases、RIP程序、Mega5.0软件、geno2pheno[coreceptor]软件,构建系统进化树、进行病毒亚型鉴定、计算基因离散率、进行细胞嗜性预测,以比较不同疾病进展组的病毒学差异。
[结果]：
1、282例中国经性途径感染HIV且CD4+T细胞已下降至350个/μl以下未治疗患者HIV感染后的疾病进展趋势快,下降至CD4+T细胞≤350个/μl的中位时间为3.46年(95%Cl：3.19～3.74),至AIDS发病的中位时间为3.40年(95%Cl：2.88-3.93)。
2、该人群中RP占69.1%,RP和NRP的中位发病时间分别为2.43年(95%Cl：2.22～2.64)、6.84年(95%CI：6.43～7.24)。
3、男男性接触者是经性途径感染HIV的主要人群,也是促进疾病进展的危险因素(RR=1.732,95% Cl:1.360～2.205,P:0.000).
4、270例中国以汉族为主、经性途径感染的HIV/AIDS未治疗患者HLA分子等位基因具有高度多态性。其中HLA-A*02等位基因可能是促进HIV感染者疾病进展的危险性因素(OR=1.797,95% Cl:1.128～2.862,P=0.014).而HLA-B*51等位基因可能是延缓HIV感染者疾病进展的保护性因素(OR=0.379,95% Cl:0.157～0.914, P=0.031).
5、35例经性途径感染HIV/AIDS患者具有不同的病毒亚型,以CRF01 AE为主(占51.4%),在RP组和NRP组分布无差异。15例北京CRF01-AE亚型患者,RP组和NRP组在HIV-1毒株ENV基因的V4区组内基因离散率变化趋势不同于其他片段。32例患者HIV-1细胞嗜性预测以CCR5为主(占78.1%),C×CR4与是否为RP组无关,但均出现在CD4+T-200个/μl的患者体内。
[结论]：
该研究首次提出中国经性途径感染HIV且CD4+T细胞已下降至350个／μl以下未治疗患者在HIV感染后疾病进展趋势快的特点。提出男男性接触、HLA-A*02等位基因可能是促进HIV感染者疾病进展的危险性因素,HLA-B*51等位基因可能是延缓HIV感染者疾病进展的保护性因素,并初步探讨了可能的病毒学机制。对评估中国经性途径感染的HIV感染者AIDS发病趋势,揭示HIV不同进展者的病毒学及免疫学发病机制,指导HIV感染者的疾病监控、提供潜在干预治疗手段、指导疫苗研发有着重要意义。
[Objective]:To study the various characteristics of disease progression from HIV infection to AIDS among Chinese treatment-naive sexually-transmitted HIV/AIDS patients with CD4+ T cells below 350cells/μl, and assess the host and virological factors associated with disease progression.
[Methods]:The patients were screened from a cohort of treatment-naive HIV/AIDS patients of the national 11th-five-year-plan and the follow-up outpatients from Clinic of Infectious Diseases, Peking Union Medical College hospital (PUMCH). The including criteria were:1) 18-65 years old; 2) Patients were found to be HIV-seropositive by standard serum enzyme-linked immunosorbent assay (ELISA) and Western blotting analysis; 3) sexually-transmitted; 4) the definite time on positive HIV antibody; 5) the time of HIV infection were relatively clear; 6) CD4+T cells≤350cells/μl; 7) treatment-naive. The excluding criteria were:1) in the acute stage; 2) the possibility of mixed transmitted infection. Rapid progressors (RP) were defined if the time from HIV seroconversion to AIDS was≤5 years; all other patients were defined as non-rapid progressors (NRP). We assessed various influencing factors of disease progression, including gender, age, ethnicity, sexual transmission mode, the baseline CD4+T lymphocyte count and baseline HIV viral load. Genomic DNA was extracted and analyzed on HLA-A, HLA-B, HLA-C, HLA-DRB1 alleles. The allele distribution was compared between RP group and NRP as well in order to evaluate different HLA polymorphism among different HIV/AIDS disease progression.35 patients were selected from two different groups (approximately by 1:1). HIV RNA was also extracted and the env (V3-V4), gag and pol were sequenced. Using Contig Express software, Bioedit 7.0 software, the United States Alamos National Laboratory Los Alamos site HIV databases, RIP program, Mega5.0 software and geno2pheno [coreceptor] software, we constructed the phylogenetic trees of HIV subtype, calculated the genetic divergence of HIV and predicted the viral tropism.
[Results]:
1、Total 282 patients were included. The trends of disease progression after HIV infection were fast in Chinese sexually-transmitted untreatable HIV/AIDS whose CD4+T cells had dropped below 350 cells/μl. The median time from HIV infection to the set of the CD4+ T cells below 350 cells/μl was 3.46 years (95% Cl:3.19～3.74). The median time from HIV infection to onset of AIDS was 3.40 years (95% Cl:2.88～3.93).
2、The RP population accounted for 69.1% of whole 282 patients. The median time from HIV infection to onset of AIDS were 2.43 years (95% Cl:2.22～2.64) and 6.84 years (95% Cl:6.43～7.24) for RP and NRP, respectively.
3、MSM accounts for majority of sexually-transmitted population. It was also a risk factor for disease progression (RR=1.732,95% Cl:1.360～2.205, P=0.000).
4～The HLA typing results showed Chinese Han ethnic HIV/AIDS patients had highly polymorphic alleles of HLA molecules. HLA-A*02 allele may promote disease progression in HIV infection (OR=1.797,95%CI:1.128～2.862, P=0.014). The HLA-B*51 allele may delay disease progression in HIV infection (OR=0.379,95% Cl:0.157～0.914, P=0.031).
5、Different subtypes of HIV-1 were found in 35 cases of sexually-transmitted HIV/AIDS, and the majority was CRF01_AE (51.4%). However, there was no difference between RP and NRP group. Among 15 patients with subtype CRF01_AE infection from Beijing, the changing trend of gene divergence on V4 region was different from other regions, and it was also different between RP and NRP group. The cell tropism predictions from 32 patients showed that the majority strains were CCR5 tropic (78.1%). CXCR4 tropic strains only occurred when patients' CD4+T cells were≤200cells/μl, which suggested that CXCR4 tropic viruses may be related to progression to AIDS stage.
[Conclusions]:
This is the first study to discuss the fast trends of progression of treatment-naive sexually-transmitted HIV/AIDS patients with CD4+T cells below 350cells/μl in China. MSM, HLA-A*02 allele maybe the risk factors to promote disease progression in HIV infection, and HLA-B*51 allele may delay HIV disease progression, and there were potential virological changes. This study not only revealed the different virological and immunological pathogenesis of different AIDS progressors, but also could guide the disease surveillance, aid potential treatments and assist vaccine development.
[方法1：筛选对象来自我国“十一五”HIV/AIDS抗病毒治疗队列一(即初治患者)以及协和医院门诊HIV/AIDS随访队列。入选标准：1)年龄18-65岁；2)ELISA检测HIV-1抗体阳性并通过免疫印迹法(Western Blot)法确认；3)经性途径感染；4)确诊HIV抗体阳性的时间明确；5)可能的HIV感染时间相对明确：6)CD4+T细胞均已下降至350个/μI以下；7)未接受过HAART治疗。排除标准：1)处于急性期；2)混合其他途径感染的可能。根据患者从HIV血清学转换至进展为AIDS发病的时间(T),将T≤5年,定义为快速进展者(Rapid progressors, RP); T>5年定义为非快速进展者(Non-rapid progressors, NRP)。评估影响AIDS不同疾病进展者的因素(包括性别、年龄、民族、性途径方式、基线CD4+T淋巴细胞计数、基线HIV病毒载量)。提取患者全血DNA基因组,进行聚合酶链反应-直接测序分型法(Polymerase Chain Reaction-sequence based typing, PCR-SBT)检测,分析HIV/AIDS患者HLA-A、HLA-B、HLA-C、HLA-DRB1位点等位基因。比较RP组和NRP组不同位点的等位基因分布频率差异,评价影响HIV/AIDS患者不同疾病进展的HLA多态性差异。按近似1：1比例从两个不同的疾病进展组中共选择35例有基线点冻存的血浆标本,提取血浆HIV-RNA,通过RT-PCR对ENV基因的V3-V4区、gag区、pol区进行扩增,序列测定。利用Contig Express软件、Bioedit 7.0软件、美国拉莫斯国家实验室Los Alamos网站上的HIV databases、RIP程序、Mega5.0软件、geno2pheno[coreceptor]软件,构建系统进化树、进行病毒亚型鉴定、计算基因离散率、进行细胞嗜性预测,以比较不同疾病进展组的病毒学差异。
[结果]：
1、282例中国经性途径感染HIV且CD4+T细胞已下降至350个/μl以下未治疗患者HIV感染后的疾病进展趋势快,下降至CD4+T细胞≤350个/μl的中位时间为3.46年(95%Cl：3.19～3.74),至AIDS发病的中位时间为3.40年(95%Cl：2.88-3.93)。
2、该人群中RP占69.1%,RP和NRP的中位发病时间分别为2.43年(95%Cl：2.22～2.64)、6.84年(95%CI：6.43～7.24)。
3、男男性接触者是经性途径感染HIV的主要人群,也是促进疾病进展的危险因素(RR=1.732,95% Cl:1.360～2.205,P:0.000).
4、270例中国以汉族为主、经性途径感染的HIV/AIDS未治疗患者HLA分子等位基因具有高度多态性。其中HLA-A*02等位基因可能是促进HIV感染者疾病进展的危险性因素(OR=1.797,95% Cl:1.128～2.862,P=0.014).而HLA-B*51等位基因可能是延缓HIV感染者疾病进展的保护性因素(OR=0.379,95% Cl:0.157～0.914, P=0.031).
5、35例经性途径感染HIV/AIDS患者具有不同的病毒亚型,以CRF01 AE为主(占51.4%),在RP组和NRP组分布无差异。15例北京CRF01-AE亚型患者,RP组和NRP组在HIV-1毒株ENV基因的V4区组内基因离散率变化趋势不同于其他片段。32例患者HIV-1细胞嗜性预测以CCR5为主(占78.1%),C×CR4与是否为RP组无关,但均出现在CD4+T-200个/μl的患者体内。
[结论]：
该研究首次提出中国经性途径感染HIV且CD4+T细胞已下降至350个／μl以下未治疗患者在HIV感染后疾病进展趋势快的特点。提出男男性接触、HLA-A*02等位基因可能是促进HIV感染者疾病进展的危险性因素,HLA-B*51等位基因可能是延缓HIV感染者疾病进展的保护性因素,并初步探讨了可能的病毒学机制。对评估中国经性途径感染的HIV感染者AIDS发病趋势,揭示HIV不同进展者的病毒学及免疫学发病机制,指导HIV感染者的疾病监控、提供潜在干预治疗手段、指导疫苗研发有着重要意义。
[Objective]:To study the various characteristics of disease progression from HIV infection to AIDS among Chinese treatment-naive sexually-transmitted HIV/AIDS patients with CD4+ T cells below 350cells/μl, and assess the host and virological factors associated with disease progression.
[Methods]:The patients were screened from a cohort of treatment-naive HIV/AIDS patients of the national 11th-five-year-plan and the follow-up outpatients from Clinic of Infectious Diseases, Peking Union Medical College hospital (PUMCH). The including criteria were:1) 18-65 years old; 2) Patients were found to be HIV-seropositive by standard serum enzyme-linked immunosorbent assay (ELISA) and Western blotting analysis; 3) sexually-transmitted; 4) the definite time on positive HIV antibody; 5) the time of HIV infection were relatively clear; 6) CD4+T cells≤350cells/μl; 7) treatment-naive. The excluding criteria were:1) in the acute stage; 2) the possibility of mixed transmitted infection. Rapid progressors (RP) were defined if the time from HIV seroconversion to AIDS was≤5 years; all other patients were defined as non-rapid progressors (NRP). We assessed various influencing factors of disease progression, including gender, age, ethnicity, sexual transmission mode, the baseline CD4+T lymphocyte count and baseline HIV viral load. Genomic DNA was extracted and analyzed on HLA-A, HLA-B, HLA-C, HLA-DRB1 alleles. The allele distribution was compared between RP group and NRP as well in order to evaluate different HLA polymorphism among different HIV/AIDS disease progression.35 patients were selected from two different groups (approximately by 1:1). HIV RNA was also extracted and the env (V3-V4), gag and pol were sequenced. Using Contig Express software, Bioedit 7.0 software, the United States Alamos National Laboratory Los Alamos site HIV databases, RIP program, Mega5.0 software and geno2pheno [coreceptor] software, we constructed the phylogenetic trees of HIV subtype, calculated the genetic divergence of HIV and predicted the viral tropism.
[Results]:
1、Total 282 patients were included. The trends of disease progression after HIV infection were fast in Chinese sexually-transmitted untreatable HIV/AIDS whose CD4+T cells had dropped below 350 cells/μl. The median time from HIV infection to the set of the CD4+ T cells below 350 cells/μl was 3.46 years (95% Cl:3.19～3.74). The median time from HIV infection to onset of AIDS was 3.40 years (95% Cl:2.88～3.93).
2、The RP population accounted for 69.1% of whole 282 patients. The median time from HIV infection to onset of AIDS were 2.43 years (95% Cl:2.22～2.64) and 6.84 years (95% Cl:6.43～7.24) for RP and NRP, respectively.
3、MSM accounts for majority of sexually-transmitted population. It was also a risk factor for disease progression (RR=1.732,95% Cl:1.360～2.205, P=0.000).
4～The HLA typing results showed Chinese Han ethnic HIV/AIDS patients had highly polymorphic alleles of HLA molecules. HLA-A*02 allele may promote disease progression in HIV infection (OR=1.797,95%CI:1.128～2.862, P=0.014). The HLA-B*51 allele may delay disease progression in HIV infection (OR=0.379,95% Cl:0.157～0.914, P=0.031).
5、Different subtypes of HIV-1 were found in 35 cases of sexually-transmitted HIV/AIDS, and the majority was CRF01_AE (51.4%). However, there was no difference between RP and NRP group. Among 15 patients with subtype CRF01_AE infection from Beijing, the changing trend of gene divergence on V4 region was different from other regions, and it was also different between RP and NRP group. The cell tropism predictions from 32 patients showed that the majority strains were CCR5 tropic (78.1%). CXCR4 tropic strains only occurred when patients' CD4+T cells were≤200cells/μl, which suggested that CXCR4 tropic viruses may be related to progression to AIDS stage.
[Conclusions]:
This is the first study to discuss the fast trends of progression of treatment-naive sexually-transmitted HIV/AIDS patients with CD4+T cells below 350cells/μl in China. MSM, HLA-A*02 allele maybe the risk factors to promote disease progression in HIV infection, and HLA-B*51 allele may delay HIV disease progression, and there were potential virological changes. This study not only revealed the different virological and immunological pathogenesis of different AIDS progressors, but also could guide the disease surveillance, aid potential treatments and assist vaccine development.
引文
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