山东省HIV-1主要流行株基因变异和人群HIV-1抗性基因的研究
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摘要
本研究共分为三部分,第一部分是山东省HIV-1主要流行株序列特征和基因变异的研究,第二部分是山东省用于HIV-1分型的HMA体系的建立,第三部分是HIV-1感染者及其密切接触者HIV-1抗性基因的研究。
第一部分采用分子生物学技术与流行病学分析相结合,实验数据与调查资料相结合的方法,从微观和宏观的角度首次较全面地对山东省HIV-1主要基因亚型流行毒株的流行特征与生物学特性、基因变异与分子进化以及它们对HIV-1传播的影响进行了研究、分析和预测,取得了具有科学价值的成果。第一部分的主要结果如下:
1、山东省流行的HIV亚型众多,共有7种亚型,其中B′亚型数量最大为71株(71/93占77.2%),CRF01_AE 9株(9/93占9.8%),CRF07-B’C、CRF0B-B’C各3株(3/93均占3.3%),B、C和CRF02_AG各2株(2/93占2.2%),CRF01-AG在全国范围内未见其他报道。B’亚型在人群和地域上分布最广,涉及献血员、受血者、二者的配偶和性乱人群,分布在10个地市,B’/C亚型以吸毒人群为主,分布在5个地市,A/E和其他亚型则主要为性乱人群,集中在几个经济发达的城市,从总的亚型流行特征来看,HIV-1在我省有流行加快的趋势。
2、env、gag、tat是HIV-1最主要的三个基因区,同源性分析显示,它们具有相一致的各亚型的来源,env区的结果显示,B’亚型已进入我省7-10年。通过同源性和各功能区氨基酸序列特征分析,各区反映的状况是一致的,每种亚型都有其特定的起源和进化趋势,3种优势亚型中,A/E变异最大,B’次之,B’/C最保守,但他们在几个不同功能区的表现又是一致的,即env区变异最大,tat区次之,gag区最为保守。因此,我们的研究结果既反映了我省三种主要流行株基因变异的共性特点,又揭示了它们之间基因变异的差异,这为我们从基因变异的层面上理解这三种主要流行株在生物学特性和传播效率上的差异奠定了理论基础。
3、env区的V3环为主要中和抗体决定簇和辅助受体的结合部位,氨基酸的序列分析显示V3环比C2、V4区具有更高的保守性,V3区并不象原来人们认为的那样高度
This study is divided into 3 parts. Part 1 is about the sequence characteristic and genetic variation of predominant circulating strains of the Human Immunodeficiency Virus Type 1 in Shandong province, part 2 is about the construction of HMA system for HIV-1 subtyping, part 3 is about the effect and the distribution of HIV-1 anti-gene (CCR2-64I, SDF1-3'A) among people infected with HIV-1 and their consanguineous contacters.First Part We use the measures of molecular biology, bioinformatics and epidemiology, to study the sequence characteristic and genetic variation of predominant circulating strains of the Human Immunodeficiency Virus Type 1 in Shandong province in 2002-2003, and analyse their effects on HIV-1 biological characteristic and HIV-1 spreading in this province, this is the first time to do this kind of research roundly in Shandong province. The results are as followings:1. There are 7 HIV-1 subtypes in Shandong province, which are B' (71/93, 77.2%), CRF01AE (9/93, 9.8%), CRF07-B'C. CRF0B-B'C(3/93,3.3% respectively ), B, C and CRF02_AG (2/93, 2.2% respectively). Subtype B' distributes in 10 cities, covering 4 kinds of groups of high risk population, especially paid blood donors, subtype B'/C distributes in 5 cities, mainly involving injecting drug users (IDUs), CRF01_AE and other subtypes distribute in several developed cities, mainly involving sex workers and whorehouse visitors.2. Gene divergence and amino acid sequence analysis of section env, gag, tat shows each subtypes' origins, B' strains are closely related to B.CN.RL42 and B'/C strains to 97CN54A and 97CNGX6F, CRF01-AE strains to 01_ae.th.90.cm2, 01_ae.jp.93.93j, while A/G and C strains are closely related respectively to standarded strains from Cameroon and Ethiopia, B strains to American B. Gene divergence of env of B' strains shows that subtype B' has come into Shandong for 7-10 years. From gene divergence and amino acid sequence, we also know that A/E strains' variation is the largest, B' strains take the second place and B7C is the least.
3. Amino acid sequence analysis of section env shows V3 is more conservative than C2, V4. The top four peptides of V3 loop shows variously, besides GPGQ and GPGR, there were 6 kinds of them in all, there is a drifting evidence from GPGR to GPGQ in B' strains. Electron affinity of 11th and 25th Amino acid shows that the NSI strains are changing to SI strains. Gag and Tat proteins take on intrinsic invariableness at their constant section, but 2 strains at Gag's and 14 strains at Tat's important section develop variation which may lead to characteristic changes.4. Gag protein shows 4 signature Amino acid sites, Env shows 7 and Tat shows 4 of B' strains. This displays that B' strains have developed a special group in Shandong province. B' strains at Env section have 9 N-glycosites, among which 7 are lost at the various extent, at Gag section, 1 of 2 is lost.All above shows that there are many kinds of subtype and CRFs, and their genomes generate obvious variation, there is a quickening trend of HIV-1 transmitting in Shandong province, The results also provide important reference for study and production of vaccine and diagnostic agents, and can be a gist to make measures of HIV-1 prevention and control for Shandong province.Second Part We select 3-4 strains of subtype B', BVC and A/E , whose env sequence are most closely related to their consensus sequence as standarded strains, construct clones with their vl-v5 segment of section env. We construct 11 standarded plasmids in all for HMA subtyping system, we also explore the best ways of PCR, heteroduplex hybridization and polyacrylamide gel electrophoresis(PAGE), et al, for this HMA system. We use the sequencing subtyping ways to evaluate this system, show that subtyping rate of 3 types get to 94%, 90% and 90% respectively.Third Part We detect the anti-gene (CCR2-64I> SDF1-3 'A) by PCR and RFLP, and analyze the relationship between anti-gene and the disease progression using statistics method. The allelic frequencies of CCR2-64K SDF1-3'A were 23.64%x 23.94% respectively, and their polymorphism conformed to the Hardy-Weinberg balance distribution. The incubation periods for AIDS patients with SDF1-3'A1 ? CCR2-64I and wild type were 8.33±1.16> 8.94±1.17,
第一部分采用分子生物学技术与流行病学分析相结合,实验数据与调查资料相结合的方法,从微观和宏观的角度首次较全面地对山东省HIV-1主要基因亚型流行毒株的流行特征与生物学特性、基因变异与分子进化以及它们对HIV-1传播的影响进行了研究、分析和预测,取得了具有科学价值的成果。第一部分的主要结果如下:
1、山东省流行的HIV亚型众多,共有7种亚型,其中B′亚型数量最大为71株(71/93占77.2%),CRF01_AE 9株(9/93占9.8%),CRF07-B’C、CRF0B-B’C各3株(3/93均占3.3%),B、C和CRF02_AG各2株(2/93占2.2%),CRF01-AG在全国范围内未见其他报道。B’亚型在人群和地域上分布最广,涉及献血员、受血者、二者的配偶和性乱人群,分布在10个地市,B’/C亚型以吸毒人群为主,分布在5个地市,A/E和其他亚型则主要为性乱人群,集中在几个经济发达的城市,从总的亚型流行特征来看,HIV-1在我省有流行加快的趋势。
2、env、gag、tat是HIV-1最主要的三个基因区,同源性分析显示,它们具有相一致的各亚型的来源,env区的结果显示,B’亚型已进入我省7-10年。通过同源性和各功能区氨基酸序列特征分析,各区反映的状况是一致的,每种亚型都有其特定的起源和进化趋势,3种优势亚型中,A/E变异最大,B’次之,B’/C最保守,但他们在几个不同功能区的表现又是一致的,即env区变异最大,tat区次之,gag区最为保守。因此,我们的研究结果既反映了我省三种主要流行株基因变异的共性特点,又揭示了它们之间基因变异的差异,这为我们从基因变异的层面上理解这三种主要流行株在生物学特性和传播效率上的差异奠定了理论基础。
3、env区的V3环为主要中和抗体决定簇和辅助受体的结合部位,氨基酸的序列分析显示V3环比C2、V4区具有更高的保守性,V3区并不象原来人们认为的那样高度
This study is divided into 3 parts. Part 1 is about the sequence characteristic and genetic variation of predominant circulating strains of the Human Immunodeficiency Virus Type 1 in Shandong province, part 2 is about the construction of HMA system for HIV-1 subtyping, part 3 is about the effect and the distribution of HIV-1 anti-gene (CCR2-64I, SDF1-3'A) among people infected with HIV-1 and their consanguineous contacters.First Part We use the measures of molecular biology, bioinformatics and epidemiology, to study the sequence characteristic and genetic variation of predominant circulating strains of the Human Immunodeficiency Virus Type 1 in Shandong province in 2002-2003, and analyse their effects on HIV-1 biological characteristic and HIV-1 spreading in this province, this is the first time to do this kind of research roundly in Shandong province. The results are as followings:1. There are 7 HIV-1 subtypes in Shandong province, which are B' (71/93, 77.2%), CRF01AE (9/93, 9.8%), CRF07-B'C. CRF0B-B'C(3/93,3.3% respectively ), B, C and CRF02_AG (2/93, 2.2% respectively). Subtype B' distributes in 10 cities, covering 4 kinds of groups of high risk population, especially paid blood donors, subtype B'/C distributes in 5 cities, mainly involving injecting drug users (IDUs), CRF01_AE and other subtypes distribute in several developed cities, mainly involving sex workers and whorehouse visitors.2. Gene divergence and amino acid sequence analysis of section env, gag, tat shows each subtypes' origins, B' strains are closely related to B.CN.RL42 and B'/C strains to 97CN54A and 97CNGX6F, CRF01-AE strains to 01_ae.th.90.cm2, 01_ae.jp.93.93j, while A/G and C strains are closely related respectively to standarded strains from Cameroon and Ethiopia, B strains to American B. Gene divergence of env of B' strains shows that subtype B' has come into Shandong for 7-10 years. From gene divergence and amino acid sequence, we also know that A/E strains' variation is the largest, B' strains take the second place and B7C is the least.
3. Amino acid sequence analysis of section env shows V3 is more conservative than C2, V4. The top four peptides of V3 loop shows variously, besides GPGQ and GPGR, there were 6 kinds of them in all, there is a drifting evidence from GPGR to GPGQ in B' strains. Electron affinity of 11th and 25th Amino acid shows that the NSI strains are changing to SI strains. Gag and Tat proteins take on intrinsic invariableness at their constant section, but 2 strains at Gag's and 14 strains at Tat's important section develop variation which may lead to characteristic changes.4. Gag protein shows 4 signature Amino acid sites, Env shows 7 and Tat shows 4 of B' strains. This displays that B' strains have developed a special group in Shandong province. B' strains at Env section have 9 N-glycosites, among which 7 are lost at the various extent, at Gag section, 1 of 2 is lost.All above shows that there are many kinds of subtype and CRFs, and their genomes generate obvious variation, there is a quickening trend of HIV-1 transmitting in Shandong province, The results also provide important reference for study and production of vaccine and diagnostic agents, and can be a gist to make measures of HIV-1 prevention and control for Shandong province.Second Part We select 3-4 strains of subtype B', BVC and A/E , whose env sequence are most closely related to their consensus sequence as standarded strains, construct clones with their vl-v5 segment of section env. We construct 11 standarded plasmids in all for HMA subtyping system, we also explore the best ways of PCR, heteroduplex hybridization and polyacrylamide gel electrophoresis(PAGE), et al, for this HMA system. We use the sequencing subtyping ways to evaluate this system, show that subtyping rate of 3 types get to 94%, 90% and 90% respectively.Third Part We detect the anti-gene (CCR2-64I> SDF1-3 'A) by PCR and RFLP, and analyze the relationship between anti-gene and the disease progression using statistics method. The allelic frequencies of CCR2-64K SDF1-3'A were 23.64%x 23.94% respectively, and their polymorphism conformed to the Hardy-Weinberg balance distribution. The incubation periods for AIDS patients with SDF1-3'A1 ? CCR2-64I and wild type were 8.33±1.16> 8.94±1.17,
引文
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2. Tatsuo S, Shinichi O, Setsuko I, et al. A naturally occurring single basic amino acid substitution in the V3 region of the human immunodeficiency virus type 1 Env protein Alters the cellular host range and antigenic structure of the virus. J Virol, 1994; 68: 7689-7696
3. Robertson DL, Anderson JP, Bradac JA, et al. HIV-1 nomenclature proposal [letter]. Science, 2000, 288: 55-56.
4. McCutchan FE: Understanding the genetic diversity of HIV-1 AIDS 2000, 14: S31-S44.
5. Dougherty JP and Temin HM. Determination of retroviral mutaton rates using speen necrosis virus-based vectors and helper cells. Bio/Technology, 1991, 16: 21-33.
6. Roberts JD, Bebenek K, Kunkel TA. The accuracy of reverse transcriptase from HIV-1. Science, 1988, 242: 1171-1173.
7. Coffin JM. Genetic diversity and evolution of retroviruses. Curr. Top. Microbiol. Immunol. 1992, 176: 143-164.
8. Brown A L and Monaghan P. Evolution of the structural proteins of human immunodeficiency virus: selective constraints on nucleotide substitution. AIDS Res. Hum. Retruvirses, 1988, 4 (6) : 399-407
9. Robertson DL, Sharp PM, McCutchan FE, et al. Recombination in HIV-1. Nature, 1995, 374 (6518) : 124-126.
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