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Relationship Of Selection Of Transmitted HIV-1 Quasispecies And Immunologic Epitopes/Tropism

Posted on:2009-07-28Degree:DoctorType:Dissertation
Country:ChinaCandidate:G Y HuangFull Text:PDF
GTID:1114360272461375Subject:Internal Medicine
Abstract/Summary:PDF Full Text Request
AIDS is a disease of the human immune system that is characterized by reduction in the numbers of CD4-bearing helper T cells to 20 percent or less of normal thereby rendering the subject highly vulnerable to life-threatening conditions and that is caused by infection with HIV commonly transmitted in infected blood and bodily secretions. The estimated number of people living with HIV was 33.2 million worldwide in 2007, consisting of adults 30.7 million and 2.5 million children under 15 years and the estimated number of AIDS death was 2.1 million in 2007. In china, 223 501 HIV positives cases had been reported, including 62 838 AIDS cases and 22 205 death cases by the end of October 2007. So AIDS is considered to be one of the most threatening public health problems in modern society.HIV is classified into two types, HIV-1 and HIV-2. While HIV-1 predominates the worldwide disaster and generally when people refer to HIV without specifying the type of virus they will be referring to HIV-1. The relatively uncommon HIV-2 type is concentrated in West Africa and is rarely found elsewhere. The strains of HIV-1 can be classified into three groups, the major group M, the outlier group O and the new group N. HIV tropism refers to the cell type that the HIV infects and replicates in. M-tropic strains of HIV-1, or non-syncytium-inducing strains (NSI) use the beta-chemokine receptor CCR5 for entry and are thus able to replicate in macrophages. T-tropic isolates, or syncitium-inducing (SI) strains replicate in primary CD4+ T-cells and use the alpha-chemokine receptor, CXCR4, for entry. Viruses that use only the CCR5 receptor are termed R5, those that only use CXCR4 are termed X4, and those that use both, X4/R5.HIV has several major genes coding for structural proteins that are found in all retroviruses, and several nonstructural ("accessory") genes that are unique to HIV. The gag gene provides the basic physical infrastructure of the virus, and pol provides the basic mechanism by which retroviruses reproduce, while the others help HIV to enter the host cell and enhance its reproduction. The envelope gene(env) encodes a glycosylated polypeptide precursor(gp160) that is processed to form the exterior envelope glycoprotein(gp120) and the transmembrance glycoprotein(gp41) which anchors the envelope complex to the virus surface. It is the viral envelope that is responsible for CD4 binding, fusion, and virus entry. V3 region of envelope gp120 determins coreceptor utilization.Mother-to-child and heterosexual transmission contribute to drive the AIDS pandemic. Although both modes of transmission most often involve a severe reduction in viral diversity from the donor quasispecies, the selective pressures are different. Our current understanding of mother-to-child transmission is that maternal neutralizing antibody are a strong selective force, but other factors including restricted glycosylation of gp120 could also be important. For heterosexual transmission, it is not just neutralization escape variants that are transmitted, because in some settings it appears that transmission results in the selection of variants that lack resistance to the donor's neutralizing antibodies.We designed and conducted the experiments as follow: selecting 4 pairs of mother-to-child and 8 pairs of heterosexual transmission as objects from 109 HIV-positive cases; analysing complexity and entropy of HIV-1 quasispecies in each pair; searching possible CTL and neutralizing antibody epitopes in env region from sequencing results; predicting tropisms of HIV-1 in each pair by geno2pheno software.The Main Research Results1. We had collected 109 AIDS patients and their couples or children HIV-1 carriers including 4 pairs of mother-to-child transmission cases and 8 pairs of heterosexual transmission cases. The most common clinical manifestations of AIDS patients are fever, losing weight and diarrhea. The maximum of CD4 cell count of these cases is 670/μl, the minimum is 2/μl and the average is 120.35±82.83/μl; The maximum of HIV-RNA is 5.222×10~7copies/ml, the minimum is 0 copy/ml and the average is 6.56×10~4copies/ml. Fifteen cases received HAART, two died during the trerapy and thirteen were still alive and maintained symptomless.2. Analysis results of clonotype number, quasispecies complexity and entropy of 4 mother-to-child transmission pairs were as follow, clonotype number, quasispecies complexity and entropy of mothers in 3 of 4 pairs were higher than those of their children respectively and the results in 1 pairs was opposite. Analysis results of CTL epitopes were as follow, the evolution of children's HIV-1 in 2 of 4 pairs produced new epitopes which could not be found in their mothers', the evolution of the children's in the other 2 pairs produced nothing special compared to their mothers'. Analysis results of neutralizing antibody epitopes were as follow, two minor and no major neutralizing antibody epitopes were found. Predicting results of HIV-1 tropisms were as follow, two pairs of mother-to-child transmission pairs were M-tropic consistently, one pair was T-tropic consistently and the mother of the last pair was M-tropic and her child was T-tropic.3. Analysis results of clonotype number, quasispecies complexity and entropy of 8 heterosexual transmission pairs were as follow, clonotype number, quasispecies complexity and entropy of males in 4 of 8 pairs were higher than those of their corresponding females respectively, the results in 3 pairs were opposite and the results of male and female in 1 pair were same. Analysis results of CTL epitopes of 8 heterosexual transmission pairs were as follow, the evolution of females'HIV-1 in 5 of 8 pairs produced new epitopes which could not be found in their partners', the evolution of the females'in the other 3 pairs produced nothing special compared to their partners'. Analysis results of neutralizing antibody epitopes were as follow, one minor and major neutralizing antibody epitope were found. Predicting results of HIV-1 tropisms were as follow, five pairs of heterosexual transmission pairs were M-tropic consistently, two pairs were T-tropic consistently and the male of the last pair was T-tropic and the female was M-tropic.Conclusion1. The number of AIDS patients had been increasing since 2001. Heterosexual transmission contribute to the most HIV infected cases. Yong and middle-aged people dominate in HIV-1 infected cases and the number of infected females are increasing. The most common clinical magnifications are all helpless to the diagnosis and AIDS patients'CD4 cell counts are all below 200/μl and their viral loads are all very high( beyond 105copies/ml). Those patients'life quality can be improved and their life time can be prolonged by HAART after their complications were controlled.2. The complexity and entropy of HIV-1 quasispecies of the mother transmitters are higher than those of the child recipients. HIV-1 usually evolutes quickly and produces new CTL epitopes after entering the child recipients. The magtitudes of HLA restricted CTL epitopes changes induced by mutated HIV-1 quasispecies after mother-to-child transmission increase as time going. M-tropic HIV-1 resistant to maternal neutralizing antibody dominates in mother-to-child transmission.3. The complexity and entropy of HIV-1 quasispecies of the male transmitters are higher than those of the femal recipients. HIV-1 usually evolutes quickly and produces new CTL epitopes after entering the female recipients. M-tropic HIV-1 dominates in heterosexual transmission.
Keywords/Search Tags:HIV, mother-to-child transmission, heterosexual transmission, CTL, neutralizing antibody, epitope, tropism
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