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HIV-1 Gag-specific CD8+T Cell Responses And Cytotoxic T Lymphocyte Escape In Chinese

Posted on:2011-12-31Degree:DoctorType:Dissertation
Country:ChinaCandidate:D D HuangFull Text:PDF
GTID:1114330338984727Subject:Internal Medicine
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Acquired immunodeficiency syndrome (AIDS), resulting from HIV-1 infection, is one of the serious infectious diseases against the human healthy and the social stability in some countries. HAART is the best regiment to treat AIDS at present, but it can not thoroughly eliminate HIV. It is very urgent to develop a vaccine to protect against HIV-1 infection or control the diseases. More and more evidence support that HIV-1 Gag-specific CD8+ T cells play a pivtol role in controlling HIV-1 replication. One of the import strategies of HIV adaptation evolution is HIV mutation in Gag region to escape the Cytotoxic T Lymphocyte response.1,In this study, 107 HIV-1 infected individuals cohort was established. HIV-1B Gag-specific CD8+ T cells response and immune escape were investigated in this study. The synthetic peptides, according to HIV-1B consensus sequence, induced HIV-1 Gag-specific CD8+ T cells response and characterized the CTL response. HLA-â… alleles of HIV-1 infected individuals in this study were typed and the best definition epitopes restrict by HLA-â… alleles were confirmed. HIV-1 viruses from individual whom carried HLA-â… alleles restricting the best definition epitopes but could not recognize all epitopes were sequenced. The mutations of HIV-1 from individuals in this study were analyzed by align the amino acid (AA) sequence from the autologous virus with the AA sequence synthetic peptides. Then, the relationship of the mutation and CTL escape or response was evaluated.2,HIV-1 B Gag-specific CTL was detected by ELIspot. Among 66 peptides, each peptide could be recognized by at least one patient's CTL. The median frequency of the peptides recognized by CTLs was 10.28%. One hundred and two individuals in this study could recognize at least one HIV-1B peptide in Gag region. The peptides that induced top 6 frequency and cumulative magnitude of CTL response were Gag-B-23, Gag-B-24, Gag-B-40, Gag-B-41, Gag-B-42, Gag-B-47.3,The positive correlations between CD4+ T cells and frequency or cumulative magnitude of CTL response were observed (P<0.001). HIV-1 viral load of the individuals in this study negative associated with the frequency or cumulative magnitude of CTL response (P<0.005).4,HLA-â… alleles of the individuals in this cohort were typed by Polymerase chain reaction with sequence-specific primers(PCR-SSP). Thirty two HLA-â… A alleles were presented in HLA-â… A locus. HLA-â… A*0201 is the most frequent HLA-â… A alleles. In HLA-â… B locus, 46 HLA-â… B alleles were observed. The highest frequency HLA-â… B alleles is HLA-â… B*4601. Twenty-four HLA-â… C alleles were presented in HLA-â… C locus. HLA-â… Cw*0201 is the highest frequency HLA-â… C alleles.5,Among all HLA-â… alleles of the individual in this cohort,the number of HLA-â… alleles that restrict the best definition epitopes is 134. Though 22 individuals carrying restricting the best definition epitopes HLA-â… alleles, the peptides including the best definition epitopes could not induce the specific CTL response. The line correlation could not be found between the number of HLA-â… alleles that restrict the best definition epitopes and the frequency or cumulative magnitude of CTLs response.6,The mutations in Gag-B-23 peptide are F32Y,E35A,V36I,V36T,F40Y,E45T.The ratio of mutation in Gag-B-23 peptide which induced CTL immune escape reaches 85.71%. While the ration of mutation in the Gag-B-23 peptide which did not induce CTL immune escape is 14.18%. The probability of the CTL immune escape which induced by mutation peptide is significant higher than CTL response,according Fisher's Exact Test analysis(P=0.026). The mutations in Gag-B-40, Gag-B-41 peptide are E159G,E159K,V165T,V165I,R167K,F168Y,L172T,R173K,A174G,S178A,E180A. The mutations of peptide were more readily induce CTL immune escape (Fisher's Exact Test, P=0.029).
Keywords/Search Tags:HIV-1, AIDS, CD8+ T lymphocyte, Cytotoxic T Lymphocyte, epitope, mutation, CTL immune escape
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