| 摘要 | 1、喜树碱类衍生物抗HIV构效关系与作用机制研究
喜树碱为传统的抗肿瘤药物。本研究对经过化学结构修饰的喜树碱类衍生物进行抗HIV活性及作用机制的研究，并初步探讨了其抗HIV构效关系。
我们对喜树碱类衍生物A系列化合物A1(喜树碱)、A2(10-羟基喜树碱)及A3(7-羟基喜树碱)进行了抗HIV活性检测。化合物A1和A3有较好的抗HIV-1和抗HIV-2活性，化合物A2没有显示抗HIV活性。表明化合物A1的C-10位上-OH基团修饰可能会降低抗HIV活性，化合物A1的C-7位上-CH2OH基团修饰和C-20位-CH3缺失可能会提高其抗HIV活性。对化合物A3和A1的抗HIV机制研究发现：二者对整合酶有一定的结合活性，对慢性感染H9/HIV-1ⅢB 和Jurkat/HIV-1ⅢB细胞中病毒复制没有抑制活性、不能阻断H9/HIV-1ⅢB与正常细胞间的融合，对重组的HIV-1蛋白酶和逆转录酶没有抑制活性。化合物A1和A3不具有选择性杀伤HIV-1ⅢB慢性感染的H9和Jurkat细胞系的作用。进一步进行化合物A3诱导 H9和H9/HIV-1ⅢB、Jurkat和Jurkat/HIV-1ⅢB的凋亡实验显示，化合物A3诱导感染HIV-1ⅢB和未感染病毒细胞的凋亡没有选择性。据此我们初步认为化合物A3和A1的抗HIV作用可能与抑制整合酶活性有关，该化合物可能还作用于其它靶点。
喜树碱类衍生物B系列中化合物B1为20(S)-O - [-O-( 1'-氧基-2',2',6',6'-四甲基哌啶-4'-丁二酸)]-20-喜树碱酯，化合物B2为20(S)-O - [-N-( 1'-氧基-2',2',6',6'-四甲基-1',2',5',6'-四氢吡啶酰胺)-4'-丙氨酸)]-20-喜树碱酯)。我们对化合物B1和B2进行了抗HIV活性检测。结果显示：化合物B2有较好的抗HIV-1和抗HIV-21、喜树碱类衍生物抗HIV构效关系与作用机制研究
喜树碱为传统的抗肿瘤药物。本研究对经过化学结构修饰的喜树碱类衍生物进行抗HIV活性及作用机制的研究，并初步探讨了其抗HIV构效关系。
我们对喜树碱类衍生物A系列化合物A1(喜树碱)、A2(10-羟基喜树碱)及A3(7-羟基喜树碱)进行了抗HIV活性检测。化合物A1和A3有较好的抗HIV-1和抗HIV-2活性，化合物A2没有显示抗HIV活性。表明化合物A1的C-10位上-OH基团修饰可能会降低抗HIV活性，化合物A1的C-7位上-CH2OH基团修饰和C-20位-CH3缺失可能会提高其抗HIV活性。对化合物A3和A1的抗HIV机制研究发现：二者对整合酶有一定的结合活性，对慢性感染H9/HIV-1ⅢB 和Jurkat/HIV-1ⅢB细胞中病毒复制没有抑制活性、不能阻断H9/HIV-1ⅢB与正常细胞间的融合，对重组的HIV-1蛋白酶和逆转录酶没有抑制活性。化合物A1和A3不具有选择性杀伤HIV-1ⅢB慢性感染的H9和Jurkat细胞系的作用。进一步进行化合物A3诱导 H9和H9/HIV-1ⅢB、Jurkat和Jurkat/HIV-1ⅢB的凋亡实验显示，化合物A3诱导感染HIV-1ⅢB和未感染病毒细胞的凋亡没有选择性。据此我们初步认为化合物A3和A1的抗HIV作用可能与抑制整合酶活性有关，该化合物可能还作用于其它靶点。
喜树碱类衍生物B系列中化合物B1为20(S)-O - [-O-( 1'-氧基-2',2',6',6'-四甲基哌啶-4'-丁二酸)]-20-喜树碱酯，化合物B2为20(S)-O - [-N-( 1'-氧基-2',2',6',6'-四甲基-1',2',5',6'-四氢吡啶酰胺)-4'-丙氨酸)]-20-喜树碱酯)。我们对化合物B1和B2进行了抗HIV活性检测。结果显示：化合物B2有较好的抗HIV-1和抗HIV-2活性，而化合物B1的抗HIV活性差。表明化合物B1的C-4’位-CH2被-NH取代，同时C-3’位-CH3修饰可能会提高其抗HIV活性。对化合物B2的抗HIV机制研究发现，化合物B2对慢性感染H9/HIV-1ⅢB细胞中病毒复制没有抑制活性、不能阻断H9/HIV-1ⅢB与正常细胞间的融合，对HIV-1蛋白酶、重组的HIV-1逆转录酶及整合酶没有抑制活性。化合物B2不具有选择性杀伤HIV-1ⅢB慢性感染的H9细胞系的作用。化合物B2抗HIV的作用机制还需进一步研究。
2、HIV/AIDS患者疱疹病毒感染状况及性病患者的HIV感染状况分析
疱疹病毒是AIDS患者合并感染的常见病原体。引起人类疾病的8种疱疹病毒与HIV感染及AIDS进展、机会性感染、恶性肿瘤密切相关。为了解HIV/AIDS患者人类8型疱疹病毒感染状况，我们检测了30例AIDS患者、40例HIV携带者及70例正常对照的液标本中8型疱疹病毒感染状况。采用ELISA法检测单纯疱疹病毒1型(HSV-1)、单纯疱疹病毒2型(HSV-2)、水痘-带状疱疹病毒(VZV)和巨细胞病毒(CMV)；采用PCR法检测EB病毒(EBV)、疱疹病毒6型(HHV-6)、疱疹病毒7型(HHV-7)及疱疹病毒8型(HHV-8)。结果显示，HIV/AIDS患者中HSV-1、HSV-2、VZV、CMV、HHV-6、HHV-8 阳性率均高于健康体检者，其中AIDS患者VZV感染率与HIV携带者有显著性差异；在AIDS患者中多种疱疹病毒共感染普遍存在，必须重视HIV/AIDS患者合并疱疹病毒感染的防治。
性病可促进HIV的传播，了解性病患者的HIV感染状况及临床特征具有重要的意义。在自愿接受HIV咨询检测的基础上，对临床确诊的412例性病患者进行HIV-1/2抗体检测，并对其临床特征进行分析研究。结果显示412例性病患者的HIV检出率为2.9%。性病患者中检出HIV阳性率依次为：尖锐湿疣(6.2%)、生殖器疱疹(4.2%)、梅毒(3.4%)、淋病(1.5%)及非淋菌性尿道炎(1.0%)。83.3%合并感染HIV的性病患者存在多性伴，商业性行为普遍存在，安全套使用率极低现象。感染HIV的尖锐湿疣及生殖器疱疹患者以频繁复发为突出表现，1例合并感染HIV的梅毒患者半年即进展为神经梅毒。性病患者是HIV感染的重要高危人群，危险性行为是其感染HIV和其它性病的主要原因，应该加强性病患者的HIV检测。对临床上频繁复发的尖锐湿疣及生殖器疱疹患者、快速进展的梅毒患者应高度怀疑合并HIV感染的可能。 |
| 其他摘要 | 1.
The anti-HIV structure-activity relationship and mechanism of camptothecin's derivatives
Camptothecin is one of the traditional drugs used to anti-cancer. This thesis focused on the anti-HIV effects and mechanism of camptothecin's derivatives, and primarily discussed its anti-HIV structure-activity relationship.
We detected the anti-HIV effects of the A series of camptothecin's derivatives, including A1 (camptothecin), A2 (10-hydroxycamptothecin) and A3 (7-hydroxycamptothecin). A1 and A3 had better anti-HIV effects, but A2 had no effects. This result indicated that the modification of -OH residues in C-10 site of A1 had decreased the anti-HIV effects of the compound, further the modification of both -CH2OH residue in C-7 and losing -CH3 residue in C-20 could increase the anti-HIV effects. Through the anti-HIV mechanism research of A1 and A3, we found both compounds had effects of binding integrase of HIV-1 to some extent, while no inhibitory effects on HIV-1 protease and recombinant reverse transcriptase. They couldn't inhibit the virus replication in the H9/HIV-1BⅢ and Jurkat/HIV-1BⅢ cells, and interrupt H9/HIV-1BⅢ syncretized with normal cells. A1 and A3 had no effects of selectively killing H9/HIV-1BⅢ and Jurkat/HIV-1BⅢ cells. Then we carried out the apoptotic experiments which used A3 induced H9, H9/HIV-1BⅢ, Jurkat, Jurkat/HIV-1BⅢ apoptosis. The result showed A3 had no selective apoptosis inducing between HIV-1BⅢ infected cells and normal cells. In conclusion, we primarily consider that the anti-HIV effects of compounds A1 and A3 are relative to the inhibitory effect of integrase. These compounds may act on other targets.
The B series of camptothecin's derivatives, included B1 and B2. B1 was 20 (s)-O-camptothecinyl--[N-(1'-oxyl-2',2',6',6'-tetramethyl-4'-Piperidinylcarbonyl)]- Succinate, B2 was 20 (s)-O-camptothecinyl- [N-(1'-oxyl-2',2',6',6'-tetramethyl
-pyridine-3-carboxylic acid-1-oxyl)]-4'-alaninoate. B2 had better anti-HIV-1 and anti-HIV-2 effects, while B1 had little effects. It indicated that -NH residues replacing -CH2 residues of B1, and simultaneously modifying -CH3 in C-3' site could increase the anti-HIV effects. B2 had no inhibitory effects on HIV-1 protease, recombinant reverse transcriptase and integrase. It couldn't inhibit the virus replication in H9/HIV-1ⅢB cells, and interrupt H9/HIV-1ⅢB syncretized with normal cells. B2 had no effects of selectively killing H9/HIV-1ⅢB cells. It needs further study to find the anti-HIV mechanism.
2. HHVs infection among HIV/AIDS patients and HIV evalence among STD patients
Immunodeficiency, malignant tumor and opportunistic infection are its characteristic clinical manifestations. Human herpesvirus (HHVs) are the common opportunistic infections among patients with AIDS. HHVs are related to HIV infection, AIDS progress, opportunistic infections and malignant tumor. We investigated the prevalence of the eight HHVs among people with HIV/AIDS. Serum samples were obtained from 30 AIDS patients, 40 persons with HIV and 70 healthy blood donors. All serum samples were tested for antibodies of Herpes simplex virus type 1 (HSV-1), Herpes simplex virus type 2 (HSV-2), Varicella zoster virus (VZV) and Cytomegalovirus (CMV) by enzyme linked immunosorbent assay (ELISA). Epstein-Barr virus (EBV), Human herpesvirus 6 (HHV-6), Human herpesvirus 7 (HHV-7) and Human herpesvirus 8 (HHV-8) were detected by PCR. The infection rates of HSV-1, HSV-2, VZV, CMV, HHV-6 and HHV-8 were higher among AIDS patients than healthy blood donors. AIDS Patients also had higher infection rates of VZV than HIV-1 infected persons. Co-infection with more than two kinds of HHVs was common among AIDS patients. It’s need to prevent and cure HHVs infection among HIV/AIDS patients.
Sexually transmitted diseases (STD) can promote HIV transmission. Investigating HIV prevalence among STD patients and analyzing clinical characteristics is important. Under HIV voluntary counseling and testing, 412 diagnosed STD patients were detected for HIV 1/2 antibody; Clinical characteristics of STD patients with HIV were analyzed. HIV positive rate was 2.9% among 412 STD patients. HIV positive rate was 6.2%, 4.2%, 3.4%, 1.5% and 1.0% among patients with condyloma acuminata, genital herpes, syphilis, gonorrhea and nongonococcal urethritis, respectively. 83.3% STD patients with HIV had multiple sexual partners. Commercial sexual behavior was common and condom use rate was very low among STD patients with HIV. The patients with HIV and condyloma acuminatum or genital herpes relapsed frequently. One patient with HIV and syphilis became neurosyphilis during 6 months. Patients with STD were the important HIV high-risk population, and unsafe sexual behavior was the major reason for catching HIV/STD. It is a clue to diagnose co-infection with HIV that patients with condyloma acuminatum or genital herpes relapses frequently, and patients with syphilis progress fast. |
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