Pathogenesis and Treatment of HIV Infection

HIV感染的发病机制和治疗

• 批准号: 10248883
• 负责人: H. Clifford Lane
• 金额: $ 176.31万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10248883
• 关键词: Acquired Immunodeficiency Syndrome; Aftercare; Animals; Antibodies; Bar Codes; Biological; Blood; CD4 Positive T Lymphocytes; Cell Count; Cell Survival; Cells; Clinical Trials; Coagulation Process; Code; DNA; DNA Sequence Alteration; Detection; Disease remission; Elements; Environment; Genome; HIV; HIV Infections; HIV-1; Homeostasis; Human; Immune response; Immune system; Immunization; Immunologic Deficiency Syndromes; Immunosuppression; Individual; Infection; Inflammation; Infusion procedures; Interruption; Intervention; Knowledge; Macaca; Macaca mulatta; Monoclonal Antibodies; Natural Immunity; Open Reading Frames; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Production; Proteins; Proviruses; RNA; RNA Viruses; Randomized Controlled Trials; Reporting; Reproducibility of Results; Risk; SIV; Secondary to; Technology; Terminator Codon; Therapeutic Trials; Tissues; Transcript; Viral; Viral Proteins; Viremia; Virus; Virus Replication; Virus-like particle; antiretroviral therapy; base; extracellular; gag Gene Products; immune activation; innovation; integrin alpha4beta7; lymph nodes; nef Protein; novel; peripheral blood; rectal; virology

Treatment of SIV-infected rhesus macaques with short-term antiretroviral therapy and partially overlapping infusions of antibody to integrin alpha4beta7 was reported to induced durable post-treatment viral suppression. In an attempt to confirm these findings and extend them to humans, two studies were conducted. In the first study, an attempt was made to precisely replicate the original findings. By treating macaques infected with the same virus using the same drugs and monoclonal antibody. Sequencing demonstrated that the virus used actually contained a stop codon in nef and thus was not a wild-type virus. In addition, no differences were noted in plasma viremia, peripheral blood CD4+ T cell counts or levels of virus in lymph node and rectal tissues when comparing the group that received the antibody to the group that did not. In the second study, a randomized controlled trial of a commercial anti-alph4beta7 antibody (vedolizumab) was conducted in humans. Similarly, the human clinical trial did not reproduce the positive effects reported in the previously reported animal study. These results demonstrate that blockade of 47 may not be an effective strategy for inducing virologic remission in HIV-infected individuals after ART interruption. In addition, taken together they illustrate that embarking on human therapeutic trials based on findings from a single animal study should be undertaken cautiously and only after careful consideration of factors, such as reproducibility of the findings in animals and the potential risks associated with the experimental intervention. HIV-1 proviruses persist in the CD4+ T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as defective by virtue of having large internal deletions and lethal genetic mutations. As these defective proviruses are unable to encode intact and replication-competent viruses, they have long been thought of as biologically irrelevant graveyard of viruses with little significance to HIV-1 pathogenesis. Contrary to this notion, we have recently demonstrated that these defective proviruses are not silent, are capable of transcribing novel unspliced forms of HIV-RNA transcripts with competent open reading frames (ORFs), and can be found in the peripheral blood CD4+ T cells of patients at all stages of HIV-1 infection. In the present study, by an approach of combining serial dilutions of CD4+ T cells and T cellcloning technologies, we are able to demonstrate that defective proviruses that persist in HIV-infected individuals during suppressive cART are translationally competent and produce the HIV-1 Gag and Nef proteins. The HIV-RNA transcripts expressed from these defective proviruses may trigger an element of innate immunity. Likewise, the viral proteins coded in the defective proviruses may form extracellular virus-like particles and may trigger immune responses. The persistent production of HIV-1 proteins in the absence of viral replication helps explain persistent immune activation despite HIV-1 levels below detection, and also presents new challenges to HIV-1 eradication.

据报道，用短期抗逆转录病毒疗法的SIV感染的恒河猕猴和对整合素α4Beta7抗体的部分重叠注入可引起耐用的治疗后病毒抑制。 为了确认这些发现并将其扩展到人类，进行了两项研究。 在第一项研究中，试图精确地复制原始发现。 通过使用相同的药物和单克隆抗体感染的猕猴感染了同一病毒。 测序表明所使用的病毒实际上在NEF中包含终止密码子，因此不是野生型病毒。 此外，在比较接收到未接受的抗体的组时，血浆病毒血症，外周血CD4+ T细胞计数或直肠组织中病毒水平或直肠组织中的病毒水平没有差异。 在第二项研究中，在人类中进行了一项商业抗Alph4beta7抗体（Vedolizumab）的随机对照试验。 同样，人类的临床试验也没有再现先前报道的动物研究中报道的积极作用。这些结果表明，47的封锁可能不是在ART中断后诱导HIV感染者病毒学缓解的有效策略。 此外，他们共同说明，只有在仔细考虑因素（例如动物中发现的可重复性）以及与实验干预相关的潜在风险之后，应谨慎地进行基于单个动物研究发现的人类治疗试验。 尽管多年的抗逆转录病毒疗法（CART）抑制HIV-1 RNA水平<40拷贝/mL，但HIV-1病毒仍在HIV感染个体的CD4+ T细胞中持续存在。在循环的外周血单核细胞（PBMC）中检测到的这些病毒中的95％以上被称为有缺陷，因为它具有较大的内部缺失和致命的遗传突变。由于这些缺陷的原病毒无法编码完整和复制能力的病毒，因此长期以来，它们被认为是生物学上无关的病毒墓地，对HIV-1发病机理没有意义。与这一概念相反，我们最近证明，这些有缺陷的病毒并不静音，能够用具有胜任的开放式阅读框（ORF）转录新型的无膜状形式的HIV-RNA转录物，并且可以在HIV-1感染的所有阶段的外周血CD4+ T细胞中找到。在本研究中，通过结合CD4+ T细胞和T细胞隆技术的系列稀释液的方法，我们能够证明，在抑制车期间持续存在HIV感染的个体的缺陷原病毒在翻译上具有胜任，并产生HIV-1 GAG-1 GAG和NEF蛋白。从这些缺陷的病理中表达的HIV-RNA转录本可能会触发先天免疫的元素。同样，在缺陷的病毒中编码的病毒蛋白可能形成细胞外病毒样颗粒，并可能触发免疫反应。在缺乏病毒复制的情况下，HIV-1蛋白的持续产生有助于解释尽管HIV-1水平低于检测，但仍为消除HIV-1带来新的挑战。