Pathogenesis and Treatment of HIV Infection

HIV感染的发病机制和治疗

基本信息

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
项目类别：
财政年份：
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

项目摘要

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和部分重叠注射整合素α4β7抗体治疗感染SIV的恒河猴，可诱导持久的治疗后病毒抑制。为了证实这些发现并将其推广到人类，进行了两项研究。在第一项研究中，试图精确复制最初的发现。通过使用相同的药物和单克隆抗体治疗感染相同病毒的猕猴。测序表明，所使用的病毒实际上在 nef 中含有终止密码子，因此不是野生型病毒。此外，将接受抗体的组与未接受抗体的组进行比较时，血浆病毒血症、外周血 CD4+ T 细胞计数或淋巴结和直肠组织中的病毒水平没有差异。在第二项研究中，对商业抗 α4β7 抗体（维多珠单抗）进行了人体随机对照试验。同样，人体临床试验也没有重现先前报道的动物研究中报道的积极效果。这些结果表明，阻断 47 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，总的来说，它们表明，基于单一动物研究结果进行人体治疗试验应谨慎进行，并且只有在仔细考虑各种因素后，例如动物研究结果的可重复性以及与实验干预相关的潜在风险。尽管经过多年联合抗逆转录病毒治疗 (cART) 并抑制 HIV-1 RNA 水平<40 拷贝/mL，HIV-1 前病毒仍持续存在于 HIV 感染者的 CD4+ T 细胞中。在循环外周血单核细胞 (PBMC) 中检测到的这些原病毒中，95% 以上由于具有大量内部缺失和致命的基因突变而被认为是有缺陷的。由于这些有缺陷的原病毒无法编码完整且具有复制能力的病毒，因此长期以来它们被认为是与生物学无关的病毒墓地，对 HIV-1 发病机制意义不大。与这一观点相反，我们最近证明这些有缺陷的原病毒不是沉默的，能够转录具有有效开放阅读框（ORF）的新型未剪接形式的HIV-RNA转录物，并且可以在以下人群的外周血CD4+T细胞中找到： HIV-1感染各个阶段的患者。在本研究中，通过将连续稀释的 CD4+ T 细胞和 T 细胞克隆技术相结合，我们能够证明，在抑制性 cART 期间，HIV 感染者体内持续存在的有缺陷的原病毒具有翻译能力，并产生 HIV-1 Gag 和 HIV-1 Gag。 Nef 蛋白。这些有缺陷的原病毒表达的 HIV-RNA 转录本可能会触发先天免疫的一个因素。同样，有缺陷的原病毒中编码的病毒蛋白可能形成细胞外病毒样颗粒，并可能引发免疫反应。在没有病毒复制的情况下持续产生 HIV-1 蛋白有助于解释尽管 HIV-1 水平低于检测水平但持续的免疫激活，并且也对根除 HIV-1 提出了新的挑战。