Optimized Adaptation of Simian-tropic R5 HIV Clade C to Pig-tailed Macaques

猿猴嗜R5 HIV Cclade C对猪尾猕猴的优化适应

• 批准号: 8714894
• 负责人: Ruth Margrit Ruprecht
• 金额: $ 90.38万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714894
• 关键词: AIDS/HIV problem; Ablation; Acquired Immunodeficiency Syndrome; Acute; Africa South of the Sahara; Animals; Antiviral Agents; Antiviral Therapy; Architecture; Area; Asorbicap; B-Lymphocytes; Biological; Biopsy; Blood Cells; Brain; CD8-Positive T-Lymphocytes; CD8B1 gene; Capsid Proteins; Cells; Cerebrospinal Fluid; Chimera organism; Consequences of HIV; Cytidine Deaminase; Developing Countries; Development; Disease Progression; Drug usage; Epidemic; Evolution; Family suidae; Generations; Genetic; HIV; HIV Infections; HIV-1; HIV-2; Host Defense; Human; Immunity; Immunocompetent; In Vitro; India; Infection; Link; Long Terminal Repeats; Lymphocyte Depletion; MS4A1 gene; Macaca; Macaca mulatta; Macaca nemestrina; Modality; Modeling; Molecular; Molecular Cloning; Molecular Evolution; Mutate; Pan Genus; Pathogenicity; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Pilot Projects; Plasma; Play; Prevalence; Prevention; Prevention strategy; Primate Lentiviruses; Primates; Property; Protein Isoforms; Proteins; Protocols documentation; RNA-Directed DNA Polymerase; Recombinants; Regimen; Role; Serial Passage; Site; Study models; Tail; Testing; Time; Tissues; Titrations; Tropism; Tumor Necrosis Factor-alpha; Vaccines; Variant; Vertebral column; Viral; Viremia; Virion; Virus; Work; Zambia; adaptive immunity; advanced disease; base; blocking factor; cytokine; fitness; improved; in vivo; lymph nodes; microbicide; mutant; nonhuman primate; novel strategies; pre-clinical; rectal; research study; simian human immunodeficiency virus; therapy development; tool; treatment strategy

DESCRIPTION (provided by applicant): HIV clade C (HIV-C) causes >56% of all cases of HIV/AIDS worldwide and predominates in sub-Saharan Africa and India. A non-human primate (NHP) model would greatly benefit the preclinical development of prevention strategies, including drugs, microbicides, and vaccines. Due to host restriction factors, HIV-1 replicates only in humans and chimpanzees, but not in other NHP species. The construction of simian-human immunodeficiency viruses (SHIVs) encoding HIV-1 vpu, tat, rev and env has yielded pathogenic models in rhesus macaques (RMs) or pig-tailed macaques (PMs~ Macaca nemestrina). A primate lentivirus model based mostly upon HIV-1 but replication-competent in macaques would greatly facilitate the preclinical development of new treatment or prevention strategies. Recently, different host restriction factors that block HIV-1 replication in RM cells have been recognized, namely 1) TRIM5?, which targets HIV-1 capsid proteins and blocks early post-entry replication steps, and 2) APOBEC3G (A3G), a cytidine deaminase that is not recognized by HIV-1 Vif and therefore escapes inhibition by this virion-associated protein. Unlike RMs, PMs lack a TRIM5 isoform, which may explain why PMs supported limited acute viremia of unmodified HIV-1 in earlier studies. Replacing HIV-1 vif with that of SIVmac239, SIVmne or HIV-2 has yielded chimeras that replicated for extended periods of time in PMs~ however, these recombinants were based upon the X4-tropic clade B clones, and did not result in persistent viremia and signs of disease progression. We have generated a simian-tropic HIV-C clone, termed stHIV-C, by replacing HIV vif with SIVmac239 vif in an infectious molecular HIV-C clone from Zambia. The chimera is replication-competent in peripheral blood mononuclear cells (PBMC) of M. nemestrina. In a pilot study, the new stHIV-C-vif239 chimera also induced viremia in two PMs~ however, adaptation is incomplete. The Specific Aims are to: 1. Select stHIV-C progeny with improved replication fitness in PMs under prolonged depletion of CD8+ and CD20+ cells~ 2. Further adapt progeny virus by serial passage through immunocompetent PMs, re-isolate virus from the last recipient, generate a large stock, and characterize it in vitro. 3. Perform an intrarectal titration and assess viral pathogenicity 4. Assess the molecular evolution of stHIV-C in the absence and presence of adaptive immunity and during disease progression. We will also compare viral evolution in different compartments (PBMC, lymph nodes, and brain). The proposed experiments are significant because they focus on the development of an NHP model of HIV-C, which predominates in developing countries where the AIDS epidemic continues to escalate and will thus create a new tool for the preclinical development of different strategies for prevention or eradication.

描述（由申请人提供）：HIV进化枝C（HIV-C）的原因> 56％的全球艾滋病毒/艾滋病病例，占撒哈拉以南非洲和印度的占主导地位。非人类灵长类动物（NHP）模型将极大地使预防策略的临床前开发，包括药物，杀生型和疫苗。由于宿主限制因素，HIV-1仅在人类和黑猩猩中复制，而在其他NHP物种中则不复制。编码HIV-1 VPU，TAT，REV和ENV编码的Simian-Human免疫缺陷病毒（SHIVS）在恒河猴猕猴（RMS）或Pig-Tailed Macaques（PMS〜Macaca Nemestrina）中产生了致病模型。灵长类动物的慢病毒模型主要基于HIV-1，但猕猴的复制能力将极大地促进新疗法或预防策略的临床前发展。 Recently, different host restriction factors that block HIV-1 replication in RM cells have been recognized, namely 1) TRIM5?, which targets HIV-1 capsid proteins and blocks early post-entry replication steps, and 2) APOBEC3G (A3G), a cytidine deaminase that is not recognized by HIV-1 Vif and therefore escapes inhibition by this virion-associated protein.与RMS不同，PMS缺乏TRIM5同工型，这可以解释为什么PM在早期研究中支持未修饰的HIV-1的有限急性病毒血症。用SIVMAC239，SIVMNE或HIV-2替换HIV-1 VIF的嵌合体在PMS〜中延长了较长的时间，但是这些重组因素是基于X4-热带进化枝B克隆的，并且并未导致持续的病毒症和疾病进展的迹象。我们通过在来自赞比亚的感染性分子HIV-C克隆中用SIVMAC239 VIF代替HIV VIF来产生一种称为STHIV-C的邻氨酸 - 热带HIV-C克隆。嵌合体在尼梅斯特菌的外周血单核细胞（PBMC）中具有复制能力。在一项试点研究中，新的STHIV-C-VIF239嵌合体在两个PMS中也引起病毒血症〜但是，适应性不完整。具体目的是：1。在CD8+和CD20+细胞长期耗竭下，选择PMS的STHIV-C后代具有改善的复制适应度。 3。进行直肠滴定并评估病毒致病性4。在不存在和存在适应性免疫和疾病进展过程中，评估STHIV-C的分子进化。我们还将比较不同隔室（PBMC，淋巴结和大脑）中的病毒进化。拟议的实验之所以重要，是因为它们专注于HIV-C的NHP模型的发展，该模型在艾滋病流行病继续升级的发展中国家占主导地位，因此将为临床前开发不同的预防或消除策略创造一个新工具。