COINFECTION OF MACAQUES WITH STLV-1 AND SIV

因为有报道说，在艾滋病的发展中， 受感染的人，有越来越多的关注， 接触并感染致病人类的人 逆转录病毒，HIV（人类免疫缺陷病毒）类型和1和2，以及 HTLV（人类T细胞白血病/淋巴瘤病毒）I型和II型。 此外，委员会认为， 癌症的发病率，特别是B细胞淋巴瘤， 在因艾滋病毒感染而延长生命的人中， 但他们的免疫系统仍然 暴露了 尽管HTLV相关增殖性疾病通常 在一小部分感染者中， 人，有可能与艾滋病毒的共同感染不仅可以缩短 潜伏期，而且还提高了发展的可能性 由HTLV引起的增殖性或神经系统疾病。 因此，一种动物 需要模型来定义这些成员之间的体内相互作用。 两个逆转录病毒家族，并评估双重 免疫缺陷和肿瘤性疾病的感染。 的发展 这种模型是这项拟议研究的长期目标，它将 通过体内和体外研究的结合来实现。 猪- 有尾猕猴（Macaca nemestrina）将单独感染或合并感染 与SIVsmm和STLV-I（sm），这是从自然感染的 曼黑猴和曼黑猴是人类病毒的猿类对应物。 期间 对动物的长期随访，各种病毒学（如病毒 负荷）、免疫学和临床参数进行比较。 病毒 从受感染动物中回收的病毒将进行基因组特征分析。 突变和生物学特性的变化，包括 伪型 STLV-I（sm）已完全测序，这将有助于 分子分析感染性分子克隆和部分克隆将 生成以帮助评价生物学特性， 与SIVsmm的互动。 了解可能的体内相互作用 在这两种病毒之间，复制动力学，细胞病变， 在原代淋巴细胞共感染期间假型的形成将 也可以在体外进行评估。 最后，将C.B-17 SCID小鼠 用来自感染STLV-I（sm）的猕猴的PBMC重建， 白血病前细胞或白血病/淋巴瘤的证据，以评估 肿瘤发生 拟议的研究将提供模型系统（i）， 在细胞和生物体水平上评估潜在的相互作用 以及对这两个逆转录病毒家族疾病的影响;（ii）定义 血液肿瘤发展中的重要因素;以及（iii） 探讨对合并感染者的治疗干预策略。

Because of reports of apparently more rapid progression to AIDS in co- infected individuals, there is concern about the increasing number of people being exposed to and becoming infected with the pathogenic human retroviruses, HIV (human immunodeficiency virus) types and 1 and 2, and HTLV (human T-cell leukemia/lymphoma virus) types I and II. Furthermore, the incidence of cancers, particularly B-cell lymphomas, appears to be increasing among HIV-infected persons whose lives have been extended due to therapeutic interventions, but whose immune systems are still compromised. Although HTLV-associated proliferative disease generally develops over more than 20 years in a small percentage of infected persons, it is possible that co-infection with HIV could not only shorten the latent period but also enhance the likelihood of developing proliferative or neurologic diseases caused by HTLV. Thus, an animal model is needed to define in vivo interactions between members of these two retrovirus families and to assess the possible consequences of dual infection on immunodeficiency and neoplastic diseases. The development of such a model is the long-term goal of this proposed research, which will be achieved through a combination of in vivo and in vitro studies. Pig- tailed macaques (Macaca nemestrina) will be singly infected or co-infected with SIVsmm and STLV-I(sm), which were isolated from a naturally infected sooty mangabey and are simian counterparts of the human viruses. During long-term follow-up of the animals, various virologic (such as virus burden), immunologic, and clinical parameters will be compared. Viruses recovered from infected animals will be characterized for genomic mutations and for changes in biologic properties, including formation of pseudotypes. STLV-I(sm) has been fully sequenced, which will facilitate molecular analyses an infectious molecular clone and partial clones will be generated to aid in the evaluation of biologic properties and interactions with SIVsmm. To understand possible in vivo interactions between these two viruses, replication kinetics, cytopathicity, and formation of pseudotypes during co-infection of primary lymphocytes will also be evaluated in vitro. Finally, C.B-17 SCID mice will be reconstituted with PBMC from macaques infected with STLV-I(sm) that have evidence of preleukemic cells or leukemia/lymphoma to evaluate tumorigenesis. The proposed research will provide model systems (i) to evaluate, at cellular and organismal levels, the potential interactions and impact on disease on these two retrovirus families; (ii) to define factors important in development of hematologic neoplasms; and (iii) to explore therapeutic intervention strategies in co-infected persons.