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Viral and host factors associated with HIV-1 vertical transmission and pathogenesis.

机译：与HIV-1垂直传播和发病机制有关的病毒和宿主因素。

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摘要

The majority of neonates and infants acquire HIV-1 infection through vertical transmission. In addition these HIV-1 infected infants have a higher viral load and progress to AIDS faster than adults, often times more rapidly than their own infected mothers. However, the mechanisms of this differential disease progression are not well understood. Several studies have shown, including work from our laboratory, that it is the transmission of the minor genotype with the R5 phenotype that is involved in transmission. We have also shown that a lower viral heterogeneity may influence vertical transmission. Moreover, we have also shown that there is a differential HIV-1 replication and HIV-1 gene expression in neonatal cells as compared to adult cells. The hypothesis of this dissertation is that viral determinants and cellular factors in neonatal and adult mononuclear cells influence HIV-1 replication and HIV-1 gene expression. In this dissertation I have molecularly characterized the HIV-1 long terminal repeat (LTR) from 6 mother-infant HIV-1 infected pairs, and shown that mutations generated during vertical transmission correlate with HIV-1 gene expression. Furthermore, I have also shown that there was a low degree of viral heterogeneity and a high conservation of critical transcription factor binding sites within the LTR. I have also shown that nuclear extracts from neonatal (cord) mononuclear cells bind with higher efficiencies to HIV-1 LTR as compared to nuclear extracts from adult mononuclear cells. In addition, I have also made strides in trying to elucidate the mechanisms of differential HIV-1 replication and gene expression. I have shown that there is a differential HIV-1 replication in naive and memory T-lymphocytes from cord vs. adults and this increased HIV-1 replication was influenced at the level of HIV-1 gene expression and not at the level of expression of receptors or coreceptors. Moreover, I have characterized the cellular gene expression profile of uninfected and infected cord monocyte-derived macrophages (MDM) as compared with adult MDMs. Evaluation of these cellular factors identified genes that fell into several classes including transcriptional activators/repressors, cytokines, and matrix metalloproteinases, all of which may be able to influence HIV-1 gene expression. To explain this differential HIV-1 gene expression, I have modulated the level of cellular factors (IL6 and STAT3) using short hairpin RNA (shRNA) technology to determine if these cellular factors were playing a role in an increased HIV-1 replication and gene expression. I found that upon downregulation of these factors, there was a decrease in HIV-1 LTR directed gene expression. Taken together, the results from this dissertation provide new insights into elucidating the mechanisms of HIV-1 vertical transmission and HIV-1 gene expression in neonates and infants. This work which has identified several cellular factors may offer new possibilities for the development of therapeutic strategies to treat pediatric AIDS.
机译：大多数新生儿和婴儿通过垂直传播感染HIV-1。此外，这些感染了HIV-1的婴儿比成人具有更高的病毒载量和发展为AIDS的速度，通常比其自己感染的母亲快几倍。但是，这种差异性疾病进展的机制尚不十分清楚。包括我们实验室的工作在内的数项研究表明，参与传播的是次基因型与R5表型的传播。我们还表明，较低的病毒异质性可能会影响垂直传播。此外，我们还显示，与成年细胞相比，新生儿细胞中HIV-1复制和HIV-1基因表达存在差异。本文的假设是，新生儿和成年单核细胞中的病毒决定因子和细胞因子会影响HIV-1复制和HIV-1基因表达。在这篇论文中，我从6对母婴HIV-1感染对中分子鉴定了HIV-1长末端重复序列（LTR），并表明在垂直传播过程中产生的突变与HIV-1基因表达相关。此外，我还表明LTR内的病毒异质性较低，并且关键转录因子结合位点的保守性很高。我还表明，与成年单核细胞的核提取物相比，新生儿（脐带）单核细胞的核提取物与HIV-1 LTR的结合效率更高。此外，我在阐明差异性HIV-1复制和基因表达的机制方面也取得了长足的进步。我已经证明，脐带与成人相比，幼稚和记忆T淋巴细胞的HIV-1复制存在差异，并且这种增加的HIV-1复制受HIV-1基因表达水平的影响，而不受HIV-1基因表达水平的影响。受体或共受体。此外，与成人MDM相比，我已经表征了未感染和感染的脐带单核细胞衍生巨噬细胞（MDM）的细胞基因表达谱。对这些细胞因子的评估确定了属于几类的基因，包括转录激活因子/阻遏因子，细胞因子和基质金属蛋白酶，所有这些因子都可能影响HIV-1基因的表达。为了解释这种HIV-1基因差异表达，我使用短发夹RNA（shRNA）技术调节了细胞因子（IL6和STAT3）的水平，以确定这些细胞因子是否在增加HIV-1复制和基因中起作用表达。我发现在这些因素下调后，HIV-1 LTR指导的基因表达下降。综上所述，本论文的结果为阐明新生儿和婴儿中HIV-1垂直传播和HIV-1基因表达的机制提供了新的见解。这项鉴定了几种细胞因子的工作可能为开发治疗小儿艾滋病的治疗策略提供新的可能性。

著录项

  • 作者

    Mehta, Roshni.;

  • 作者单位

    The University of Arizona.$bImmunobiology.;

  • 授予单位 The University of Arizona.$bImmunobiology.;
  • 学科 Biology Virology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 216 p.
  • 总页数 216
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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