Viral evolution in peripheral macrophages and brain during progression to AIDS

艾滋病进展过程中外周巨噬细胞和大脑中的病毒进化

基本信息

批准号：
10205180
负责人：
MARCO SALEMI
金额：
$ 63.24万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205180
关键词：
Acquired Immunodeficiency Syndrome Anatomy Animals Anti-Retroviral Agents Antiviral Agents Autopsy Behavior Blood Blood specimen Bone Marrow Brain Cell Separation Cells Central Nervous System Infections Central Nervous System Viral Diseases DNA Data Development Diagnosis Disease Encephalitis Evolution Exhibits Funding Future Gene Expression Gene Expression Profile Goals Grant HIV HIV Infections HIV-1 HIV-associated neurocognitive disorder Human Immune system Immunologic Deficiency Syndromes Infection Interruption Lesion Link Longevity Lung Lymphoid Cell Macaca Macaca mulatta Measures Meninges Methodology Methods Microglia Modeling Monkeys Myeloid Cells Neuraxis Patients Pattern Penetration Peripheral Permeability Pharmaceutical Preparations Phylogenetic Analysis Plasma Population Prevention Production RNA Regulation Research Design Role SIV Source Structure of choroid plexus T-Lymphocyte Techniques Technology Therapeutic Time Tissue Sample Tissue-Specific Gene Expression Tissues United States National Institutes of Health Variant Viral Viremia Virus antiretroviral therapy base brain tissue cell type chronic infection cytotoxic digital drug resistant virus experience genome sequencing in vivo innovation laser capture microdissection macrophage migration monocyte neuroAIDS peripheral blood transcriptome sequencing viral DNA viral rebound

项目摘要

Project Summary: An estimated 50% of HIV+ patients still exhibits central nervous system (CNS) viral infection, with 30% of patients progressing to some form of HIV-associated neurocognitive disorder (HAND) despite combined anti- retroviral therapy (cART). In the previously funded NIH R01 (NS063897-01A2) project – Viral evolution in peripheral macrophages and brain during progression to AIDS – we used the SIV-infected macaque model of neuroAIDS to show that in untreated animals SIV can enter the CNS multiple times, as early as 10 days post infection, throughout the course of the disease. SIV subpopulations infecting the brain are evolutionarily related to viral strains infecting myeloid cells in peripheral tissues, such as bone marrow and lung, which accumulate in the meninges and choroid plexus in early infection, and in the perivascular space and SIV-associated encephalitis (SIVE) lesions in late infection. Moreover, we found evidence that ongoing evolution in peripheral tissues leads, late in infection, to the emergence of viral lineages adapted to enter and replicate in the CNS microenvironment that may be linked to SIVE onset. However, the impact of cART on the timing and mode of entry of virus into the CNS has yet to be analyzed, which is crucial to explain why HAND is present even in virally suppressed patients. The present proposal for a competitive renewal seeks to extend the studies of the original project by characterizing the evolutionary behavior of the virus leading up to CNS infection and subsequent regulation of CNS-specific viral and host genes expression in the presence of cART. We seek to evaluate, in particular, peripheral blood monocytes and monocyte/macrophage rich tissues as potential source of CNS virus during cART, and the contribution of persisting CNS (and peripheral tissues) virus to viral rebound after therapy interruption. Two specific aims are proposed: Specific Aim 1 – Determine the impact of early cART on viral evolutionary patterns, as well as viral and host gene expression patterns, associated with viral entry and replication in the CNS of SIV-infected rhesus macaques; Specific Aim 2 – Determine relative contribution of SIV-infected macrophage subsets in the CNS and peripheral tissues to low-level viremia during cART and viral rebound following cART interruption. The elucidation of viral evolutionary patterns and the contribution of specific infected tissues/cell populations to CNS infection, in the presence or subsequent absence of cART, would be highly beneficial to future studies designed to adjust current therapeutic strategies toward the prevention and elimination of neuroAIDS, and formation of the CNS reservoir, which is a necessary step for the development of an HIV cure.

项目概要：据估计，50% 的 HIV+ 患者仍表现出中枢神经系统 (CNS) 病毒感染，其中 30% 尽管联合抗-药物治疗，患者仍进展为某种形式的 HIV 相关神经认知障碍 (HAND) 在先前资助的 NIH R01 (NS063897-01A2) 项目中——病毒进化艾滋病进展过程中的外周巨噬细胞和大脑——我们使用了感染 SIV 的猕猴模型神经艾滋病表明，在未经治疗的动物中，SIV 可以多次进入中枢神经系统，最早在治疗后 10 天感染大脑的 SIV 亚群在进化上相关感染外周组织（例如骨髓和肺）中的骨髓细胞的病毒株，这些细胞会积聚早期感染时的脑膜和脉络丛，以及血管周围空间和 SIV 相关的此外，我们发现了感染后期脑炎（SIVE）病变持续演变的证据。在感染后期，组织导致适应进入中枢神经系统并在中枢神经系统复制的病毒谱系的出现可能与 SIVE 发病有关的微环境然而，cART 对 SIVE 发生时间和模式的影响。病毒进入中枢神经系统的情况仍有待分析，这对于解释为什么 HAND 存在于甚至在目前的竞争性更新提案旨在扩大对病毒抑制的患者的研究。原始项目通过表征导致中枢神经系统感染的病毒的进化行为和我们寻求在 cART 存在下对 CNS 特异性病毒和宿主基因表达的后续调节。特别评估外周血单核细胞和富含单核细胞/巨噬细胞的组织作为潜在来源 cART 期间中枢神经系统病毒的作用，以及持续存在的中枢神经系统（和外周组织）病毒对病毒的贡献提出了两个具体目标：具体目标 1 – 确定治疗中断后的影响。早期 cART 研究病毒进化模式以及病毒和宿主基因表达模式，感染 SIV 的恒河猴的中枢神经系统中的病毒进入和复制；具体目标 2 – 确定相关性中枢神经系统和外周组织中 SIV 感染的巨噬细胞亚群对低水平病毒血症的贡献 cART 和 cART 中断后的病毒反弹。病毒进化模式的阐明和在存在或随后的情况下，特定受感染组织/细胞群对中枢神经系统感染的贡献缺乏 cART，将对旨在调整当前治疗策略的未来研究非常有益预防和消除神经艾滋病以及中枢神经系统储库的形成是必要的开发艾滋病毒治疗方法的一步。

项目成果

期刊论文数量（36）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Empirical validation of viral quasispecies assembly algorithms: state-of-the-art and challenges.

DOI：
10.1038/srep02837
发表时间：
2013-10-03
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Prosperi, Mattia C. F.;Yin, Li;Nolan, David J.;Lowe, Amanda D.;Goodenow, Maureen M.;Salemi, Marco
通讯作者：
Salemi, Marco

The meningeal lymphatic system: a route for HIV brain migration?

DOI：
10.1007/s13365-015-0399-y
发表时间：
2016-06
期刊：
Journal of neurovirology
影响因子：
3.2
作者：
Lamers SL;Rose R;Ndhlovu LC;Nolan DJ;Salemi M;Maidji E;Stoddart CA;McGrath MS
通讯作者：
McGrath MS

Brain tissue transcriptomic analysis of SIV-infected macaques identifies several altered metabolic pathways linked to neuropathogenesis and poly (ADP-ribose) polymerases (PARPs) as potential therapeutic targets.

DOI：
10.1007/s13365-020-00927-z
发表时间：
2021-03
期刊：
Journal of neurovirology
影响因子：
3.2
作者：
Mavian C;Ramirez-Mata AS;Dollar JJ;Nolan DJ;Cash M;White K;Rich SN;Magalis BR;Marini S;Prosperi MCF;Amador DM;Riva A;Williams KC;Salemi M
通讯作者：
Salemi M

A method for obtaining simian immunodeficiency virus RNA sequences from laser capture microdissected and immune captured CD68+ and CD163+ macrophages from frozen tissue sections of bone marrow and brain.

一种从骨髓和脑冷冻组织切片中激光捕获显微切割和免疫捕获的 CD68 和 CD163 巨噬细胞获取猿猴免疫缺陷病毒 RNA 序列的方法。

DOI：
10.1016/j.jim.2017.01.003
发表时间：
2017
期刊：
Journal of immunological methods
影响因子：
2.2
作者：
Mallard,Jaclyn;Papazian,Emily;Soulas,Caroline;Nolan,DavidJ;Salemi,Marco;Williams,KennethC
通讯作者：
Williams,KennethC

Evolution of transmitted HIV-1 drug resistance in HIV-1-infected patients in Italy from 2000 to 2010.