Mechanisms Underlying the HIV-HSV-2 Syndemic

HIV-HSV-2 综合征的潜在机制

基本信息

  • 批准号:
    10305681
  • 负责人:
  • 金额:
    $ 48.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-12-05 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

The HIV and HSV-2 syndemic is well recognized, but the biological mechanisms that contribute are not understood. The recent recognition that HSV-2 is characterized by a frequent state of subclinical shedding suggests that the virus might contribute to persistent immune activation and prompted us to examine the impact of HSV-2 on peripheral blood T cells and on HIV reservoirs. Taking advantage of our biorepository of peripheral blood mononuclear cells (PBMC) from well-characterized HIV+ women on antiretroviral therapy who were or were not HSV-2 seropositive (HIV+/HSV-2+ vs. HIV+/HSV-2-), we found a significant difference in the phenotype of CD4+ (but not CD8+) T cells in HIV+/HSV-2+ compared to HIV+/HSV-2- women. These changes included an increase in the frequency of activated cells, but a paradoxical decrease in the expression of IL-32, an intracellular cytokine presumed to be associated with inflammation. Moreover, when CD4+ T cells isolated from virally suppressed HIV+/HSV-2+ women were stimulated with latency reversal agents, the addition of recombinant IL-32 to the cultures blocked HIV reactivation. These observations suggest that IL-32 plays a pivotal role in controlling HIV reactivation and suggest a new paradigm underlying the HIV-HSV-2 syndemic. We hypothesize that HSV-2 triggers changes in local (at the site of HSV-2 genital skin outbreaks) and peripheral blood CD4+ T cells including a reduction in intracellular IL-32 levels that promote HIV reactivation. Conversely, high levels of IL-32 contribute to the maintenance of HIV reservoirs suggesting that IL-32 blockade may synergize with strategies to reactivate HIV as part of a “shock and kill” approach to cure. To test these hypotheses, we will analyze serial samples of PBMC from HIV infected women before and after HSV-2 acquisition from two unique cohorts: women enrolled in Microbicides Trial Network (MTN)-015, a longitudinal study of African women who seroconverted to HIV while participating in pre-exposure prophylaxis trials, and U.S. women with established HIV infection enrolled in the Bronx Women's Interagency Study (WIHS). We will also compare PBMC in HIV-infected men who are or are not coninfected with HSV-2. We will phenotype immune cell subpopulations to define the changes that occur in association with HSV-2 acquisition and the impact of these changes on plasma viral loads and HIV reservoirs. We will prepare CD4+ T cell libraries of IL- 32lo cells and determine whether these subpopulations are enriched in HSV-2 and/or HIV reactive cells and whether decreased IL-32 interferes with immune functions. We will also take advantage of our repository of genital skin biopsies (herpes lesion and unaffected contralateral side) and analyze the CD4+ T cells to determine whether they are enriched for cells of specific phenotypes in situ. We will determine how IL-32 blocks the response to latency reactivating stimuli and how IL-32 antagonists promote HIV reactivation. These studies will identify pathways and molecules that could be targeted to block HIV reactivation in response to HSV-2 or conversely, enhance latency reversal as part of “shock and kill” HIV eradication strategies.
HIV和HSV-2综合征是公认的,但造成这种综合征的生物学机制还不清楚。 明白最近认识到HSV-2的特征是亚临床脱落的频繁状态, 表明该病毒可能有助于持续的免疫激活,并促使我们检查 HSV-2对外周血T细胞和HIV储库影响。利用我们的生物储存库 外周血单核细胞(PBMC)来自接受抗逆转录病毒治疗的HIV阳性女性, HSV-2血清阳性或非HSV-2血清阳性(HIV +/HSV-2 + vs. HIV +/HSV-2-), 与HIV +/HSV-2-女性相比,HIV +/HSV-2+女性中的CD4+(而非CD8+)T细胞表型。这些变化 包括激活细胞频率的增加,但IL-32表达的反常减少, 一种推测与炎症相关的细胞内细胞因子。此外,当CD4 + T细胞分离时, 来自病毒抑制的HIV +/HSV-2+女性的受试者用潜伏期逆转剂刺激,加入 重组IL-32阻断HIV再活化。这些观察结果表明,IL-32发挥了重要作用。 在控制HIV再激活中的关键作用,并提出了一种新的模式,潜在的HIV-HSV-2综合征。 我们假设HSV-2引发局部(HSV-2生殖器皮肤爆发部位)和 外周血CD4 + T细胞,包括促进HIV再活化的细胞内IL-32水平的降低。 相反,高水平的IL-32有助于维持HIV储库,这表明IL-32阻断 可能与作为“休克和杀死”治疗方法的一部分的重新激活艾滋病毒的策略协同作用。测试这些 假设,我们将分析来自HIV感染妇女的PBMC在HSV-2之前和之后的系列样品 从两个独特的队列中获得:参加杀微生物剂试验网络(MTN)-015的妇女,一个纵向的 对在参与暴露前预防试验期间血清转化为艾滋病毒的非洲妇女的研究,以及 美国布朗克斯妇女机构间研究(WIHS)中登记的已确定感染艾滋病毒的妇女。我们将 还比较了HIV感染者中是否同时感染HSV-2的PBMC。我们将显型 免疫细胞亚群,以确定与HSV-2获得相关的变化, 这些变化对血浆病毒载量和HIV储库的影响。我们将制备IL-4的CD4 + T细胞文库, 32lo细胞,并确定这些亚群是否富集HSV-2和/或HIV反应性细胞, 降低IL-32是否会干扰免疫功能。我们还将利用我们的存储库, 生殖器皮肤活检(疱疹病变和未受影响的对侧),并分析CD4 + T细胞, 确定它们是否原位富集特定表型的细胞。我们将确定IL-32 阻断对潜伏期再激活刺激的反应以及IL-32拮抗剂如何促进HIV再激活。这些 研究将确定可能靶向阻断HIV再激活的途径和分子, HSV-2或相反,增强潜伏期逆转作为"休克和杀死" HIV根除策略的一部分。

项目成果

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Betsy C. Herold其他文献

Amp C β-lactamase-producing Escherichia coli in neonatal meningitis: diagnostic and therapeutic challenge
新生儿脑膜炎中产 Amp C β-内酰胺酶的大肠杆菌:诊断和治疗挑战
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    2.9
  • 作者:
    E. Fakioglu;A. Queenan;Karen Bush;Stephen G. Jenkins;Betsy C. Herold
  • 通讯作者:
    Betsy C. Herold
1192: Placental transfer of HSV-specific antibodies from mothers to newborns
  • DOI:
    10.1016/j.ajog.2019.11.1204
  • 发表时间:
    2020-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Aakash Mahant;Fatima A. Estrada Trejo;Anayeli Correa;Lip Loh;Benjamin Galen;Betsy C. Herold
  • 通讯作者:
    Betsy C. Herold
GLYCOPROTEIN C(gC) of HERPES SIMPLEX VIRUS (HSV) TYPE 1 BINDS TWO DISTINCT POLYSACCHARIDE POPULATIONS WITHIN HEPARIN. † 704
  • DOI:
    10.1203/00006450-199704001-00724
  • 发表时间:
    1997-04-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Susan I. Gerber;Ronald E. Hileman;Jonathan R. Fromm;Robert J. Linhardt;Betsy C. Herold
  • 通讯作者:
    Betsy C. Herold
50 Years Ago in <span class="small-caps"><em>The Journal of Pediatrics</em></span>: Revisiting a Diagnostic Dilemma 50 Years Later: Partially Treated Bacterial Meningitis
  • DOI:
    10.1016/j.jpeds.2020.04.013
  • 发表时间:
    2020-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Brenda I. Anosike;Betsy C. Herold
  • 通讯作者:
    Betsy C. Herold
Mounting Evidence Suggests Safety and Efficacy of Immunizations Posttransplantation
越来越多的证据表明移植后免疫接种的安全性和有效性

Betsy C. Herold的其他文献

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{{ truncateString('Betsy C. Herold', 18)}}的其他基金

Optimizing the Generation of Monoclonal Antibodies for Prevention and Treatment of HSV Disease
优化用于预防和治疗 HSV 疾病的单克隆抗体的生成
  • 批准号:
    10717320
  • 财政年份:
    2023
  • 资助金额:
    $ 48.31万
  • 项目类别:
Impact of the vaginal microbiome on topical HIV pre-exposure prophylaxis (PrEP)
阴道微生物组对局部 HIV 暴露前预防 (PrEP) 的影响
  • 批准号:
    10612363
  • 财政年份:
    2019
  • 资助金额:
    $ 48.31万
  • 项目类别:
Impact of the vaginal microbiome on topical HIV pre-exposure prophylaxis (PrEP)
阴道微生物组对局部 HIV 暴露前预防 (PrEP) 的影响
  • 批准号:
    9914110
  • 财政年份:
    2019
  • 资助金额:
    $ 48.31万
  • 项目类别:
Impact of the vaginal microbiome on topical HIV pre-exposure prophylaxis (PrEP)
阴道微生物组对局部 HIV 暴露前预防 (PrEP) 的影响
  • 批准号:
    10372984
  • 财政年份:
    2019
  • 资助金额:
    $ 48.31万
  • 项目类别:
Mechanisms Underlying the HIV-HSV-2 Syndemic
HIV-HSV-2 综合征的潜在机制
  • 批准号:
    10063474
  • 财政年份:
    2017
  • 资助金额:
    $ 48.31万
  • 项目类别:
Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring Pr*
药物在正确的地方
  • 批准号:
    8435762
  • 财政年份:
    2013
  • 资助金额:
    $ 48.31万
  • 项目类别:
Impact of Mucosal Immune Enviroment and semen on Prep and PD
粘膜免疫环境和精液对 Prep 和 PD 的影响
  • 批准号:
    8448474
  • 财政年份:
    2013
  • 资助金额:
    $ 48.31万
  • 项目类别:
Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring PrEP
药物在正确的地方
  • 批准号:
    9132494
  • 财政年份:
    2013
  • 资助金额:
    $ 48.31万
  • 项目类别:
Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring PrEP
药物在正确的地方
  • 批准号:
    8988532
  • 财政年份:
    2013
  • 资助金额:
    $ 48.31万
  • 项目类别:
Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring Pr*
药物在正确的地方
  • 批准号:
    8606159
  • 财政年份:
    2013
  • 资助金额:
    $ 48.31万
  • 项目类别:

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