The impact of TB co-infection on the reservoir of persistent HIV in vivo

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Recent studies highlight the importance of targeting the persistent HIV reservoir to attain a functional cure. The role of the myeloid cell lineage in maintaining a persistent viral reservoir is poorly understood. Mycobacterium tuberculosis (Mtb) directly infects macrophages, and is associated with increased HIV viral loads and worse clinical outcomes despite treatment for both pathogens. This is unlike other opportunistic infections, such as Pneumocystis Pneumonia (PCP), in which increases in circulating viral loads quickly respond to treatment. Thus, Mtb infection may facilitate the persistence and even expansion of a myeloid reservoir of HIV. Our objective is to describe the myeloid reservoir of HIV in the setting of active tuberculosis (TB) in vivo. To that end, we plan to visually detect HIV DNA and RNA within TB granuloma-associated macrophages and alveolar macrophages, to assess cellular co-localization of DNA or RNA from HIV and Mtb, and to discern whether there is resolution of this putative myeloid reservoir of HIV after treatment for HIV and Mtb. We hypothesize that active or recently active TB will be associated with a sustained reservoir of HIV infection despite treatment for HIV and Mtb; that HIV and Mtb will co-localize within macrophages; and that TB granuloma-associated macrophages will more frequently contain HIV DNA and RNA. Demonstration of a quantifiable Mtb-dependent HIV reservoir within tissue macrophages that persists despite HIV and Mtb treatment will be important for future strategies aimed at HIV eradication, particularly in those many places around the world where TB is rampant. We have assembled a multidisciplinary team of TB researchers and HIV immunologists with expertise in ultra-sensitive methods of HIV detection and clinical study design. Our work leverages existing research cohorts funded by the NIH and the Wellcome Trust, accessing biobanked formalin-fixed paraffin- embedded tissue from HIV-infected subjects with and without active TB, and prospectively collecting bronchoalveolar lavage (BAL) and peripheral blood from subjects with HIV and active TB or HIV and PCP. Samples will be used to: (1) detect and quantify the tissue myeloid reservoir of HIV; (2) assess cellular co- localization o HIV with intracellular Mtb; (3) compare persistence of the alveolar macrophage HIV reservoir in HIV-infected subjects started on ART and recently treated for active TB or acute PCP. Should this exploratory study reveal the existence of an Mtb-specific myeloid reservoir of HIV, we will pursue more comprehensive prospective studies to investigate the mechanisms by which Mtb infection might sustain the persistent HIV reservoir, even in the face of antiretroviral therapy.