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dc.contributor.advisorPillai, Shiv
dc.contributor.authorSchiff, Abigail Esther
dc.date.accessioned2019-12-11T10:04:20Z
dash.embargo.terms2020-11-01
dc.date.created2019-11
dc.date.issued2019-08-15
dc.date.submitted2019
dc.identifier.citationSchiff, Abigail Esther. 2019. HIV Infection of Alveolar Macrophages and Its Association With Mycobacterium Tuberculosis Intracellular Growth. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42013120*
dc.description.abstractAlveolar macrophages (AMs) are the most abundant cell type in the lung airspace and are a primary line of defense against airborne pathogens. AMs from people with untreated HIV have impaired function which is believed to contribute to the increased susceptibility to active tuberculosis (TB) seen in this population. The lung is an early site of HIV replication and HIV RNA and DNA have been detected in AMs in the initial stages of infection, even though HIV at this stage does not enter macrophages efficiently in vitro. The mechanism of entry of HIV into AMs is unknown, and so are the impacts of untreated HIV infection on macrophage susceptibility to active TB. We performed bronchoscopy in HIV-infected antiretroviral therapy (ART)-naïve or uninfected control subjects living in South Africa. We isolated primary HIV envelope RNA sequences from AMs and plasma and used them to produce replication-competent virus. Primary HIV isolates from AMs and plasma were T cell tropic and replicated inefficiently in monocyte-derived macrophages (MDMs), but could productively infect macrophages via a mechanism that required contact with HIV-infected CD4+ T cells. We performed RNA sequencing on AMs and found HIV-associated alterations in multiple pathways, including a strong upregulation of beta chemokines. These chemokines preferentially recruited monocytes, which were more susceptible to intracellular Mycobacterium tuberculosis (Mtb) growth than mature MDMs or AMs. Finally, we found that inhibitors of two HIV-induced proteins reduced intracellular Mtb growth in MDMs. We conclude that AM-derived HIV isolates are T cell tropic and can enter macrophages through contact with infected CD4+ T cells, which results in productive HIV infection of AMs. AMs from people with untreated HIV infection produce beta chemokines which recruit monocytes that are permissive to Mtb infection, and these AMs have alterations in gene expression that decrease Mtb intracellular growth when inhibited. CD4+ T cell-dependent HIV entry into AMs and HIV-driven monocyte recruitment to the lung may be important contributors to the active TB risk seen in people living with HIV.
dc.description.sponsorshipMedical Sciences
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectHIV
dc.subjecttuberculosis
dc.subjectmacrophage
dc.subjectmonocyte recruitment
dc.subjectHIV-TB coinfection
dc.subjectHIV entry
dc.subjectHIV tropism
dc.subjectimmunology
dc.subjectvirology
dc.subjectalveolar macrophage
dc.titleHIV Infection of Alveolar Macrophages and Its Association With Mycobacterium Tuberculosis Intracellular Growth
dc.typeThesis or Dissertation
dash.depositing.authorSchiff, Abigail Esther
dash.embargo.until2020-11-01
dc.date.available2019-12-11T10:04:20Z
thesis.degree.date2019
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberKuritzkes, Daniel
dc.contributor.committeeMemberLe Gall, Sylvie
dc.contributor.committeeMemberSagar, Manish
dc.type.materialtext
thesis.degree.departmentMedical Sciences
thesis.degree.departmentMedical Sciences
dash.identifier.vireo
dc.identifier.orcid0000-0002-7233-489X
dash.author.emailabby.schiff@gmail.com


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