1. Microbiology and Infectious Disease
Download icon

Mechanisms of virus dissemination in bone marrow of HIV-1-infected humanized BLT mice

  1. Mark S Ladinsky
  2. Wannisa Khamaikawin
  3. Yujin Jung
  4. Samantha Lin
  5. Jennifer Lam
  6. Dong Sung An
  7. Pamela J Bjorkman
  8. Collin Kieffer  Is a corresponding author
  1. California Institute of Technology, United States
  2. University of California, Los Angeles, United States
  3. University of Illinois at Urbana-Champaign, United States
Research Article
  • Cited 9
  • Views 1,350
  • Annotations
Cite this article as: eLife 2019;8:e46916 doi: 10.7554/eLife.46916

Abstract

Immune progenitor cells differentiate in bone marrow (BM) and then migrate to tissues. HIV-1 infects multiple BM cell types, but virus dissemination within BM has been poorly understood. We used light microscopy and electron tomography to elucidate mechanisms of HIV-1 dissemination within BM of HIV-1–infected BM/thymus/liver (BLT) mice. Tissue clearing combined with confocal and light sheet fluorescence microscopy revealed distinct populations of HIV-1 p24-producing cells in BM early after infection, and quantification of these populations identified macrophages as the principal subset of virus-producing cells in BM over time. Electron tomography demonstrated three modes of HIV-1 dissemination in BM: (i) semi-synchronous budding from T-cell and macrophage membranes, (ii) mature virus association with virus-producing T-cell uropods contacting putative target cells, and (iii) macrophages engulfing HIV-1–producing T-cells and producing virus within enclosed intracellular compartments that fused to invaginations with access to the extracellular space. These results illustrate mechanisms by which the specialized environment of the BM can promote virus spread locally and to distant lymphoid tissues.

Data availability

Source data files have been provided for graphs from Figure 1.

Article and author information

Author details

  1. Mark S Ladinsky

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.

  2. Wannisa Khamaikawin

    School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  3. Yujin Jung

    School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  4. Samantha Lin

    School of Nursing, UCLA AIDS Institute,, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  5. Jennifer Lam

    School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  6. Dong Sung An

    School of Nursing, UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  7. Pamela J Bjorkman

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    Pamela J Bjorkman, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2277-3990

  8. Collin Kieffer

    Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, United States
    For correspondence
    collink@illinois.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9051-3819

Funding

National Institute of Allergy and Infectious Diseases (1R01AI100652-01A1)

  • Dong Sung An

National Institute of Allergy and Infectious Diseases (AI028697)

  • Dong Sung An

National Institute of General Medical Sciences (2 P50 GM082545-08)

  • Pamela J Bjorkman

California HIV/AIDS Research Program (ID15-CT-017)

  • Pamela J Bjorkman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animals were maintained at the UCLA CFAR Humanized Mouse Core laboratory in accordance with a protocol approved by the UCLA Animal Research Committee. Experiments conformed to all relevant regulatory standards.(UCLA ARC # 2007-092-41A).

Reviewing Editor

  1. Julie Overbaugh, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: March 15, 2019
  2. Accepted: October 27, 2019
  3. Accepted Manuscript published: October 28, 2019 (version 1)
  4. Version of Record published: November 8, 2019 (version 2)

Copyright

© 2019, Ladinsky et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,350
    Page views
  • 193
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Microbiology and Infectious Disease

    A Tad-like apparatus is required for contact-dependent prey killing in predatory social bacteria

    Sofiene Seef et al.
    Research Article Updated

    Myxococcus xanthus, a soil bacterium, predates collectively using motility to invade prey colonies. Prey lysis is mostly thought to rely on secreted factors, cocktails of antibiotics and enzymes, and direct contact with Myxococcus cells. In this study, we show that on surfaces the coupling of A-motility and contact-dependent killing is the central predatory mechanism driving effective prey colony invasion and consumption. At the molecular level, contact-dependent killing involves a newly discovered type IV filament-like machinery (Kil) that both promotes motility arrest and prey cell plasmolysis. In this process, Kil proteins assemble at the predator-prey contact site, suggesting that they allow tight contact with prey cells for their intoxication. Kil-like systems form a new class of Tad-like machineries in predatory bacteria, suggesting a conserved function in predator-prey interactions. This study further reveals a novel cell-cell interaction function for bacterial pili-like assemblages.

    1. Medicine
    2. Microbiology and Infectious Disease

    Non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy is associated with lower cell-associated HIV RNA and DNA levels compared to protease inhibitor-based therapy

    Alexander O Pasternak et al.
    Research Article Updated

    Background:

    It remains unclear whether combination antiretroviral therapy (ART) regimens differ in their ability to fully suppress human immunodeficiency virus (HIV) replication. Here, we report the results of two cross-sectional studies that compared levels of cell-associated (CA) HIV markers between individuals receiving suppressive ART containing either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI).

    Methods:

    CA HIV unspliced RNA and total HIV DNA were quantified in two cohorts (n = 100, n = 124) of individuals treated with triple ART regimens consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either an NNRTI or a PI. To compare CA HIV RNA and DNA levels between the regimens, we built multivariable models adjusting for age, gender, current and nadir CD4+ count, plasma viral load zenith, duration of virological suppression, NRTI backbone composition, low-level plasma HIV RNA detectability, and electronically measured adherence to ART.

    Results:

    In both cohorts, levels of CA HIV RNA and DNA strongly correlated (rho = 0.70 and rho = 0.54) and both markers were lower in NNRTI-treated than in PI-treated individuals. In the multivariable analysis, CA RNA in both cohorts remained significantly reduced in NNRTI-treated individuals (padj = 0.02 in both cohorts), with a similar but weaker association between the ART regimen and total HIV DNA (padj = 0.048 and padj = 0.10). No differences in CA HIV RNA or DNA levels were observed between individual NNRTIs or individual PIs, but CA HIV RNA was lower in individuals treated with either nevirapine or efavirenz, compared to PI-treated individuals.

    Conclusions:

    All current classes of antiretroviral drugs only prevent infection of new cells but do not inhibit HIV RNA transcription in long-lived reservoir cells. Therefore, these differences in CA HIV RNA and DNA levels by treatment regimen suggest that NNRTIs are more potent in suppressing HIV residual replication than PIs, which may result in a smaller viral reservoir size.

    Funding:

    This work was supported by ZonMw (09120011910035) and FP7 Health (305522).

    1. Evolutionary Biology
    2. Microbiology and Infectious Disease

    Common host variation drives malaria parasite fitness in healthy human red cells

    Emily R Ebel et al.
    Research Article

    The replication of Plasmodium falciparum parasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. Deleterious alleles like hemoglobin S are well-known to confer strong resistance to malaria, but the effects of common RBC variation are largely undetermined. Here we collected fresh blood samples from 121 healthy donors, most with African ancestry, and performed exome sequencing, detailed RBC phenotyping, and parasite fitness assays. Over one third of healthy donors unknowingly carried alleles for G6PD deficiency or hemoglobinopathies, which were associated with characteristic RBC phenotypes. Among non-carriers alone, variation in RBC hydration, membrane deformability, and volume was strongly associated with P. falciparum growth rate. Common genetic variants in PIEZO1, SPTA1/SPTB, and several P. falciparum invasion receptors were also associated with parasite growth rate. Interestingly, we observed little or negative evidence for divergent selection on non-pathogenic RBC variation between Africans and Europeans. These findings suggest a model in which globally widespread variation in a moderate number of genes and phenotypes modulates P. falciparum fitness in RBCs.