Impact of a decade of successful antiretroviral therapy initiated at HIV-1 seroconversion on blood and rectal reservoirs

Abstract

Persistent reservoirs remain the major obstacles to achieve an HIV-1 cure. Prolonged early antiretroviral therapy (ART) may reduce the extent of reservoirs and allow for virological control after ART discontinuation. We compared HIV-1 reservoirs in a cross-sectional study using PCR-based techniques in blood and tissue of early treated seroconverters, late treated patients, ART-naïve seroconverters and long-term non-progressors (LTNPs) who have spontaneous virological control without treatment. A decade of early ART reduced total and integrated HIV-1 DNA levels compared to later treatment initiation, but not reaching the low levels of LTNPs. Total HIV-1 DNA in rectal biopsies did not differ between cohorts. Importantly, lower viral transcription (unspliced RNA) and enhanced immune preservation (CD4/CD8) reminiscent of LTNPs were found in early compared to late treated patients. This suggests that early treatment is associated with some immuno-virological features of LTNPs that may improve the outcome of future interventions aimed at a functional cure.

Article and author information

Author details

  1. Eva Malatinkova

    HIV Translational Research Unit, Department of Internal Medicine, Faculty of Medicine and Health Sciences, Universitair Ziekenhuis Gent, Ghent University, Ghent, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  2. Ward De Spiegelaere

    HIV Translational Research Unit, Department of Internal Medicine, Faculty of Medicine and Health Sciences, Universitair Ziekenhuis Gent, Ghent University, Ghent, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  3. Pawel Bonczkowski

    HIV Translational Research Unit, Department of Internal Medicine, Faculty of Medicine and Health Sciences, Universitair Ziekenhuis Gent, Ghent University, Ghent, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  4. Maja Kiselinova

    HIV Translational Research Unit, Department of Internal Medicine, Faculty of Medicine and Health Sciences, Universitair Ziekenhuis Gent, Ghent University, Ghent, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  5. Karen Vervisch

    HIV Translational Research Unit, Department of Internal Medicine, Faculty of Medicine and Health Sciences, Universitair Ziekenhuis Gent, Ghent University, Ghent, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Wim Trypsteen

    HIV Translational Research Unit, Department of Internal Medicine, Faculty of Medicine and Health Sciences, Universitair Ziekenhuis Gent, Ghent University, Ghent, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  7. Margaret Johnson

    Division of Infection and Immunity, Royal Free Hospital, Royal Free London NHS Foundation Trust, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Chris Verhofstede

    AIDS Reference Laboratory, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  9. Danny de Looze

    Department of Gastroenterology, Universitair Ziekenhuis Gent, Ghent University, Ghent, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  10. Charles Murray

    Department of Gastroenterology, Royal Free Hospital, Royal Free London NHS Foundation Trust, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Sabine Kinloch-de Loes

    Division of Infection and Immunity, Royal Free Hospital, Royal Free London NHS Foundation Trust, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Linos Vandekerckhove

    HIV Translational Research Unit, Department of Internal Medicine, Faculty of Medicine and Health Sciences, Universitair Ziekenhuis Gent, Ghent University, Ghent, Belgium
    For correspondence
    linos.vandekerckhove@ugent.be
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Human subjects: Patient written informed consent was obtained from all the study participants.The study was approved by the Ethical Committee of Ghent University Hospital (Reference number: B670201317826) and Royal Free Hospital (Reference number: 13/LO/0729).

Copyright

© 2015, Malatinkova 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

  • 2,254
    views
  • 427
    downloads
  • 32
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Eva Malatinkova
  2. Ward De Spiegelaere
  3. Pawel Bonczkowski
  4. Maja Kiselinova
  5. Karen Vervisch
  6. Wim Trypsteen
  7. Margaret Johnson
  8. Chris Verhofstede
  9. Danny de Looze
  10. Charles Murray
  11. Sabine Kinloch-de Loes
  12. Linos Vandekerckhove
(2015)
Impact of a decade of successful antiretroviral therapy initiated at HIV-1 seroconversion on blood and rectal reservoirs
eLife 4:e09115.
https://doi.org/10.7554/eLife.09115

Share this article

https://doi.org/10.7554/eLife.09115

Further reading

    1. Microbiology and Infectious Disease
    Nicolas Flaugnatti, Loriane Bader ... Melanie Blokesch
    Research Article

    The type VI secretion system (T6SS) is a sophisticated, contact-dependent nanomachine involved in interbacterial competition. To function effectively, the T6SS must penetrate the membranes of both attacker and target bacteria. Structures associated with the cell envelope, like polysaccharides chains, can therefore introduce spatial separation and steric hindrance, potentially affecting the efficacy of the T6SS. In this study, we examined how the capsular polysaccharide (CPS) of Acinetobacter baumannii affects T6SS's antibacterial function. Our findings show that the CPS confers resistance against T6SS-mediated assaults from rival bacteria. Notably, under typical growth conditions, the presence of the surface-bound capsule also reduces the efficacy of the bacterium's own T6SS. This T6SS impairment is further enhanced when CPS is overproduced due to genetic modifications or antibiotic treatment. Furthermore, we demonstrate that the bacterium adjusts the level of the T6SS inner tube protein Hcp according to its secretion capacity, by initiating a degradation process involving the ClpXP protease. Collectively, our findings contribute to a better understanding of the dynamic relationship between T6SS and CPS and how they respond swiftly to environmental challenges.

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease
    Qian Wang, Jinxin Liu ... Qian Liu
    Research Article

    Paramyxovirus membrane fusion requires an attachment protein for receptor binding and a fusion protein for membrane fusion triggering. Nipah virus (NiV) attachment protein (G) binds to ephrinB2 or -B3 receptors, and fusion protein (F) mediates membrane fusion. NiV-F is a class I fusion protein and is activated by endosomal cleavage. The crystal structure of a soluble GCN4-decorated NiV-F shows a hexamer-of-trimer assembly. Here, we used single-molecule localization microscopy to quantify the NiV-F distribution and organization on cell and virus-like particle membranes at a nanometer precision. We found that NiV-F on biological membranes forms distinctive clusters that are independent of endosomal cleavage or expression levels. The sequestration of NiV-F into dense clusters favors membrane fusion triggering. The nano-distribution and organization of NiV-F are susceptible to mutations at the hexamer-of-trimer interface, and the putative oligomerization motif on the transmembrane domain. We also show that NiV-F nanoclusters are maintained by NiV-F–AP-2 interactions and the clathrin coat assembly. We propose that the organization of NiV-F into nanoclusters facilitates membrane fusion triggering by a mixed population of NiV-F molecules with varied degrees of cleavage and opportunities for interacting with the NiV-G/receptor complex. These observations provide insights into the in situ organization and activation mechanisms of the NiV fusion machinery.