1. Microbiology and Infectious Disease
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USP49 potently stabilizes APOBEC3G protein by removing ubiquitin and inhibits HIV-1 replication

Research Article
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Cite this article as: eLife 2019;8:e48318 doi: 10.7554/eLife.48318

Abstract

The antiviral activity of host factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G, A3G) and its degradation mediated by human immunodeficiency virus type 1 (HIV-1) Vif protein are important topics. Although accumulating evidence indicates the importance of deubiquitination enzymes (DUBs) in innate immunity, it is unknown if they participate in A3G stability. Here, we found that USP49 directly interacts with A3G and efficiently removes ubiquitin, consequently increasing A3G protein expression and significantly enhancing its anti-HIV-1 activity. Unexpectedly, A3G degradation was also mediated by a Vif- and cullin-ring-independent pathway, which was effectively counteracted by USP49. Furthermore, clinical data suggested that USP49 is correlated with A3G protein expression and hypermutations in Vif-positive proviruses, and inversely with the intact provirus ratio in the HIV-1 latent reservoir. Our studies demonstrated a mechanism to effectively stabilize A3G expression, which could comprise a target to control HIV-1 infection and eradicate the latent reservoir.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Ting Pan

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Zheng Song

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Liyang Wu

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Guangyan Liu

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Xiancai Ma

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4934-4221
  6. Zhilin Peng

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Mo Zhou

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Liting Liang

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Bingfeng Liu

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Jun Liu

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Junsong Zhang

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Xuanhong Zhang

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Ryan Huang

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Jiacong Zhao

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Yonghong Li

    Department of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Xuemei Ling

    Department of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  17. Yuewen Luo

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  18. Xiaoping Tang

    Department of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  19. Weiping Cai

    Department of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  20. Kai Deng

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  21. Linghua Li

    Department of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou, China
    For correspondence
    llheliza@126.com
    Competing interests
    The authors declare that no competing interests exist.
  22. Hui Zhang

    Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
    For correspondence
    zhangh92@mail.sysu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3620-610X

Funding

National Special Research Program of China for Important Infectious Diseases (2018ZX10302103; 2017ZX10202102)

  • Hui Zhang

The Important Key Program of the Natural Science Foundation of China (81730060)

  • Hui Zhang

The International Collaboration Program of the Natural Science Foundation of China and the U.S. NIH (81561128007)

  • Hui Zhang

The Joint-Innovation Program in Healthcare for Special Scientific Research Projects of Guangzhou (201803040002)

  • Hui Zhang

The Science and Technology Planning Project of Guangzhou (201704020226)

  • Ting Pan

Pearl River S and T Nova Program of Guangzhou (201806010118)

  • Ting Pan

National Natural Science Foundation of China (8197080527)

  • Ting Pan

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

Ethics

Human subjects: All human samples were anonymously coded in accordance with the local ethical guidelines (as stipulated by the Declaration of Helsinki). The Ethics Review Board of Sun Yat-Sen University and the Ethics Review Board of Guangzhou 8th People's Hospital approved this study.Written informed consents were provided by all study participants, and the protocol was approved by the IRB of Guangzhou Eighth People's Hospital (Guangzhou, China).

Reviewing Editor

  1. Guangxia Gao, Institute of Biophysics, Chinese Academy of Sciences, China

Publication history

  1. Received: May 9, 2019
  2. Accepted: August 8, 2019
  3. Accepted Manuscript published: August 9, 2019 (version 1)
  4. Version of Record published: August 20, 2019 (version 2)

Copyright

© 2019, Pan 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.

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Further reading

    1. Medicine
    2. Microbiology and Infectious Disease
    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
    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.