APOBEC3 Host Restriction Factors of HIV-1 Can Change the Template Switching Frequency of Reverse Transcriptase

Mammalian cells have evolved several mechanisms to prevent or block lentiviral infection and spread. Among the innate immune mechanisms, the signaling cascade triggered by type I interferon (IFN) plays a pivotal role in limiting the burden of HIV-1. In the presence of IFN, human cells upregulate the expression of a number of genes, referred to as IFN-stimulated genes (ISGs), many of them acting as antiviral restriction factors (RFs). RFs are dominant proteins that target different essential steps of the viral cycle, thereby providing an early line of defense against the virus. The identification and characterization of RFs have provided unique insights into the molecular biology of HIV-1, further revealing the complex host-pathogen interplay that characterizes the infection. The presence of RFs drove viral evolution, forcing the virus to develop specific proteins to counteract their activity. The knowledge of the mechanisms that prevent viral infection and their viral counterparts may offer new insights to improve current antiviral strategies. This review provides an overview of the RFs targeting HIV-1 replication and the mechanisms that regulate their expression as well as their impact on viral replication and the clinical course of the disease.

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Accessory Regulatory Proteins of HIV-1 and Host Restriction Factors Interactions

Biomedical Journal of Scientific & Technical Research ◽

10.26717/bjstr.2020.31.005120 ◽

2020 ◽

Vol 31 (4) ◽

Author(s):

Lopez Hernandez

Keyword(s):

Regulatory Proteins ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Hiv 1

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Specific Deubiquitinating Enzymes Promote Host Restriction Factors Against HIV/SIV Viruses

Frontiers in Immunology ◽

10.3389/fimmu.2021.740713 ◽

2021 ◽

Vol 12 ◽

Author(s):

Wenying Gao ◽

Yajuan Rui ◽

Guangquan Li ◽

Chenyang Zhai ◽

Jiaming Su ◽

...

Keyword(s):

Viral Replication ◽

Ectopic Expression ◽

Specific Inhibitor ◽

Restriction Factors ◽

Deubiquitinating Enzymes ◽

Host Restriction ◽

Host Restriction Factors ◽

Virion Infectivity Factor ◽

Specific Protease ◽

Hiv 1

Hijacking host ubiquitin pathways is essential for the replication of diverse viruses. However, the role of deubiquitinating enzymes (DUBs) in the interplay between viruses and the host is poorly characterized. Here, we demonstrate that specific DUBs are potent inhibitors of viral proteins from HIVs/simian immunodeficiency viruses (SIVs) that are involved in viral evasion of host restriction factors and viral replication. In particular, we discovered that T cell-functioning ubiquitin-specific protease 8 (USP8) is a potent and specific inhibitor of HIV-1 virion infectivity factor (Vif)-mediated apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3)G (A3G) degradation. Ectopic expression of USP8 inhibited Vif-induced A3G degradation and suppressed wild-type HIV-1 infectivity even in the presence of Vif. In addition, specific DUBs repressed Vpr-, Vpu-, and Vpx-triggered host restriction factor degradation. Our study has revealed a previously unrecognized interplay between the host’s DUBs and viral replication. Enhancing the antiviral activity of DUBs therefore represents an attractive strategy against HIVs/SIVs.

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Dodging the Host Interferon-Stimulated Gene Mediated Innate Immunity by HIV-1: A Brief Update on Intrinsic Mechanisms and Counter-Mechanisms

Frontiers in Immunology ◽

10.3389/fimmu.2021.716927 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kumaraswami Chintala ◽

Krishnaveni Mohareer ◽

Sharmistha Banerjee

Keyword(s):

Innate Immunity ◽

Life Cycle ◽

Innate Immune ◽

Therapeutic Interventions ◽

Innate Immune Responses ◽

Restriction Factors ◽

Host Restriction ◽

Interferon Stimulated Genes ◽

Host Restriction Factors ◽

Hiv 1

Host restriction factors affect different phases of a viral life cycle, contributing to innate immunity as the first line of defense against viruses, including HIV-1. These restriction factors are constitutively expressed, but triggered upon infection by interferons. Both pre-integration and post-integration events of the HIV-1 life cycle appear to play distinct roles in the induction of interferon-stimulated genes (ISGs), many of which encode antiviral restriction factors. However, HIV-1 counteracts the mechanisms mediated by these restriction factors through its encoded components. Here, we review the recent findings of pathways that lead to the induction of ISGs, and the mechanisms employed by the restriction factors such as IFITMs, APOBEC3s, MX2, and ISG15 in preventing HIV-1 replication. We also reflect on the current understanding of the counter-mechanisms employed by HIV-1 to evade innate immune responses and overcome host restriction factors. Overall, this mini-review provides recent insights into the HIV-1-host cross talk bridging the understanding between intracellular immunity and research avenues in the field of therapeutic interventions against HIV-1.

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O5 The expression profile of host restriction factors in different cohorts of HIV-1-infected patients

Journal of Virus Eradication ◽

10.1016/s2055-6640(20)30821-9 ◽

2017 ◽

Vol 3 ◽

pp. 2

Author(s):

C. Van Hecke ◽

E. Malatinkova ◽

W. De Spiegelaere ◽

M. Sips ◽

K. Vervisch ◽

...

Keyword(s):

Expression Profile ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Hiv 1

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Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors

Nature Medicine ◽

10.1038/nm910 ◽

2003 ◽

Vol 9 (9) ◽

pp. 1138-1143 ◽

Cited By ~ 284

Author(s):

Greg J Towers ◽

Theodora Hatziioannou ◽

Simone Cowan ◽

Stephen P Goff ◽

Jeremy Luban ◽

...

Keyword(s):

Cyclophilin A ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Hiv 1

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Antiretroviral Drug Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Increase Template-Switching Frequency

Journal of Virology ◽

10.1128/jvi.78.16.8761-8770.2004 ◽

2004 ◽

Vol 78 (16) ◽

pp. 8761-8770 ◽

Cited By ~ 60

Author(s):

Galina N. Nikolenko ◽

Evguenia S. Svarovskaia ◽

Krista A. Delviks ◽

Vinay K. Pathak

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Rnase H ◽

Switching Frequency ◽

Template Switching ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Template-switching events during reverse transcription are necessary for completion of retroviral replication and recombination. Structural determinants of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) that influence its template-switching frequency are not known. To identify determinants of HIV-1 RT that affect the frequency of template switching, we developed an in vivo assay in which RT template-switching events during viral replication resulted in functional reconstitution of the green fluorescent protein gene. A survey of single amino acid substitutions near the polymerase active site or deoxynucleoside triphosphate-binding site of HIV-1 RT indicated that several substitutions increased the rate of RT template switching. Several mutations associated with resistance to antiviral nucleoside analogs (K65R, L74V, E89G, Q151N, and M184I) dramatically increased RT template-switching frequencies by two- to sixfold in a single replication cycle. In contrast, substitutions in the RNase H domain (H539N, D549N) decreased the frequency of RT template switching by twofold. Depletion of intracellular nucleotide pools by hydroxyurea treatment of cells used as targets for infection resulted in a 1.8-fold increase in the frequency of RT template switching. These results indicate that the dynamic steady state between polymerase and RNase H activities is an important determinant of HIV-1 RT template switching and establish that HIV-1 recombination occurs by the previously described dynamic copy choice mechanism. These results also indicate that mutations conferring resistance to antiviral drugs can increase the frequency of RT template switching and may influence the rate of retroviral recombination and viral evolution.

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TRIM5 and the Regulation of HIV-1 Infectivity

Molecular Biology International ◽

10.1155/2012/426840 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 13

Author(s):

Jeremy Luban

Keyword(s):

Innate Immune ◽

Target Cells ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Innate Immune Signaling ◽

Ubiquitin Ligase Activity ◽

Species Specific ◽

Anti Hiv ◽

Hiv 1

The past ten years have seen an explosion of information concerning host restriction factors that inhibit the replication of HIV-1 and other retroviruses. Among these factors is TRIM5, an innate immune signaling molecule that recognizes the capsid lattice as soon as the retrovirion core is released into the cytoplasm of otherwise susceptible target cells. Recognition of the capsid lattice has several consequences that include multimerization of TRIM5 into a complementary lattice, premature uncoating of the virion core, and activation of TRIM5 E3 ubiquitin ligase activity. Unattached, K63-linked ubiquitin chains are generated that activate the TAK1 kinase complex and downstream inflammatory mediators. Polymorphisms in the capsid recognition domain of TRIM5 explain the observed species-specific differences among orthologues and the relatively weak anti-HIV-1 activity of human TRIM5. Better understanding of the complex interaction between TRIM5 and the retrovirus capsid lattice may someday lead to exploitation of this interaction for the development of potent HIV-1 inhibitors.

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Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx

PLoS Pathogens ◽

10.1371/journal.ppat.1009609 ◽

2021 ◽

Vol 17 (10) ◽

pp. e1009609

Author(s):

Michaël M. Martin ◽

Roy Matkovic ◽

Pauline Larrous ◽

Marina Morel ◽

Angélique Lasserre ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Restriction Factors ◽

Viral Dna ◽

Host Restriction ◽

Viral Expression ◽

Host Restriction Factors ◽

Human Immunodeficiency Viruses ◽

Hiv 1

Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) succeed to evade host immune defenses by using their viral auxiliary proteins to antagonize host restriction factors. HIV-2/SIVsmm Vpx is known for degrading SAMHD1, a factor impeding the reverse transcription. More recently, Vpx was also shown to counteract HUSH, a complex constituted of TASOR, MPP8 and periphilin, which blocks viral expression from the integrated viral DNA. In a classical ubiquitin ligase hijacking model, Vpx bridges the DCAF1 ubiquitin ligase substrate adaptor to SAMHD1, for subsequent ubiquitination and degradation. Here, we investigated whether the same mechanism is at stake for Vpx-mediated HUSH degradation. While we confirm that Vpx bridges SAMHD1 to DCAF1, we show that TASOR can interact with DCAF1 in the absence of Vpx. Nonetheless, this association was stabilized in the presence of Vpx, suggesting the existence of a ternary complex. The N-terminal PARP-like domain of TASOR is involved in DCAF1 binding, but not in Vpx binding. We also characterized a series of HIV-2 Vpx point mutants impaired in TASOR degradation, while still degrading SAMHD1. Vpx mutants ability to degrade TASOR correlated with their capacity to enhance HIV-1 minigenome expression as expected. Strikingly, several Vpx mutants impaired for TASOR degradation, but not for SAMHD1 degradation, had a reduced binding affinity for DCAF1, but not for TASOR. In macrophages, Vpx R34A-R42A and Vpx R42A-Q47A-V48A, strongly impaired in DCAF1, but not in TASOR binding, could not degrade TASOR, while being efficient in degrading SAMHD1. Altogether, our results highlight the central role of a robust Vpx-DCAF1 association to trigger TASOR degradation. We then propose a model in which Vpx interacts with both TASOR and DCAF1 to stabilize a TASOR-DCAF1 complex. Furthermore, our work identifies Vpx mutants enabling the study of HUSH restriction independently from SAMHD1 restriction in primary myeloid cells.

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HIV-1 Vpr Degrades TET2 to Suppress IRF7 and Interferon Expression in Plasmacytoid Dendritic Cells

10.1101/823328 ◽

2019 ◽

Author(s):

Qi Wang ◽

Li-Chung Tsao ◽

Lei Lv ◽

Yanping Xu ◽

Liang Cheng ◽

...

Keyword(s):

Dendritic Cells ◽

Viral Infections ◽

Constitutive Expression ◽

Plasmacytoid Dendritic Cells ◽

Type I Interferons ◽

Type I ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Hiv 1

AbstractPlasmacytoid dendritic cells (pDCs) are the major source of type I interferons (IFN-I) in rapid response to viral infections, with constitutive expression of interferon regulatory factor 7 (IRF7). HIV-1 expresses several accessory proteins to counteract specific IFN-induced host restriction factors. As one abundant virion-associated protein, HIV-1 Vpr remains enigmatic in enhancing HIV-1 infection via unclear mechanisms. Here we report that Vpr impaired IFN-I induction in pDCs to enhance HIV-1 replication in CD4+ T cells. Blockade of IFN-I signaling abrogated the effect of Vpr on HIV-1 replication. Virion-associated Vpr suppressed IFN-I induction in pDC by TLR7 agonists. Modulation of IFN-I induction by Vpr was genetically dependent on its activity of TET2 degradation. We further demonstrate that Vpr-mediated TET2 degradation reduced expression of IRF7 in pDCs. Finally, degradation of TET2 in pDCs by Vpr reduced the demethylation level of the IRF7 promoter via CXXC5-dependent recruitment. We conclude that HIV-1 Vpr functions to promote HIV-1 replication by suppressing TET2-dependent IRF7 expression and IFN-I induction in pDCs. The Vpr-TET2-IRF7 axis provides a novel therapeutic target to control HIV-1 infection.

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