HIV replication

Sauter, Daniel; Kirchhoff, Frank

doi:10.1097/coh.0000000000000233

Cited by 27 publications

(16 citation statements)

References 103 publications

(98 reference statements)

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“…For HIV, recent studies suggest that such newly transcribed HIV RNA can be differentiated from cellular RNAs by its high degree of secondary structure, including stem-loops or panhandles and other modifications. Therefore, HIV RNA can be differentially sensed by RIGI in the 5= and 3= untranslated regions, including the TAR stem-loop, which are likely to be recognized by RIGI and are probably more exposed in monomers than dimers (46,47). Solis et al (30) showed that both purified monomeric and, to a lesser extent, dimeric genomic RNA (which is transcribed from cDNA and exposed in the cytoplasm prior to packaging) stimulated RIGI, but not MDA5, using knockdowns.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Interferon-Stimulated Gene Induction in HIV-1-Infected Macrophages

Nasr

Alshehri

Wright

et al. 2017

J Virol

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Viruses manipulate the complex interferon and interferon-stimulated gene (ISG) system in different ways. We have previously shown that HIV inhibits type I and III interferons in its key target cells but directly stimulates a subset of >20 ISGs in macrophages and dendritic cells, many of which are antiviral. Here, we examine the mechanism of induction of ISGs and show this occurs in two phases. The first phase was transient (0 to 24 h postinfection [hpi]), induced mainly by extracellular vesicles and one of its component proteins, HSP90α, contained within the HIV inoculum. The second, dominant, and persistent phase (>48 hpi) was induced via newly transcribed HIV RNA and sensed via RIGI, as shown by the reduction in ISG expression after the knockdown of the RIGI adaptor, MAVS, by small interfering RNA (siRNA) and the inhibition of both the initiation and elongation of HIV transcription by short hairpin RNA (shRNA) transcriptional silencing. We further define the induction pathway, showing sequential HIV RNA stimulation via Tat, RIGI, MAVS, IRF1, and IRF7, also identified by siRNA knockdown. IRF1 also plays a key role in the first phase. We also show that the ISGs IFIT1 to -3 inhibit HIV production, measured as extracellular infectious virus. All induced antiviral ISGs probably lead to restriction of HIV replication in macrophages, contributing to a persistent, noncytopathic infection, while the inhibition of interferon facilitates spread to adjacent cells. Both may influence the size of macrophage HIV reservoirs Elucidating the mechanisms of ISG induction may help in devising immunotherapeutic strategies to limit the size of these reservoirs. HIV, like other viruses, manipulates the antiviral interferon and interferon-stimulated gene (ISG) system to facilitate its initial infection and establishment of viral reservoirs. HIV specifically inhibits all type I and III interferons in its target cells, including macrophages, dendritic cells, and T cells. It also induces a subset of over 20 ISGs of differing compositions in each cell target. This occurs in two temporal phases in macrophages. Extracellular vesicles contained within the inoculum induce the first, transient phase of ISGs. Newly transcribed HIV RNA induce the second, dominant ISG phase, and here, the full induction pathway is defined. Therefore, HIV nucleic acids, which are potent inducers of interferon and ISGs, are initially concealed, and antiviral ISGs are not fully induced until replication is well established. These antiviral ISGs may contribute to persistent infection in macrophages and to the establishment of viral reservoirs .

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Section: Discussionmentioning

confidence: 99%

Mechanism of Interferon-Stimulated Gene Induction in HIV-1-Infected Macrophages

Nasr

Alshehri

Wright

et al. 2017

J Virol

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“…Cells are equipped with a plethora of pattern recognition receptors (PRRs) that induce an antiviral immune response upon sensing of patterns associated with viral infection. Among them are cytosolic receptors such as cGAS, PQBP1, IFI16, and RIG-I recognizing viral DNA or RNA species, as well as restriction factors such as TRIM5α and Tetherin that sense viral capsids or budding virions, respectively [ 1 ]. The signaling cascades initiated by these receptors converge in the activation of a few key transcription factors ( i .…”

Section: Introductionmentioning

confidence: 99%

“…e . NF-κB, IRF3 and IRF7), which induce the expression of interferons (IFNs) and other antiviral factors [ 1 , 2 ]. HIV and related simian lentiviruses have evolved sophisticated means to evade these innate sensing pathways.…”

Section: Introductionmentioning

confidence: 99%

Primate lentiviruses use at least three alternative strategies to suppress NF-κB-mediated immune activation

et al. 2017

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Primate lentiviruses have evolved sophisticated strategies to suppress the immune response of their host species. For example, HIV-2 and most simian immunodeficiency viruses (SIVs) use their accessory protein Nef to prevent T cell activation and antiviral gene expression by downmodulating the T cell receptor CD3. This Nef function was lost in HIV-1 and other vpu-encoding viruses suggesting that the acquisition of Vpu-mediated NF-κB inhibition reduced the selection pressure for inhibition of T cell activation by Nef. To obtain further insights into the modulation of NF-κB activity by primate lentiviral accessory factors, we analyzed 32 Vpr proteins from a large panel of divergent primate lentiviruses. We found that those of SIVcol and SIVolc infecting Colobinae monkeys showed the highest efficacy in suppressing NF-κB activation. Vpr-mediated inhibition of NF-κB resulted in decreased IFNβ promoter activity and suppressed type I IFN induction in virally infected primary cells. Interestingly, SIVcol and SIVolc differ from all other primate lentiviruses investigated by the lack of both, a vpu gene and efficient Nef-mediated downmodulation of CD3. Thus, primate lentiviruses have evolved at least three alternative strategies to inhibit NF-κB-dependent immune activation. Functional analyses showed that the inhibitory activity of SIVolc and SIVcol Vprs is independent of DCAF1 and the induction of cell cycle arrest. While both Vprs target the IKK complex or a factor further downstream in the NF-κB signaling cascade, only SIVolc Vpr stabilizes IκBα and inhibits p65 phosphorylation. Notably, only de-novo synthesized but not virion-associated Vpr suppressed the activation of NF-κB, thus enabling NF-κB-dependent initiation of viral gene transcription during early stages of the replication cycle, while minimizing antiviral gene expression at later stages. Our findings highlight the key role of NF-κB in antiviral immunity and demonstrate that primate lentiviruses follow distinct evolutionary paths to modulate NF-κB-dependent expression of viral and antiviral genes.

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“…Viruses, which have coevolved with their host, develop strategies to counteract the signaling cascades of the innate immune system and ensure their replication. Recently, several reviews were published, describing the innate immune evasion strategies of individual viruses or virus families, such as influenza virus (2,3), Phleboviruses (4), Herpes viruses (5)(6)(7), Coronaviruses severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) (8), human immunodeficiency virus (HIV) (9,10), as well as multiple RNA viruses (11,12). Moreover, there are recent articles that review how viruses prevent detection by pathogen recognition receptors (PRRs) (13,14) and how viruses modulate innate immune signaling by use of viral deubiquitinases (15).…”

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confidence: 99%

Viral Evasion Strategies in Type I IFN Signaling – A Summary of Recent Developments

2016

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The immune system protects the organism against infections and the damage associated with them. The first line of defense against pathogens is the innate immune response. In the case of a viral infection, it induces the interferon (IFN) signaling cascade and eventually the expression of type I IFN, which then causes an antiviral state in the cells. However, many viruses have developed strategies to counteract this mechanism and prevent the production of IFN. In order to modulate or inhibit the IFN signaling cascade in their favor, viruses have found ways to interfere at every single step of the cascade, for example, by inducing protein degradation or cleavage, or by mediate protein polyubiquitination. In this article, we will review examples of viruses that modulate the IFN response and describe the mechanisms they use.

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HIV replication

Cited by 27 publications

References 103 publications

Mechanism of Interferon-Stimulated Gene Induction in HIV-1-Infected Macrophages

Mechanism of Interferon-Stimulated Gene Induction in HIV-1-Infected Macrophages

Primate lentiviruses use at least three alternative strategies to suppress NF-κB-mediated immune activation

Viral Evasion Strategies in Type I IFN Signaling – A Summary of Recent Developments

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