The CDK Inhibitor p21<sup>Cip1/WAF1</sup>Is Induced by FcγR Activation and Restricts the Replication of Human Immunodeficiency Virus Type 1 and Related Primate Lentiviruses in Human Macrophages

Bergamaschi, Anna; David, Annie; Rouzic, Erwann Le; Nisole, Sébastien; Barré‐Sinoussi, Françoise; Pancino, Gianfranco

doi:10.1128/jvi.01395-09

Cited by 65 publications

(72 citation statements)

References 83 publications

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“…The mechanism underlying p21-mediated HIV-1 inhibition in macrophages remains to be elucidated. In particular, we did not detect p21 interactions with HIV-1 proteins involved in reverse transcription/integration, including Viral protein R, matrix, reverse transcriptase, and Integrase (28). Although p21 causes a preintegrative HIV-1 blockade in human hematopoietic stem cells (29), it has been reported to either inhibit or enhance HIV-1 transcription in MDMs and T cells (30)(31)(32).…”

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confidence: 66%

“…We have previously shown that p21 Waf1/Cip1 (referred to hereafter as p21) restricts HIV replication in MDMs (28). p53-independent p21 induction by immune complex aggregation of FcγRs leads to a strong reduction in reverse transcripts of HIV-1, HIV-2, SIVmac, and SIVagm in MDMs whereas siRNA-mediated p21 depletion rescues viral replication (28).…”

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confidence: 99%

“…p53-independent p21 induction by immune complex aggregation of FcγRs leads to a strong reduction in reverse transcripts of HIV-1, HIV-2, SIVmac, and SIVagm in MDMs whereas siRNA-mediated p21 depletion rescues viral replication (28). A further minor block of viral integration by p21 has been also observed (28) that would be a consequence of the major block of reverse transcription leading to the formation of incomplete reverse transcripts unable to integrate properly. The mechanism underlying p21-mediated HIV-1 inhibition in macrophages remains to be elucidated.…”

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confidence: 99%

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p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

Allouch

David

Amie

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Macrophages are a major target cell for HIV-1, and their infection contributes to HIV pathogenesis. We have previously shown that the cyclin-dependent kinase inhibitor p21 inhibits the replication of HIV-1 and other primate lentiviruses in human monocyte-derived macrophages by impairing reverse transcription of the viral genome. In the attempt to understand the p21-mediated restriction mechanisms, we found that p21 impairs HIV-1 and simian immunodeficiency virus (SIV)mac reverse transcription in macrophages by reducing the intracellular deoxyribonucleotide (dNTP) pool to levels below those required for viral cDNA synthesis by a SAM domain and HD domain-containing protein 1 (SAMHD1)-independent pathway. We found that p21 blocks dNTP biosynthesis by down-regulating the expression of the RNR2 subunit of ribonucleotide reductase, an enzyme essential for the reduction of ribonucleotides to dNTP. p21 inhibits RNR2 transcription by repressing E2F1 transcription factor, its transcriptional activator. Our findings unravel a cellular pathway that restricts HIV-1 and other primate lentiviruses by affecting dNTP synthesis, thereby pointing to new potential cellular targets for anti-HIV therapeutic strategies.

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confidence: 66%

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confidence: 99%

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confidence: 99%

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p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

Allouch

David

Amie

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…p21) [92]. Host cells appear to have evolved a number of restriction factors that can block infection at different stages of the viral replication cycle.…”

Section: Insights Into Immune Responses Conferring Spontaneous Contromentioning

confidence: 99%

“…Non-neutralizing antibodies form immune complexes with soluble HIV antigens that stimulate Fcg receptors expressed by myeloid cells, particularly macrophages. Fcg receptor aggregation provokes a blockade of viral replication through the induction of p21 and the alteration of the de novo synthesis pathway of dNTPs, which are necessary for the reverse transcription step of viral replication [92,180]. By contrast, anti-HIV antibodies may compete with complement to opsonize viral particles.…”

Section: (C) Humoral Responsesmentioning

confidence: 99%

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

Sáez‐Cirión

Jacquelin

Barré‐Sinoussi

et al. 2014

Phil. Trans. R. Soc. B

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International audienceHIV research has made rapid progress and led to remarkable achievements in recent decades, the most important of which are combination antiretroviral therapies (cART). However, in the absence of a vaccine, the pandemic continues, and additional strategies are needed. The 'towards an HIV cure' initiative aims to eradicate HIV or at least bring about a lasting remission of infection during which the host can control viral replication in the absence of cART. Cases of spontaneous and treatment-induced control of infection offer substantial hope. Here, we describe the scientific knowledge that is lacking, and the priorities that have been established for research into a cure. We discuss in detail the immunological lessons that can be learned by studying natural human and animal models of protection and spontaneous control of viraemia or of disease progression. In particular, we describe the insights we have gained into the immune mechanisms of virus control, the impact of early virus-host interactions and why chronic inflammation, a hallmark of HIV infection, is an obstacle to a cure. Finally, we enumerate current interventions aimed towards improving the host immune response

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The bitter side of sweet: the role of Galectin-9 in immunopathogenesis of viral infections

2015

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In recent years, a critical role for β-galactoside-binding protein, Galectin-9 (Gal-9) has emerged in infectious disease, autoimmunity, and cancer. It is a ligand for T cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic viral infections. Gal-9 exerts its pivotal immunomodulatory effects by inducing apoptosis or suppressing effector functions via engagement with its receptor, Tim-3. Recent studies report elevation of circulating Gal-9 in humans infected with different viral infections. Interaction of soluble Gal-9 with Tim-3 expressed on the surface of activated CD4+ T cells renders them less susceptible to HIV-1 infection, while enhanced HIV infection occurs when Gal-9 interacts with a different receptor than Tim-3. This indicates the versatile role of Gal-9 in viral pathogenesis. For instance, higher expression of Tim-3 during chronic viral infection and elevation of plasma Gal-9 may have evolved to limit persistent immune activation and pathogenic T cells activity. In contrast, Gal-9 can suppress the effectiveness of immunity against viral infections. In agreement, Gal-9 knockout mice mount a more robust and vigorous virus-specific immune response in acute and chronic viral infections resulting in rapid viral clearance. In line with this observation, blocking Gal-9 signals to Tim-3-expressing T cells result in improved immune responses. Here we review the biological and immunological properties of Gal-9 in viral infections (HIV, HCV, HBV, HSV, CMV, influenza, and dengue virus). Manipulating Gal-9 signals may have immunotherapeutic potential and could represent an alternative approach for improving immune responses to viral infections/vaccines.

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The CDK Inhibitor p21^Cip1/WAF1Is Induced by FcγR Activation and Restricts the Replication of Human Immunodeficiency Virus Type 1 and Related Primate Lentiviruses in Human Macrophages

Cited by 65 publications

References 83 publications

p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

The bitter side of sweet: the role of Galectin-9 in immunopathogenesis of viral infections

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The CDK Inhibitor p21Cip1/WAF1Is Induced by FcγR Activation and Restricts the Replication of Human Immunodeficiency Virus Type 1 and Related Primate Lentiviruses in Human Macrophages

Cited by 65 publications

References 83 publications

p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

The bitter side of sweet: the role of Galectin-9 in immunopathogenesis of viral infections

Contact Info

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The CDK Inhibitor p21^Cip1/WAF1Is Induced by FcγR Activation and Restricts the Replication of Human Immunodeficiency Virus Type 1 and Related Primate Lentiviruses in Human Macrophages