IL-7 Induces SAMHD1 Phosphorylation in CD4+ T Lymphocytes, Improving Early Steps of HIV-1 Life Cycle

Coiras, Mayte; Bermejo, Mercedes; Descours, Benjamin; Mateos, Elena; García-Pérez, Javier; López-Huertas, María Rosa; Lederman, Michael M.; Benkirane, Monsef; Alcamı́, José

doi:10.1016/j.celrep.2016.02.022

Cited by 66 publications

(82 citation statements)

References 43 publications

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“…Our results suggest that this lack of activity is not due to an increased expression of the restriction factors SAMHD1 or APOBEC3G, nor to the methylation status of the LTR. These observations are in agreement with a recent report by Coiras et al (2016) showing that IL-7 treatment of CD4 + T cells induces SAMHD1 phosphorylation abrogating its antiviral activity. Although additional epigenetic regulation cannot be ruled out, altogether these results point to a mechanism of HIV control in resting naïve CD4 + T cells that may be distinct from that in TCR-stimulated memory/effector CD4 + T cells.…”

Section: Discussionsupporting

confidence: 93%

Homeostatically Maintained Resting Naive CD4+ T Cells Resist Latent HIV Reactivation

et al. 2016

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Homeostatic proliferation (HSP) is a major mechanism by which long-lived naïve and memory CD4+ T cells are maintained in vivo and suggested to contribute to the persistence of the latent HIV-1 reservoir. However, while many in vitro latency models rely on CD4+ T cells that were initially differentiated via T-cell receptor (TCR) stimulation into memory/effector cells, latent infection of naïve resting CD4+ T cells maintained under HSP conditions has not been fully addressed. Here, we describe an in vitro HSP culture system utilizing the cytokines IL-7 and IL-15 that allows studying latency in naïve resting CD4+ T cells. CD4+ T cells isolated from several healthy donors were infected with HIV pseudotypes expressing GFP and cultured under HSP conditions or TCR conditions as control. Cell proliferation, phenotype, and GFP expression were analyzed by flow cytometry. RNA expression was quantified by qRT-PCR. Under HSP culture conditions, latently HIV-1 infected naïve cells are in part maintained in the non-dividing (= resting) state. Although a few HIV-1 provirus+ cells were present in these resting GFP negative cells, the estimated level of GFP transcripts per infected cell seems to indicate a block at the post-transcriptional level. Interestingly, neither TCR nor the prototypic HDAC inhibitor SAHA were able to reactivate HIV-1 provirus from these cells. This lack of reactivation was not due to methylation of the HIV LTR. These results point to a mechanism of HIV control in HSP-cultured resting naïve CD4+ T cells that may be distinct from that in TCR-stimulated memory/effector T cells.

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Section: Discussionsupporting

confidence: 93%

Homeostatically Maintained Resting Naive CD4+ T Cells Resist Latent HIV Reactivation

et al. 2016

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“…As such, retaining CD3 expression could make HIV-1 infected primary T cells more responsive to stimulation, thereby boosting viral gene expression and replication. To explore this, resting primary CD4+ T cells were treated with IL-7 to make them permissive to HIV-1 infection without T cell activation (33), infected with viruses that cannot down-regulate CD3 (NL4.3, L4 LF, and K2 LF), and subsequently stimulated with anti-CD3/CD28 antibodies to induce TCR triggering and activation ( Fig. 5A and SI Appendix, Fig.…”

Section: Cd3-mediated Enhancement Of Virion Infectivity and T Cellmentioning

confidence: 99%

Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

Mesner

Hotter

Kirchhoff

et al. 2020

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

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Nef is an accessory protein of primate lentiviruses that is essential for efficient replication and pathogenesis of HIV-1. A conserved feature of Nef proteins from different lentiviral lineages is the ability to modulate host protein trafficking and down-regulate a number of cell surface receptors to enhance replication and promote immune evasion. Notably, the inability of Nef to down-regulate CD3 from infected T cells distinguishes HIV-1 Nef and its direct simian precursors from other primate lentiviruses. Why HIV-1 does not employ this potential immune evasion strategy is not fully understood. Using chimeric HIV-1 constructs expressing lentiviral Nef proteins that differ in their ability to down-modulate CD3, we show that retaining CD3 on the surface of infected primary T cells results in increased viral replication and cell-to-cell spread. We identified increased expression of envelope (Env) trimers at the cell surface and increased Env incorporation into virions as the determinants for the Nef-and CD3-dependent enhancement of viral infectivity. Importantly, this was independent of Nef-mediated antagonism of the host restriction factor SERINC5. CD3 retention on the surface of infected primary T cells also correlated with increased T cell signaling, activation, and cell death during cell-tocell spread. Taken together, our results show that loss of an otherwise conserved function of Nef has a positive effect on HIV-1 replication, allowing for more efficient replication while potentially contributing to HIV-1 pathogenesis by triggering T cell activation and cell death during viral spread.HIV | CD3 | Nef | T cell | Env

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“…In contrast, a decrease in chemokine levels, as was observed in the productive infection of MDCs, would result in loss of CD4 chemoattraction and lessened infection in the immune synapse. Furthermore, it has been described that these chemokines are involved in the induction of efficient latent proviral integration in IL-2-activated CD4 lymphocytes (74)(75)(76). Accordingly, we describe that trans-infection and viral integration in CD4 lymphocytes were decreased when autologous lymphocytes were cocultured with MDCs previously infected with Vpx-loaded particles.…”

Section: Chemokine Expression During MDC Infectionmentioning

confidence: 59%

Different Expression of Interferon-Stimulated Genes in Response to HIV-1 Infection in Dendritic Cells Based on Their Maturation State

Calonge

Bermejo

Díez-Fuertes

et al. 2017

J Virol

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Dendritic cells (DCs) are professional antigen-presenting cells whose functions are dependent on their degree of differentiation. In their immature state, DCs capture pathogens and migrate to the lymph nodes. During this process, DCs become resident mature cells specialized in antigen presentation. DCs are characterized by a highly limiting environment for human immunodeficiency virus type 1 (HIV-1) replication due to the expression of restriction factors such as SAMHD1 and APOBEC3G. However, uninfected DCs capture and transfer viral particles to CD4 lymphocytes through a trans-enhancement mechanism in which chemokines are involved. We analyzed changes in gene expression with whole-genome microarrays when immature DCs (IDCs) or mature DCs (MDCs) were productively infected using Vpx-loaded HIV-1 particles. Whereas productive HIV infection of IDCs induced expression of interferon-stimulated genes (ISGs), such induction was not produced in MDCs, in which a sharp decrease in ISG-and CXCR3-binding chemokines was observed, lessening trans-infection of CD4 lymphocytes. Similar patterns of gene expression were found when DCs were infected with HIV-2 that naturally expresses Vpx. Differences were also observed under conditions of restrictive HIV-1 infection, in the absence of Vpx. ISG expression was not modified in IDCs, whereas an increase of ISG-and CXCR3-binding chemokines was observed in MDCs. Overall these results suggest that sensing and restriction of HIV-1 infection are different in IDCs and MDCs. We propose that restrictive infection results in increased virulence through different mechanisms. In IDCs avoidance of sensing and induction of ISGs, whereas in MDCs increased production of CXCR3-binding chemokines, would result in lymphocyte attraction and enhanced infection at the immune synapse.

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IL-7 Induces SAMHD1 Phosphorylation in CD4+ T Lymphocytes, Improving Early Steps of HIV-1 Life Cycle

Cited by 66 publications

References 43 publications

Homeostatically Maintained Resting Naive CD4+ T Cells Resist Latent HIV Reactivation

Homeostatically Maintained Resting Naive CD4+ T Cells Resist Latent HIV Reactivation

Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

Different Expression of Interferon-Stimulated Genes in Response to HIV-1 Infection in Dendritic Cells Based on Their Maturation State

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