Cell-to-Cell Spreading of HIV-1 in Myeloid Target Cells Escapes SAMHD1 Restriction

Xie, Meili; Leroy, Héloïse; Mascarau, Rémi; Woottum, Marie; Dupont, Maeva; Ciccone, Camille; Schmitt, Alain; Raynaud-Messina, Brigitte; Vérollet, Christel; Bouchet, Jérôme; Bracq, Lucie; Bénichou, Serge

doi:10.1128/mbio.02457-19

Cited by 21 publications

(42 citation statements)

References 67 publications

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“…Acquisition of actin and nuclei staining was performed by microscopy as indicated in the histomorphometry section, and quantitative image analysis was performed using Fiji software, in which a region of interest was defined using actin staining. The number of nuclei per cell was analyzed from images of at least 100 cells, as previously described (Xie et al, 2019) and multinucleated cells (with three or more nuclei) were counted.…”

Section: Methodsmentioning

confidence: 99%

NLRP3 is involved in long bone edification and the maturation of osteogenic cells

Detzen

Cheat

Besbes

et al. 2020

Journal Cellular Physiology

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Overexpression of the nucleotide-binding leucine-rich repeat protein 3 (NLRP3) inflammasome in chronic auto-immune diseases leads to skeletal anomalies, with severe osteopenia due to the activation of osteoclasts. Reproducing this phenotype in Nlrp3 knock-in mice has provided insights into the role of NLRP3 in bone metabolism. We studied the role of NLRP3 in physiological bone development using a complete Nlrp3 knockout mouse model. We found impaired skeletal development in Nlrp3 −/− mice, resulting in a shorter stature than that of Nlrp3 +/+ mice. These growth defects were associated with altered femur bone growth, characterized by a deficient growth plate and an osteopenic profile of the trabeculae. No differences in osteoclast recruitment or activity were observed. Instead, Nlrp3 −/− femurs showed a less mineralized matrix in the trabeculae than those of Nlrp3 +/+ mice, as well as less bone sialoprotein (BSP) expressing hypertrophic chondrocytes. In vitro, primary osteoblasts lacking NLRP3 expression showed defective mineralization, together with the downregulation of BSP expression. Finally, follow-up by micro-CT highlighted the role of NLPR3 in bone growth, occurring early in living mice, as the osteopenic phenotype diminishes over time. Overall, our data suggest that NLRP3 is involved in bone edification via the regulation of hypertrophic chondrocyte maturation and osteoblast activity. Furthermore, the defect appeared to be transitory, as the skeleton recovered with aging.

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Section: Methodsmentioning

confidence: 99%

NLRP3 is involved in long bone edification and the maturation of osteogenic cells

Detzen

Cheat

Besbes

et al. 2020

Journal Cellular Physiology

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“…Direct contact between infected CD4 + T cells and uninfected macrophages can also cause cell fusion, which ultimately leads to the formation of giant multinucleated cells [91]. This process does not require reverse transcription, which evades the restriction imposed by SAMHD1 [92][93][94] and thereby increases infection of macrophages, DCs, and osteoclasts [95]. Combined, these findings demonstrate that HIV replication is significantly enhanced by cell-to-cell transmission between macrophages and T cells, which explains the earlier observation that the presence of macrophages boosts viral burden in lymphoid tissues [81].…”

Section: Hiv Infection Of Macrophages Contributes To Pathogenesismentioning

confidence: 99%

Vpr Is a VIP: HIV Vpr and Infected Macrophages Promote Viral Pathogenesis

Lubow

Collins

2020

Viruses

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HIV infects several cell types in the body, including CD4+ T cells and macrophages. Here we review the role of macrophages in HIV infection and describe complex interactions between viral proteins and host defenses in these cells. Macrophages exist in many forms throughout the body, where they play numerous roles in healthy and diseased states. They express pattern-recognition receptors (PRRs) that bind viral, bacterial, fungal, and parasitic pathogens, making them both a key player in innate immunity and a potential target of infection by pathogens, including HIV. Among these PRRs is mannose receptor, a macrophage-specific protein that binds oligosaccharides, restricts HIV replication, and is downregulated by the HIV accessory protein Vpr. Vpr significantly enhances infection in vivo, but the mechanism by which this occurs is controversial. It is well established that Vpr alters the expression of numerous host proteins by using its co-factor DCAF1, a component of the DCAF1–DDB1–CUL4 ubiquitin ligase complex. The host proteins targeted by Vpr and their role in viral replication are described in detail. We also discuss the structure and function of the viral protein Env, which is stabilized by Vpr in macrophages. Overall, this literature review provides an updated understanding of the contributions of macrophages and Vpr to HIV pathogenesis.

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“…Myeloid cells, such as macrophages and DCs, are indeed poorly infected by cell-free viruses because of the high expression of host cell restriction factors, such as sterile alpha motif and HD-domain–containing protein 1 (SAMHD1), an enzyme that cleaves deoxynucleoside triphosphates (dNTPs) and depletes the pool of intracellular nucleotides necessary for efficient HIV-1 replication in these non-cycling myeloid cells. Therefore, virus cell-to-cell transfer trough cell-cell fusion of myeloid cells may likely represent a dominant mode of virus dissemination in vivo and may allow for productive infection of these cell types [ 191 , 192 ]. Macrophages have been proposed to participate in virus dissemination and establishment of persistent virus reservoirs in numerous host tissues, including lymph nodes, spleen, lungs, genital and digestive tracts, and the central nervous system (CNS) [ 193 , 194 , 195 , 196 , 197 ].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, the presence of HIV-1-infected syncytia derived from DCs and expressing specific markers of DCs and T cells was found at the surface of the nasopharyngeal tonsils, adenoids and parotid glands of HIV-1-infected patients [ 206 , 207 , 208 ]. While several groups showed the presence of infected multinucleated macrophages or DCs in tissues, and, more specifically, in the brain of HIV-1-infected patients and monkeys experimentally infected with SIVs, the cellular and molecular mechanisms related to this MGC formation remained poorly investigated [ 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 ]. Interestingly, we have recently revealed that HIV-1 uses a specific and common two-step cell-cell fusion mechanism for virus transfer and dissemination from infected CD4+ T lymphocytes to myeloid target cells, including macrophages, immature DCs, and osteoclasts [ 191 , 192 , 210 ].…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, despite their large size, these infected MGCs migrate faster than their infected mononucleated counterparts, and may facilitate virus dissemination in tissues [ 211 ]. These recent studies indicate that this two-step cell-cell fusion process leading to the formation of highly virus-productive MGCs allows to bypass the restriction imposed by some host cell restriction factors, such as SAMHD1 [ 192 ], and may represent, compared to cell-free virus infection, an original and largely more efficient mode of virus transmission for viral spreading in myeloid cells and may be a major determinant for virus dissemination in vivo. These infected MGCs could indeed survive for a long time in host tissues to produce infectious virus particles as shown in vivo in lymphoid organs and especially in the CNS of HIV-1-infected patients and SIV-infected monkeys [ 198 , 199 , 200 , 201 , 202 , 203 , 204 , 208 , 209 , 210 , 211 , 212 , 213 ].…”

Section: Introductionmentioning

confidence: 99%

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Virus-Mediated Cell-Cell Fusion

Leroy

Han

Woottum

et al. 2020

IJMS

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Cell-cell fusion between eukaryotic cells is a general process involved in many physiological and pathological conditions, including infections by bacteria, parasites, and viruses. As obligate intracellular pathogens, viruses use intracellular machineries and pathways for efficient replication in their host target cells. Interestingly, certain viruses, and, more especially, enveloped viruses belonging to different viral families and including human pathogens, can mediate cell-cell fusion between infected cells and neighboring non-infected cells. Depending of the cellular environment and tissue organization, this virus-mediated cell-cell fusion leads to the merge of membrane and cytoplasm contents and formation of multinucleated cells, also called syncytia, that can express high amount of viral antigens in tissues and organs of infected hosts. This ability of some viruses to trigger cell-cell fusion between infected cells as virus-donor cells and surrounding non-infected target cells is mainly related to virus-encoded fusion proteins, known as viral fusogens displaying high fusogenic properties, and expressed at the cell surface of the virus-donor cells. Virus-induced cell-cell fusion is then mediated by interactions of these viral fusion proteins with surface molecules or receptors involved in virus entry and expressed on neighboring non-infected cells. Thus, the goal of this review is to give an overview of the different animal virus families, with a more special focus on human pathogens, that can trigger cell-cell fusion.

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Cell-to-Cell Spreading of HIV-1 in Myeloid Target Cells Escapes SAMHD1 Restriction

Cited by 21 publications

References 67 publications

NLRP3 is involved in long bone edification and the maturation of osteogenic cells

NLRP3 is involved in long bone edification and the maturation of osteogenic cells

Vpr Is a VIP: HIV Vpr and Infected Macrophages Promote Viral Pathogenesis

Virus-Mediated Cell-Cell Fusion

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