Cell-to-cell infection by HIV contributes over half of virus infection

Iwami, Shingo; Takeuchi, Junko; Nakaoka, Shinji; Mammano, Fabrizio; Clavel, François; Inaba, Hisashi; Kobayashi, Tomoko; Misawa, Naoko; Aihara, Kazuyuki; Koyanagi, Yoshio; Sato, Kei

doi:10.7554/elife.08150

Cited by 151 publications

(150 citation statements)

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“…Along this line of thought, SFI antibodies may limit virus dissemination. A recent report documented that cell-to-cell infection by HIV-1 contributes to over half of the virus infection compared to cell-free virus infection and suggested that solely blocking cell-free virus infection in the absence of a cell-to-cell block would only partially limit virus dissemination (31). This conclusion may be applicable to viruses other than HIV, such as herpesviruses (e.g., HCMV and herpes simplex virus [HSV]).…”

Section: Discussionmentioning

confidence: 86%

Monoclonal Antibodies to Different Components of the Human Cytomegalovirus (HCMV) Pentamer gH/gL/pUL128L and Trimer gH/gL/gO as well as Antibodies Elicited during Primary HCMV Infection Prevent Epithelial Cell Syncytium Formation

Gerna

Percivalle

Perez

et al. 2016

J Virol

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Human cytomegalovirus (HCMV) may cause disseminated/end-organ disease in congenitally infected newborns and immunosuppressed transplant recipients. Two glycoprotein complexes, gH/gL/gO and gH/gL/pUL128/pUL130/pUL131 (gH/gL/ pUL128L; referred to as the pentamer), are required for HCMV entry into fibroblasts and endothelial/epithelial cells, respectively, in the presence of the viral fusion protein gB. In addition, gH/gL/gO was recently reported to also be required for infection of endothelial/epithelial cells. Virus entry into human fibroblasts involves fusion of the virus envelope with the plasma membrane, whereas entry into endothelial/epithelial cells involves macropinocytosis or endocytosis and low-pH-dependent fusion with endosomes. A large set of neutralizing monoclonal antibodies (MAbs), directed to gH, gB, and multiple components of the pentamer, was developed. In addition, novel anti-gO human monoclonal antibodies were recently isolated. It is known that epithelial cell infection with a wild HCMV strain at a high multiplicity of infection produces a large number of syncytia. Incubation of heavily HCMV VR1814-infected ARPE-19 epithelial cells with neutralizing MAbs to one, two, or three components of the pUL128L portion of the pentamer blocked syncytium formation at an antibody concentration of 10 g/ml, whereas only a partial inhibitory effect was displayed for MAbs to gO, gH, or gB at the same concentration. A blocking effect was also exhibited by convalescent-phase sera from primary HCMV infections. These findings indicate that the pentamer is required for syncytium formation in epithelial cells. IMPORTANCE Human cytomegalovirus (HCMV) mostly infects epithelial and endothelial cells in vivo.Recently, the pentamer protein complex (gH/gL/pUL128L) was identified as being required for infection of these cells, in association with the other protein complex, gH/ gL/gO. In primary infections, HCMV migrates to endothelial cells and then to leukocytes, which disseminate the infection throughout the body. The virus then spreads to organs and tissues, mostly infecting either single cells or multinucleated epithelial giant cells (syncytia), depending on the viral load. Potent neutralizing human MAbs directed to distinct binding sites of the pUL128L portion of the pentamer were shown in the past to block virus dissemination. In the present study, MAbs to pUL128L were shown to block syncytium formation with a higher potency than that of MAbs to gO, gH, or gB, thus suggesting their role in limiting virus dissemination. This finding provides additional information useful for the development of anti-HCMV therapeutic antibodies and subunit vaccines. Human cytomegalovirus (HCMV) is still a major cause of morbidity and mortality in immunocompromised transplant recipients and congenitally infected fetuses. Development of an HCMV vaccine has been given the highest priority by the Institute of Medicine of the United States (1). Following its initial isolation from human embryonic lung fibroblasts, HCMV was found to in...

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Section: Discussionmentioning

confidence: 86%

Monoclonal Antibodies to Different Components of the Human Cytomegalovirus (HCMV) Pentamer gH/gL/pUL128L and Trimer gH/gL/gO as well as Antibodies Elicited during Primary HCMV Infection Prevent Epithelial Cell Syncytium Formation

Gerna

Percivalle

Perez

et al. 2016

J Virol

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“…Recently, it was suggested that merely blocking cell-free virus infection in the absence of cell-tocell blocking would only partially limit HIV virus dissemination [81].…”

Section: Immune Response To Pc and Protection From Hcmv Infection/dismentioning

confidence: 99%

“…It has recently been reported that >50 % of HIV dissemination occurs cell-to-cell rather than through cell-free virus infection [81]. Following this line of thought, we tested the dissemination-inhibiting activity of HCMV-neutralizing antibodies, both mAbs and convalescent-phase sera from primary infections, by using three different assays: (i) plaque formation (cell-to-cell spreading) inhibition (PFI) ( [74,79] (Fig.…”

Section: Antibody Response To Pc and The Other Glycoprotein Complexesmentioning

confidence: 99%

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Gerna

Revello

Baldanti

et al. 2017

Journal of General Virology

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Between the 1980s and 1990s, three assays were developed for diagnosis of human cytomegalovirus (HCMV) infections: leuko (L)-antigenemia, L-viremia and L-DNAemia, detecting viral protein pp65, infectious virus and viral DNA, respectively, in circulating leukocytes Repeated initial attempts to reproduce the three assays in vitro using laboratory-adapted strains and infected cell cultures were consistently unsuccessful. Results were totally reversed when wild-type HCMV strains were used to infect either fibroblasts or endothelial cells. Careful analysis and sequencing of plaque-purified viruses from recent clinical isolates drew attention to the ULb¢ region of the HCMV genome. Using bacterial artificial chromosome technology, it was shown by both gain-of-function and loss-of-function experiments that UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. In addition, a number of clinical isolates passaged in human fibroblasts had lost both properties (leuko-tropism and endothelial cell-tropism) when displaying a mutation in the UL131-128 locus

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“…Cell-free HIV-1 infects both T cells and MDDCs, but infection is more efficient after cell-to-cell transfer (26,27). Using mathematical models, Iwami et al estimated that cell-to-cell transfer of HIV-1 contributes to 60% of viral infection (28). In contrast, cell-free HTLV-1 is poorly capable of infecting either CD4 ϩ T cells or MDDCs (20,29,30).…”

Section: Cell-free or Cell-associated Viruses Use Specific Entry Andmentioning

confidence: 99%

Cell-Free versus Cell-to-Cell Infection by Human Immunodeficiency Virus Type 1 and Human T-Lymphotropic Virus Type 1: Exploring the Link among Viral Source, Viral Trafficking, and Viral Replication

Dutartre

Claviere

Journo

et al. 2016

J Virol

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Human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1) are complex retroviruses mainly infecting CD4؉ T lymphocytes. In addition, antigen-presenting cells such as dendritic cells (DCs) are targeted in vivo by both viruses, although to a lesser extent. Interaction of HIV-1 with DCs plays a key role in viral dissemination from the mucosa to CD4؉ T lymphocytes present in lymphoid organs. While similar mechanisms may occur for HTLV-1 as well, most HTLV-1 data were obtained from T-cell studies, and little is known regarding the trafficking of this virus in DCs. We first compared the efficiency of cell-free versus cell-associated viral sources of both retroviruses at infecting DCs. We showed that both HIV-1 and HTLV-1 cell-free particles are poorly efficient at productively infecting DCs, except when DC-SIGN has been engaged. Furthermore, while SAMHD-1 accounts for restriction of cell-free HIV-1 infection, it is not involved in HTLV-1 restriction. In addition, cell-free viruses lead mainly to a nonproductive DC infection, leading to trans-infection of T-cells, a process important for HIV-1 spread but not for that of HTLV-1. Finally, we show that T-DC cell-to-cell transfer implies viral trafficking in vesicles that may both increase productive infection of DCs ("cis-infection") and allow viral escape from immune surveillance. Altogether, these observations allowed us to draw a model of HTLV-1 and HIV-1 trafficking in DCs. Human T-lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-1) infect 5 to 10 million (1) and 30 million (2) individuals worldwide, respectively. HTLV-1 is present in clusters of high endemicity such as in Japan, intertropical Africa, the Caribbean, and South America (3), whereas HIV-1 is pandemic. Interestingly, while both viruses infect CD4 ϩ T cells in vivo, the consequences of infection are opposite. After a long period of clinical latency, HTLV-1 infection leads either to adult T-cell leukemia (ATL) (4), an uncontrolled CD4 ϩ T lymphocyte proliferation with a very poor prognosis, or to an inflammatory disorder named HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) in a fraction of infected individuals (5). On the other hand, HIV-1 is associated with CD4 ϩ T-lymphocyte death and causes AIDS (for a review, see reference 6).Interestingly, both viruses also infect antigen-presenting cells (APCs) to a lesser extent, among which are different subtypes of dendritic cells (DCs), such as myeloid DCs, monocyte-derived DCs (MDDCs), and plasmacytoid DCs (pDCs) (7-10). After viral entry in mucosal tissues during sexual intercourse or breastfeeding (11,12), DCs can be used as viral carriers, thus allowing the virus to reach lymphoid organs, where it infects CD4 ϩ T lymphocytes (13). Thus, both retroviruses may hijack (i) the ability of DCs to capture pathogens and (ii) their vesicular traffic pathways in order to be transmitted to target cells without requiring a productive viral cycle (i.e., by trans-infection of T cells). tra...

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Cell-to-cell infection by HIV contributes over half of virus infection

Cited by 151 publications

References 32 publications

Monoclonal Antibodies to Different Components of the Human Cytomegalovirus (HCMV) Pentamer gH/gL/pUL128L and Trimer gH/gL/gO as well as Antibodies Elicited during Primary HCMV Infection Prevent Epithelial Cell Syncytium Formation

Monoclonal Antibodies to Different Components of the Human Cytomegalovirus (HCMV) Pentamer gH/gL/pUL128L and Trimer gH/gL/gO as well as Antibodies Elicited during Primary HCMV Infection Prevent Epithelial Cell Syncytium Formation

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

Cell-Free versus Cell-to-Cell Infection by Human Immunodeficiency Virus Type 1 and Human T-Lymphotropic Virus Type 1: Exploring the Link among Viral Source, Viral Trafficking, and Viral Replication

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