B Cells of HIV-1–Infected Patients Bind Virions through Cd21–Complement Interactions and Transmit Infectious Virus to Activated T Cells

Moir, Susan; Malaspina, Angela; Li, Yuexia; Chun, Tae‐Wook; Lowe, Tomeka; Adelsberger, Joseph W.; Baseler, Michael; Ehler, Linda; Liu, Shuying; Davey, Richard T.; Mican, Jo Ann M.; Fauci, Anthony S.

doi:10.1084/jem.192.5.637

Cited by 172 publications

(164 citation statements)

References 41 publications

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“…This led us to assume that virus binding to B lymphocytes is essential for the infection process. These findings are in line with previous reports indicating that peripheral and lymphoid B cells bind HIV by CR2 ligation in vivo [9,11]. The involvement of complement and CR2 was independent on viral subtypes and tropism.…”

Section: Discussionsupporting

confidence: 93%

“…So far, only indirect evidence has been provided that virus is opsonized in vivo [4, 11,15]. A virus capture assay coupled to real-time PCR allowed us to directly identify C3 fragments and antibodies on the viral surface of virus obtained from HIV-infected individuals (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…Since the presentation of an MHC II-peptide complex by the B cell is unlikely [9,11], HIV-associated superantigens may contribute to T cell activation by TCR triggering [17,19,20]. However, if HIVassociated gp120 indeed acted as viral superantigen in B cell/T cell co-cultures, infection with non-opsonized virus should also lead to viral replication and p24 antigen production.…”

Section: Discussionmentioning

confidence: 99%

“…Various indirect methods indicate that HIV is coated with C3-fragments and antibodies [4, 9,11]. Therefore, we established a virus capture assay (VCA), which allowed targeting these opsonins on viruses obtained directly from plasma of HIV-infected individuals.…”

Section: C3-fragments and Igg Are Present On Hiv-1 Isolated From Plasmentioning

confidence: 99%

“…This not only requires close contact with FDC but also with T cells, which may facilitate virus transmission [10]. Moir et al [11] recovered B lymphocytes from both peripheral blood and LT, which carried replicationcompetent virus on their surface bound via CR2. Therefore, the presence of B lymphocytes and complement seems to create a highly permissive environment to pro-mote HIV infection of non-prestimulated autologous T lymphocytes [2,9,12].…”

Section: Introductionmentioning

confidence: 99%

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Mechanism(s) promoting HIV‐1 infection of primary unstimulated T lymphocytes in autologous B cell/T cell co‐cultures

et al. 2003

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Resting CD4 + T cells in the lymphoid tissue (LT) are essential producers of virions at the beginning of HIV infection in vivo. We previously developed a model that allowed in vitro infection of non-prestimulated T lymphocytes in the presence of autologous B lymphocytes and complement. In this study, we try to clarify the mechanism(s) responsible for virus transmission in unstimulated autologous B cell/T cell co-cultures. Ex vivo analyses of patient plasma samples revealed that HIV was opsonized. Flow cytometry showed that opsonized virus preferentially bound to complement receptor (CR)-2 on B lymphocytes in primary B cell/T cell co-cultures. As indicated by cytokine measurements and transwell experiments, soluble factors seemed to play a minor role in enabling infection. Rather, direct interaction between B and T lymphocytes and direct binding of opsonized virus to CR2 on B cells turned out to be essential for productive infection. Antibodies blocking cell-cell adhesion inhibited p24 antigen production. An anti-CR2 antibody blocking C3d-CR2 binding also significantly reduced viral replication. Since the infection of unstimulated T cells by opsonized primary HIV isolates in the presence of B cells was highly efficient independent of the tropism of the virus, this mechanism may be critical in the pathogenesis of HIV.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: C3-fragments and Igg Are Present On Hiv-1 Isolated From Plasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mechanism(s) promoting HIV‐1 infection of primary unstimulated T lymphocytes in autologous B cell/T cell co‐cultures

et al. 2003

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C‐type lectin‐independent interaction of complement opsonized HIV with monocyte‐derived dendritic cells

et al. 2005

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HIV directly activates the complement cascade and is, therefore, opsonized with C3-cleavage products in vivo. This cloud of C3 fragments on the viral surface may impair the interaction of the HIV envelope glycoproteins gp120/gp41 with C-type lectins expressed on immature dendritic cells (iDC). Therefore, we determined the accessibility of gp120 after opsonization and compared the interaction of DC with non-opsonized or complement-opsonized HIV. The recognition of native gp120 was drastically impaired when the virus was covered by complement. Independent of opsonization, similar amounts of HIV bound to DC. The interaction of iDC and the infection of DC-PBL cocultures with non-opsonized virus was significantly reduced by mannan and antibodies which inhibit the ICAM-1-CR3 interaction. The binding of opsonized virus to iDC was reduced by an anti-CR3-antibody, which interferes with the binding of C3 fragments, but was not affected by mannan. Complement enhanced the HIV infection of DC and DC-PBL co-cultures significantly. Mannan did not inhibit the complement-dependent enhancement of infection. Thus, non-opsonized and opsonized HIV interacted with iDC, although the binding mechanisms seemed to differ. As HIV is opsonized in vivo, the Ctype lectin-independent interaction of opsonized viruses with iDC has to be taken into account.

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Preferential association of hepatitis C virus with CD19+ B cells is mediated by complement system

et al. 2016

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Extrahepatic disease manifestations are common in chronic hepatitis C virus (HCV) infection. The mechanism of HCV-related lymphoproliferative disorders is not fully understood. Recent studies have found that HCV in peripheral blood mononuclear cells (PBMCs) from chronically infected patients is mainly associated with CD19+ B cells. To further elucidate this preferential association of HCV with B cells, we used in vitro cultured virus and uninfected PBMCs from healthy blood donors to investigate the necessary serum components that activate the binding of HCV to B cells. First, we found that the active serum components were present not only in HCV carriers, but also in HCV recovered patients and HCV negative healthy blood donors and that the serum components were heat labile. Second, the preferential binding activity of HCV to B cells could be blocked by anti-complement C3 antibodies. In experiments with complement-depleted serum and purified complement proteins, we demonstrated that complement proteins C1, C2, and C3 were required to activate such binding activity. Complement protein C4 was partially involved in this process. Third, using antibodies against cell surface markers, we showed that the binding complex mainly involved CD21 (complement receptor 2), CD19, CD20, and CD81; CD35 (complement receptor 1) was involved but had lower binding activity. Fourth, both anti-CD21 and anti-CD35 antibodies could block the binding of patient-derived HCV to B cells. Fifth, complement also mediated HCV binding to Raji cells, a cultured B cell line derived from Burkitt’s lymphoma. Conclusion In chronic HCV infection, the preferential association of HCV with B cells is mediated by the complement system, mainly through complement receptor 2 (CD21), in conjunction with the CD19 and CD81 complex.

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B Cells of HIV-1–Infected Patients Bind Virions through Cd21–Complement Interactions and Transmit Infectious Virus to Activated T Cells

Cited by 172 publications

References 41 publications

Mechanism(s) promoting HIV‐1 infection of primary unstimulated T lymphocytes in autologous B cell/T cell co‐cultures

Mechanism(s) promoting HIV‐1 infection of primary unstimulated T lymphocytes in autologous B cell/T cell co‐cultures

C‐type lectin‐independent interaction of complement opsonized HIV with monocyte‐derived dendritic cells

Preferential association of hepatitis C virus with CD19+ B cells is mediated by complement system

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