Complement dependent trapping of infectious HIV in human lymphoid tissues

Bánki, Zoltán; Kacani, Laco; Rusert, Peter; Pruenster, Monika; Wilflingseder, Doris; Falkensammer, Barbara; Stellbrink, Hans‐Jürgen; Lunzen, Jan van; Trkola, Alexandra; Dierich, Manfred P.; Stoiber, Heribert

doi:10.1097/01.aids.0000162336.20439.8d

Cited by 49 publications

(36 citation statements)

References 19 publications

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“…While confirming these recognized features of the tonsil epithelium, we also identified an increased expression of molecules that could conceivably promote HIV binding and entry in this site, such as the Fc␥RIII, complement receptor 2, complement components, and the co-receptor CXCR4, all of which have previously been linked with HIV and could be expressed by the epithelium or the infiltrating lymphocytes and dendritic cells. 6,26,33 This together with a reduction in innate antiviral mediators, including SLPI, may encour- 3 Although the molecules responsible for viral capture were not identified in these studies, a number of candidates emerge from our microarray analysis and include Fc␥RIII, complement components, and complement receptor 2 (CR2). After entrapment, actual viral entry requires fusion of the viral glycoproteins with the cell membrane through CD4 or possibly the alternate epithelial receptor GalCer and co-receptors CXCR4 and CCR5, 40,41 all of which were previously found to be present in the tonsil epithelium of pediatric tonsillitis patients (age 3 to 20 years).…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, an increased presence of immune cells in the tonsil epithelium may favor HIV entry and access to target cells. 26 Within the differentially overexpressed tonsil genes were Fc␥ receptor III, 31 complement receptor CR2, and various complement components 26 (FDR Ͻ10%). Other key HIV-binding molecules such as the adhesion molecule ICAM-3, 32 the dendritic cell-specific C-type lectin DC-SIGN, 33 and syndecan-1 34 were not significantly differentially expressed ( Figure 3B).…”

Section: Gene Expression Profile Of the Tonsil Includes Hiv Traffickimentioning

confidence: 99%

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Tonsil Epithelial Factors May Influence Oropharyngeal Human Immunodeficiency Virus Transmission

Moutsopoulos

Nares

Nikitakis

et al. 2007

The American Journal of Pathology

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Tonsil epithelium has been implicated in human immunodeficiency virus (HIV) pathogenesis, but its role in oral transmission remains controversial. To study characteristics of this tissue, which may influence susceptibility or resistance to HIV, we performed microarray analysis of the tonsil epithelium. Our data revealed that genes related to immune functions such as antibody production and antigen processing were increasingly expressed in tonsil compared with the epithelium of another oropharyngeal site, the gingival epithelium. Importantly, tonsil epithelium highly expressed genes associated with HIV entrapment and/or transmission, including the HIV co-receptor CXCR4 and the potential HIV-binding molecules FcR␥III, complement receptor 2, and various complement components. Immunohistochemical staining confirmed the increased presence of CXCR4 in the tonsil epithelium compared with multiple oral epithelial sites, particularly in basal and parabasal layers. This increased expression of molecules involved in viral recognition , binding , and entry may favor virus-epithelium interactions in an environment with reduced innate antiviral mechanisms. Specifically , secretory leukocyte protease inhibitor , an innate molecule with anti-HIV activity , was minimal in the tonsil epithelium , in contrast to oral mucosa. Collectively , our data suggest that increased expression of molecules associated with HIV binding and entry coupled with decreased innate antiviral factors may render the tonsil a potential site for oral transmission.

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Section: Discussionmentioning

confidence: 99%

Section: Gene Expression Profile Of the Tonsil Includes Hiv Traffickimentioning

confidence: 99%

Tonsil Epithelial Factors May Influence Oropharyngeal Human Immunodeficiency Virus Transmission

Moutsopoulos

Nares

Nikitakis

et al. 2007

The American Journal of Pathology

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“…uman immunodeficiency virus infection results in the activation of the complement system even in the absence of HIV-specific Abs (1), which results in deposition of C3 fragments on the viral surface both in vitro (2,3) and in vivo (4). HIV bound extracellularly to the follicular dendritic cells (FDC) 3 in germinal centers of lymph nodes represent by far the largest viral reservoir in HIV-infected individuals (5,6).…”

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confidence: 99%

“…HIV bound extracellularly to the follicular dendritic cells (FDC) 3 in germinal centers of lymph nodes represent by far the largest viral reservoir in HIV-infected individuals (5,6). The binding of this infectious pool of HIV in the germinal centers depends mainly on interactions of complement receptor type (CR) 2 expressed on FDC (or B cells) with C3d fragments on the viral surface (4,7). In addition, an association of complement-opsonized HIV with peripheral B cells through CR2-C3d interactions was described in HIV-infected individuals (8).…”

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confidence: 99%

“…As a consequence of the generation of C3d fragments, released HIV binds efficiently to CR2-expressing cells, which facilitates the B cell-mediated transmission of opsonized HIV to T cells. This fI-mediated sequential processing of C3 fragments from C3b to C3d on the surface of HIV is likely to have in vivo relevance since C3d-coated viruses are predominantly found on FDC in germinal centers, which represent by far the largest viral reservoir in HIV-infected individuals (4,5,7).…”

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Factor I-Mediated Processing of Complement Fragments on HIV Immune Complexes Targets HIV to CR2-Expressing B Cells and Facilitates B Cell-Mediated Transmission of Opsonized HIV to T Cells

Bánki

Wilflingseder

Ammann

et al. 2006

The Journal of Immunology

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Our study demonstrates that binding of complement-opsonized HIV to complement receptor type 1 on human erythrocytes (E) via C3b fragments is followed by a rapid normal human serum-mediated detachment of HIV from E. The release was dependent on the presence of factor I indicating a conversion of C3b fragments to iC3b and C3d on the viral surface. This in turn resulted in an efficient binding of opsonized HIV to CR2-expressing B cells, thus facilitating B cell-mediated transmission of HIV to T cells. These data provide a new dynamic view of complement opsonization of HIV, suggesting that association of virus with E might be a transient phenomenon and the factor I-mediated processing of C3b to iC3b and C3d on HIV targets the virus to complement receptor type 2-expressing cells. Thus, factor I in concert with CR1 on E and factor H in serum due to their cofactor activity are likely to be important contributors for the generation of C3d-opsonized infectious HIV reservoirs on follicular dendritic cells and/or B cells in HIV-infected individuals.

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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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Complement dependent trapping of infectious HIV in human lymphoid tissues

Abstract: These findings indicate that in the GC infectious virus is trapped on CR2-expressing FDC (or B cells). Reduction of this pool of HIV could be a therapeutic goal.

Cited by 49 publications

References 19 publications

Tonsil Epithelial Factors May Influence Oropharyngeal Human Immunodeficiency Virus Transmission

Tonsil Epithelial Factors May Influence Oropharyngeal Human Immunodeficiency Virus Transmission

Factor I-Mediated Processing of Complement Fragments on HIV Immune Complexes Targets HIV to CR2-Expressing B Cells and Facilitates B Cell-Mediated Transmission of Opsonized HIV to T Cells

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

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