Direct Binding of Complement Component C1q to Human Immunodeficiency Virus (HIV) and Human T Lymphotrophic Virus-I (HTLV-I) Coinfected Cells

Abstract

Previous studies have shown that coinfection of the human T lymphotrophic virus type I (HTLV-I) chronically infected cell line MT4 with human immunodeficiency virus type 1 (HIV-1) results in cells which spontaneously activate complement via the classical pathway. This complement activation was antibody independent, yet required C2, suggesting either direct C1, C4, or C2 activation. Because some animal retroviruses have been shown to bind human C1q directly, the present study investigated the possible direct binding of C1q by HIV coinfected MT4 cells. Coinfected cells bound both C1q present in serum and highly purified C1q. Binding of C1q resulted in formation of active C1 on the cell surface, which could in turn activate complement as shown by C4 consumption. The C1q binding was not HIV-isolate specific since infection of MT4 cells with any of three diverse isolates all induced C1q binding. Purified collagen-like region (CLR) and globular region (GR) fragments of C1q both bound to coinfected cells, suggesting a mechanism of binding by C1q similar to that of fibronectin-C1q binding. However, culture of coinfected cells in serum-free (fibronectin-free) medium did not reduce C1q binding. A second HTLV-I chronically infected line, SLB-1, also displayed increased binding of C1q after HIV infection. The H9 cell line, which is not HTLV-I infected, did not bind C1q after HIV infection. These results suggest that a retrovirus protein expressed by coinfected cells directly binds C1q resulting in classical complement activation. This type of activation may have profound biological effects in persons coinfected with HIV-1 and HTLV-I.

Antibody-independent classical complement pathway activation and homologous C3 deposition in xeroderma pigmentosum cell lines

“…Direct binding of C1q but not of mannose binding lectin (MBL to XP cells induces activation of homologous C leading to C3 deposition. Similar activation pro®les of C have been reported in HIV- [8,9] and cytomegalovirus (CMV)-infected cells [10,11]. Our results infer that this type of C activation occurs not only in infection but also in non-viral malignant transformation.…”

“…In the present study, we demonstrated that activation of the antibodyindependent classical C pathway occurs on human tumour cell lines similarly to virus-infected cells. Indeed, gp41 of HIV [9] and unidenti®ed molecules of CMV [11] may cause classical pathwaymediated C3 deposition, but no molecules capable of inducing such homologous C3 deposition have been identi®ed on tumour cells. To our knowledge, this is the ®rst report on antibodyindependent classical pathway activation in human malignant cell lines.…”

Complement-dependent cytotoxic antibodies to human T lymphotropic virus type I (HTLV-I)-infected cells in the sera of HTLV-I-infected individuals

“…It is possible that the antibodies initiate activation of the human complement cascade. Several studies demonstrated this phenomenon with HIV/HTLV-Icoinfected cells [17,18]. Thus, the effects of the HTLV-I-specific cytotoxic antibodies in vivo would be closely related to the biologic activities of the released complement fragments.…”

“…This retrovirus has also been shown with HIV-1/HTLV-I-coinfected cells to induce human complement activation without being affected by its lytic activity [17,18]. To our knowledge, the presence of cytotoxic antibodies specific for HTLV-I in the sera of HTLV-I-infected patients has never been studied.…”

The good and evil of complement activation in HIV-1 infection

“…17 Moreover, the HIV-1 surface proteins gp41 and gp120 further enhance Ab-mediated complement activation by binding C1q or MBL, respectively. [18][19][20][21][22][23][24][25] Using serum from an uninfected C1q-or C3-deficient individual as a source of complement does not mediate any anti-HIV-1 activity, which indicates that the classical pathways contribute mainly to the complement activation against HIV-1. 26 Several reports demonstrate that complement-dependent virus lysis occurs in vivo 27,28 and that the complement can enhance the effect of neutralizing Ab both in vivo and in vitro.…”