The envelope glycoprotein of HIV‐1 gp120 and human complement protein C1q bind to the same peptides derived from three different regions of gp41, the transmembrane glycoprotein of HIV‐1, and share antigenic homology

Abstract

gp41, the transmembrane glycoprotein of HIV-1, has been shown to be non-covalently associated with gp120. We have shown that it also binds human C1q. To analyze the interaction site(s) of gp41 with these two molecules, we established an enzyme-linked immunosorbent assay (ELISA) system using recombinant soluble gp41 [amino acids (aa) 539-684] and peptides thereof. In the cell-external part of gp41 three sites (aa 526-538, aa 590-613 and aa 625-655) were found to bind both gp120 and C1q. That gp120 and C1q use the same sites was evidenced by the fact that these proteins competed with each other for the same sites in recombinant soluble gp41 and gp41 peptides. It could be demonstrated by ELISA, that rabbit antibodies against human C1q recognized gp120, and rabbit antibodies against gp120 cross-reacted with C1q. Rabbit anti-gp120, HIV-1-positive human sera and anti-gp120 obtained from such sera agglutinated sensitized sheep erythrocytes with human C1q (EAC1q). These data suggest that in addition to functional homology between C1q and gp120 structural homology between these two molecules exists. This molecular mimicry might become the basis for immunologically relevant autoimmune phenomena.

C1q Autoantibodies in HIV Infection: Correlation to Elevated Levels of Autoantibodies against 60-kDa Heat-Shock Proteins

“…This possibility was strongly supported by the observations of Stoiber et al (12) on the functional and structural similarities of C1q and gp120, the external glycoprotein of HIV-1. The two proteins were found to compete for the same binding sites on gp41 (12). In addition, rabbit antibod-ies to human C1q recognized gp120 and rabbit antibodies to gp120 cross-reacted with C1q (12).…”

“…The two proteins were found to compete for the same binding sites on gp41 (12). In addition, rabbit antibod-ies to human C1q recognized gp120 and rabbit antibodies to gp120 cross-reacted with C1q (12). Based on these results, Stoiber et al (12) postulated the possibility of development of C1qAb in HIV infection and found nine sera from HIV-infected subjects to agglutinate erythrocytes coated with antibody and C1q (EAC1q).…”

“…In addition, rabbit antibod-ies to human C1q recognized gp120 and rabbit antibodies to gp120 cross-reacted with C1q (12). Based on these results, Stoiber et al (12) postulated the possibility of development of C1qAb in HIV infection and found nine sera from HIV-infected subjects to agglutinate erythrocytes coated with antibody and C1q (EAC1q). Metlas et al (13) found a sequence similarity between V3 loop of gp120 of an HIV-1 isolate and collagen-like region of C1q, and also raised the possibility of formation of C1qAb in AIDS.…”

“…In C1q, the gp41 binding site appears to be at the junction between the collagen-like stem and globular heads (11). In the gp41, the main C1q-binding site is located within the immunodominant domain (HIVenv 590 -620) (9), but two additional C1q binding sites exist in the extracellular region of the HIV protein (12). The C1q binding and activation can markedly be increased by anti-gp41 antibodies (10).…”

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.…”