Recently we reported the basic phenomenon of an interaction between the envelope glycoproteins of HIV-1 gp120 and gp41 and components of the human complement system, i.e. activated C4 (C4b) and activated C3 (C3b) and the complement regulator proteins factor H and properdin. In this study we analyze these interactions in detail. Using 46 overlapping peptides of gp120 attached to microtiter plates, binding of activated human C3 to 6 regions in gp120 was found (aa 100-129, 161-190, 231-250, 301-328, 410-449, 470-499). In competition assays with soluble peptides, representatives of four of these regions were capable to partially inhibit C3b binding to immobilized gp120. Activated human C4 interacted only with peptides covering aa 410-449, but both in direct binding assays and fluid phase inhibition studies. The multi-reactivity of gp120 with C3b was also supported by the fact that gp120 agglutinated erythrocytes coated with C3b. Guided by partial aa sequence homology of gp120 and human C4b binding protein (C4bp) as well as human properdin we detected binding of anti-properdin to aa 100-129 in gp120 and of anti-C4bp to aa 410-449 in gp120. This cross-reactivity was also confirmed by a monoclonal antibody directed against aa 416-443 of gp120, which could be shown to bind C4bp. Interestingly, aa 310-328, part of the V3-loop, were found to show an aa sequence similarity to human complement receptor type 3 (alpha-chain). Consequently, of the 4 (or possibly 6) interaction sites of gp120 with activated human C3, 3 may bind due to imitation of either properdin, CR3 or C4bp. In addition to C4b and C3b, we detected interaction of factor H with gp120; it selectively bound to aa 102-129. Using 14 overlapping peptides of gp41 attached to plates, we identified 4 areas in gp-41 (aa 561-585, 587-605, 615-635, 651-675) which bound human factor H. All of them except the first region partially inhibited factor H binding to gp41 in competition assays with soluble peptides. Properdin bound only to 2 regions (aa 584-614, 651-675). The first 3 sites in gp41 were already shown by us to share homology to sites in human C3. The region around aa 651-675 now also turned out to be similar to human C3. These data demonstrate that the interaction of both, gp120 and gp41, with the complement system is polyvalent and complex.(ABSTRACT TRUNCATED AT 400 WORDS)