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PubMed1984

Characterization of the interaction of human C4b-binding protein with physiological ligands.

The binding of C4b to C4b-binding protein (C4BP) was demonstrated at physiological ionic strength by analytical ultracentrifugation. The sedimentation rate of C4BP gradually increased from 9.4 S to a maximum of 18.5 S with increasing C4b concentration. The stoichiometry of different C4BP X C4b complexes was calculated from the sedimentation-velocity data. A linear relationship was established between the number of C4b bound per C4BP and the sedimentation rate of the complex. In order to define further the C4BP-C4b interaction, sucrose density gradient ultracentrifugation was also used. Trace amounts of 125I-C4BP were centrifuged through 12 sucrose density gradients, each of which contained a different concentration of C4b throughout the gradient. The sedimentation rate of the C4BP increased with increasing C4b input to a maximum of 19.5 S. These binding data, in conjunction with the stoichiometry measurements determined in the analytical ultracentrifuge, were analyzed by the methods of Scatchard and Hill. At physiological ionic strength, C4BP exhibited four binding sites for C4b, each having an association constant of 1.2 X 10(7) M-1. A Hill coefficient of 1.1 was calculated, indicating that the four binding sites were independent. At reduced ionic strength, two additional sites were detected. The sedimentation coefficient of C4BP(C4b)6 was 24 S. The hydrodynamic data suggest that after four C4b molecules have bound to C4BP, the binding of additional C4b is sterically hindered. This interpretation implies that all six binding sites on C4BP are identical. C4BP also bound C4(H2O) (the product resulting from spontaneous hydrolysis of the thiol ester bond in native C4) and weakly bound C4c, but had no measurable affinity for native C4 or C4d at physiological ionic strength. A low-affinity interaction between C3b and C4BP was also demonstrated in the analytical ultracentrifuge. The C4BP X C3b complex was specific because C4BP mediated the cleavage of C3b by Factor I to C3bi with concomitant dissociation of the complex.

Carrier Proteins↗

PubMed1995

Terminal complement pathway activation and low lysis inhibitors in rheumatoid arthritis synovial fluid.

OBJECTIVE: To investigate terminal complement activation and lysis inhibitors in rheumatoid arthritis (RA). METHODS: C5a, vitronectin and clusterin were quantitated by enzyme immunoassays in plasma and synovial fluid (SF) in RA (n = 30) and osteoarthritis (OA) (n = 11). RESULTS: In RA the concentration of C5a was 3-fold increased in plasma (21.9 vs 7.2 micrograms/l) and 5-fold increased in SF (7.8 vs 1.7 micrograms/l) compared to OA. The SF/plasma ratios for C5a, vitronectin and clusterin were 0.35, 0.36 and 0.23, respectively, not significantly different in the 2 diseases. CONCLUSION: SF terminal pathway activation in RA combined with low local levels of lysis inhibitors might allow lytic or sublytic attacks on local cells, resulting in inflammation and cell damage.

Arthritis, Rheumatoid↗

PubMed1998

High-dose intravenous immunoglobulin treatment activates complement in vivo.

Several complement modulating effects of high-dose intravenous immunoglobulins (IVIG) have been proposed from in vitro studies and experimental animal models. However, the in vivo effects of IVIG on plasma complement in humans are yet not known. We have investigated the in vivo effects of IVIG on complement in seven women with unexplained recurrent spontaneous abortion who were without evidence of autoimmune disease. Samples were obtained before and after the very first infusion of IVIG. There was a marked increase in immunoglobulin G (IgG) from (median and range) 12.4 (9.4-15.9) to 26.8 (22.4-30.0) g/l but no change in immunoglobulin A (IgA) or immunoglobulin M (IgM). A significantly increased complement activation was demonstrated using neoepitope-specific enzyme immunoassays to the activation products C3bc (median increased from 9.8 to 31.2 AU/ml), Bb (0.66-1.66 g/ml), C5a (10.5-12.7 ng/ml), and TCC (0.81-2.19 AU/ml) (P = 0.015 for all). There were no changes in antigenic concentrations of individual complement components or regulators (C1q, C4, C3, C1-inhibitor, C4b-binding protein) and no decrease in complement haemolytic activity (classical and alternative CH50), which were all within the normal range. The classical pathway activation products C1rs/C1-inhibitor complexes, C4bc and C4d were elevated in all patients before IVIG treatment and did not change significantly during treatment. In conclusion, IVIG induced a significant activation of complement in vivo.

Abortion, Habitual↗

PubMed2005

Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein.

Factor H-related protein 5 (FHR-5) is a recently discovered member of the factor H (fH)-related protein family. FHR proteins are structurally similar to the complement regulator fH, but their biological functions remain poorly defined. FHR-5 is synthesized in the liver and consists of 9 short consensus repeats (SCRs), which display various degrees of homology to those of fH and the other FHR proteins. FHR-5 colocalizes with complement deposits in vivo and binds C3b in vitro, suggesting a role in complement regulation or localization. The current study examined whether rFHR-5 exhibits properties similar to those of fH, including heparin binding, CRP binding, cofactor activity for the factor I-mediated degradation of C3b and decay acceleration of the C3 convertase. rFHR-5 bound heparin-BSA and heparin-agarose and a defined series of truncations expressed in Pichia pastoris localized the heparin-binding region to within SCRs 5-7. rFHR-5 bound CRP, and this binding was also localized to SCRs 5-7. FHR-5 inhibited alternative pathway C3 convertase activity in a fluid phase assay; however, dissociation of the convertase was not observed in a solid phase assay. rFHR-5 displayed factor I-dependent cofactor activity for C3b cleavage, although it was apparently less effective than fH. In addition, we demonstrate association of FHR-5 with high density lipid lipoprotein complexes in human plasma. These results demonstrate that FHR-5 shares properties of heparin and CRP binding and lipoprotein association with one or more of the other FHRs but is unique among this family of proteins in possessing independent complement-regulatory activity.

Blood Proteins↗

PubMed1994

Identification and characterization of membrane cofactor protein (CD46) in the human kidneys.

Membrane cofactor protein (MCP, CD46) is an integral protein that serves as a cofactor for factor I in inactivating C3b/C4b deposited on the same cell membrane as C3bi/C4c+C4d. This C3b/C4b inactivation is closely associated with self-protection of host cells from autologous complement attack. We have studied the distribution and properties of MCP in the normal human kidney by immunohistochemical and immunoblotting methods using monoclonal antibodies against MCP. MCP was predominantly expressed on the juxtaglomerular apparatus. Glomerular capillary walls, mesangial areas, and tubulus were also MCP positive. Glomerulus MCP was composed of two major bands of 45-65 kDa, which were similar to those of lymphocyte MCP. The proportion of the high and low molecular weight components in glomerulus MCP, however, was considerably different from that of lymphocyte MCP among the individual samples tested. Glomerular epithelial cells and mesangial cells from an individual having equal amounts of high and low molecular weight components in the lymphocytes were cultured separately and the properties of their MCP investigated. MCP in the mesangial cells and glomerular epithelial cells showed profiles in which the upper band was predominant. The results may explain the unique distribution of the high and low molecular weight forms in the glomerulus. These forms of MCP together with factor I were all capable of inactivating C3b to C3bi. Message analysis suggested that glomerular epithelial cells and mesangial cells synthesized a single species of mRNA of 4.2 kb from which the polymorphic MCP species were generated. Flow cytometric analysis suggested that MCP was minimal in mesangial cells. These results, taken together with the previous reports on the distribution of other complement regulatory proteins, infer that the distribution profile of MCP is rather similar to that of DAF but differs from those of CD59 and CR1 in the normal human kidney; this may reflect the differences between their roles or functional properties in renal tissue.

Antigens, CD↗

PubMed1986

Control of C1 activation by nascent C3b and C4b: a mechanism of feedback inhibition.

We have demonstrated that immune complexes turn over C1, i.e., limiting quantities of immune complexes activate an excess of C1. This was readily apparent in a system of purified C1 and C1-inhibitor (C1-In) but not in normal human serum (NHS). The following results indicate that C3 and C4 are the serum factors responsible for the inhibition of C1 turnover by immune complexes. 1) In a purified protein system composed of C1 and C1-In at pH 7.5, ionic strength 0.14 M, doses of immune complexes that activated all the C1 in 60 min at 37 degrees C yielded no detectable C1 activation when C2, C3, and C4 were also present. All proteins were at their physiologic concentrations. Activation was quantified by SDS-PAGE analysis and hemolytic titration 2) In order to inactivate C3 and C4, NHS was treated with 50 mM methylamine (MeAm) for 15 min at 37 degrees C, after which the MeAm was removed by dialysis. The activities of C1, C2, and C1-In were unaffected by this treatment. Doses of immune complexes that consumed no C1 in NHS, consumed all the C1 in MeAm-treated NHS (MeAm-NHS). 3) Reconstitution of MeAm-NHS with physiologic concentrations of C3 and C4 rendered the serum again resistant to excessive C1 consumption by immune complexes. Immune complexes used in these studies included EA-IgG, EA-IgM, tetanus-human anti-tetanus, and aggregated human IgG. There appeared to be specificity to the inhibition reaction since C4 by itself could inhibit C1 consumption by EA-IgM, whereas the presence of C3 was also required to control EA-IgG. Finally, N-acetyl-L-tyrosine was added to NHS at a final concentration of 30 mM. This nucleophile did not interact with native C3 or C4, nor did it directly activate C1. However, upon the addition of low doses of immune complexes, acetyl tyrosine did yield uncontrolled C1 activation, presumably by binding nascent C3b and C4b and thereby blocking their attachment to the immune complexes. We conclude that in NHS there is a mechanism of feedback inhibition by which nascent C3b and C4b inhibit C1 turnover by immune complexes. This mechanism of control might be physiologically important in that it prevents excessive complement activation by low concentrations of immune complexes.

Antigen-Antibody Complex↗

PubMed1992

Regulation of complement activity by vaccinia virus complement-control protein.

A major protein secreted by vaccinia virus-infected cells has structural similarity to the super-family of complement-control proteins. This vaccinia complement-control protein (VCP) was studied to determine how it regulates complement activation. VCP was bound by C4b and C3b and served as a cofactor with factor I in cleaving these two molecules. VCP inhibited the formation and accelerated the decay of the classical C3 convertase. It also accelerated decay of the alternative pathway convertase, although higher concentrations were apparently needed. In vitro, therefore, VCP interfered with the classical and alternative complement pathways at several steps. In vivo, this interference may increase the virulence of vaccinia virus by enabling it to escape attack by the host's complement system.

Complement Activation↗

PubMed1999

Control of C3b and C5b deposition by CD46 (membrane cofactor protein) after alternative but not classical complement activation.

C3b and C5b deposition following complement activation, and its regulation by CD46 were studied using xenogenic Chinese hamster ovary (CHO) cells as targets and cytofluorometry. Following activation of the alternative pathway, an initial low level of C3b deposition was observed on CHO cell surfaces after a lag time of approximately 4 min. This was followed by a secondary high level of C3b deposition with a slower rate. C3b deposition was maximal within 15 min. When CD46 was expressed (B2 isoform), the kinetics of C3b deposition were essentially unchanged, but the onset of the secondary high C3b deposition was fully prevented. C5b deposition was also observed on CHO but not on CHO.CD46 cells following activation of the alternative pathway. Activation of the classical pathway on CHO and CHO.CD46 cells, using factor B-depleted human serum and anti-CHO antibodies, resulted in almost identical single-peak C3b deposition profiles. Accordingly, no regulation of C5b deposition by CD46 was evident following activation of the classical pathway. These data indicate that CD46 prevents the C3b deposition amplification loop mediated by the alternative C3 convertase and, consequently, inhibits the formation of the alternative C5 convertase. But CD46 prevents neither the spontaneous tick-over C3b deposition leading to the formation of the alternative C3 convertase nor the formation of the functional classical C3 and C5 convertases.

Animals↗

PubMed1987

The mechanism of action of decay-accelerating factor (DAF). DAF inhibits the assembly of C3 convertases by dissociating C2a and Bb.

DAF is a 70,000-Mr membrane protein that inhibits the amplification of the complement cascade on the cell surface, and protects cells from damage by complement. The precise mechanism of action of DAF is not entirely clear. Purified DAF was incorporated into the membrane of EAC4b cells. EAC4b2 and EDAF AC4b2 cells were prepared with radiolabeled C2. The same amount of labeled C2 bound to both cells, showing that DAF does not prevent the binding of C2 zymogen to C4b. After adding Cl, the radioactivity of bound C2 dissociated more rapidly from EDAF AC4b cells than from EAC4b cells. In EAC4b cells, bound C2 was converted to C2a, which gradually dissociated into the supernatants. In the DAF-treated cells, on the other hand, a large amount of C2a rapidly appeared in the supernatants and only a small amount of C2a remained on the cells. In a similar experiment using EhuAC4b, DAF on human erythrocyte membrane also dissociated the C2a from the cells. These results were confirmed by hemolytic assay and the accelerated decay of C2a caused the rapid depletion of C2 from the fluid phase. In addition, we found that DAF functions on the alternative pathway C3 convertase, C3bBb in the same manner. Thus, DAF, which associates with C4b and C3b in the membrane, acts on C2a and Bb, but not on intact C2 and B, and dissociates them rapidly from the binding sites, thereby preventing the assembly of the classical and alternative pathways C3 convertases.

Animals↗

PubMed1988

Detection of the terminal complement complex in patient plasma following acute myocardial infarction.

The mechanisms of inflammation responsible for the myocardial tissue damage seen after an acute myocardial infarction (AMI) have not been clearly identified. Recent lines of evidence, demonstrating depressed sera levels of individual complement components in patients after myocardial infarction, have suggested involvement of the complement (C) system in micro- and macrovascular injury subsequent to AMI. The present study assessed the role of complement as a mediator of myocardial inflammation by quantifying products of complement activation including, the terminal complement complex (TCC) the cytolytic component of the complement system, C1rC1s-C1 inhibitor complex and C3bBbP complex, formed following activation of the classical and alternative pathway, respectively, and anaphylatoxins C3a and C5a in 41 patients following AMI. Plasma TCC and C1rC1s-C1 inhibitor complex concentrations increased up to 32-fold (P less than 0.001) and 8-fold (P less than 0.001), respectively, while the C3bBbP complex, C3a des-Arg and C5a des-Arg each increased over 2-fold (P less than 0.001) 16 h after AMI, and were only minimally detectable during non-inflammatory myocardial conditions. Furthermore, TCC concentrations increased over 150% (P less than 0.001) one day after patients reinfarcted, subsequent to hospitalization for a primary AMI. These results demonstrate activation of complement after AMI and suggest that inflammatory mediators of the complement system may contribute to myocardial tissue damage during the infarction process.

Adult↗

PubMed1988

Complement activation occurs through both classical and alternative pathways prior to onset and resolution of adult respiratory distress syndrome.

We have previously reported that plasma concentrations of the terminal complement (C) complex (TCC), C5b-9, increased significantly 2 days prior to onset of adult respiratory distress syndrome (ARDS) and also 1 day preceding its resolution. To determine the pathway of complement activation that preceded development and resolution of this acute inflammatory lung injury in septic patients, we quantified the C1rC1s-C1 inhibitor complex and the C3bP complex, which are generated following activation of classical and alternative complement pathways, respectively. Two days prior to diagnosis of ARDS, the plasma C1rC1s-C1 inhibitor complex and C3bP complex levels increased 22 and 14%, respectively. Furthermore, significant correlations were identified between concentrations of the TCC and C1rC1s-C1 inhibitor complex (r = 0.73, P = 0.003) and also with the levels of the TCC and C3bP complex (r = 0.81, P = 0.002) before onset of ARDS. Equally of interest, the C1rC1s-C1 inhibitor complex and C3bP complex concentrations increased 68 and 35%, respectively, 1 day before resolution of ARDS. Similarly, significant elevations of TCC concentrations preceding resolution of ARDS correlated with C1rC1s-C1 inhibitor complex (r = 0.66, P = 0.02) and also with C3bP complex (r = 0.72, P = 0.002) levels. Our results indicate that both the classical and alternative complement pathways are activated prior to onset of ARDS and also before its resolution in septic patients.

Complement Activating Enzymes↗

PubMed2002

Structural aspects and design of low-molecular-mass complement inhibitors.

We present a mini-review on the structure-based design of three promising complement inhibitors. Firstly, we review compstatin, a 13-residue cyclic peptide that binds to C3 and inhibits the cleavage of C3 to C3a and C3b. Secondly, we review a six-residue cyclic peptide that binds to C5aR and antagonizes the binding of C5a to its receptor C5aR. Finally, we review three small molecules that bind to Factor D and inhibit the enzymic action of Factor D, during which Factor D proteolytically cleaves Factor B in complex with C3 or C3b.

Animals↗

PubMed1996

Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library.

We have screened a phage-displayed random peptide library for binding to C3b, the proteolytically activated form of complement component C3, and have identified a novel peptide that suppresses complement activation. This phage-displayed peptide bound to C3, C3b, and C3c, but not to C3d, indicating that it binds to the C3c region of C3. A synthetic 27-amino acid peptide corresponding to the phage-displayed peptide also bound to C3 and C3 fragments and inhibited both the classical and alternative pathways of complement activation. The inhibition of complement activation was reversible. Studies with overlapping peptides indicated that the functional activity was located in the cyclic 13-amino acid N-terminal region (ICVVQDWGHHRCT) of the parent peptide. Reduction and alkylation of this 13-residue synthetic peptide destroyed its inhibitory activity. Analysis of the mechanism of inhibition revealed that the peptide inhibited C3 cleavage in normal human serum as well as when the alternative pathway was reconstituted with purified complement components, and the observed inhibition was not due to sterically hindered access to the C3a/C3b cleavage site. Further, the peptide did not inhibit the cleavage of factor B, indicating that it did not affect the interaction of CA with factor B or the formation of C3b,Bb. The peptide also had no effect on the binding of properdin to C3, demonstrating that the observed inhibition of C3 cleavage in normal human serum was not due in part to its effect on the properdin-stabilized C3 convertase, C3b,Bb,P. These results indicate that the peptide we have identified interacts with C3 to inhibit its activation.

Amino Acid Sequence↗

PubMed1981

Nucleophilic modification of human complement protein C3: correlation of conformational changes with acquisition of C3b-like functional properties.

Inactivation of C3 by enzymatic cleavage, nucleophilic addition, or slow freezing and thawing resulted in the acquisition of similar end-state conformations as judged by near-UV circular dichroism. Although inactivation by the two nonenzymatic processes involves no peptide bond scission, the inactivated C3 resembled C3b in that it possessed a free sulfhydryl group not present in the native protein and an increased surface hydrophobicity as evidenced by enhanced binding of the fluorophore 8-anilino-1-naphthalensulfonate (ANS). The C3b-like functional properties of modified C3 [Pangburn, M. K., & Müller-Eberhard, H. J. (1980) J. Exp. Med. 152, 1102-1114] may thus be understood in terms of the similarity of its conformation to that of C3b. The rate of the conformational change following proteolytic cleavage was fast and appeared to be limited by the rate of the enzymatic reaction. In contrast, the rate of conformational change following addition of methylamine was slow and rate limited by the conformational rearrangement itself, not by the chemical modification. A kinetic analysis of the changes in circular dichroism and ANS fluorescence enhancement suggested that the nucleophilic addition was spectroscopically undetectable and was followed by a minimally biphasic, spectroscopically demonstrable conformational rearrangement. The appearance of C3b-like functional activity in nucleophile-modified C3 largely parallels the time course of the spectroscopically detectable conformational change but is distinctly slower than the rate at which hemolytic activity is lost. While fully transconformed methylamine-inactivated C3 can bind factor B and is susceptible to cleavage by C3b inactivator and its cofactor beta 1H, this cleavage occurs at a substantially slower rate than the equivalent process in C3b. The implications of these findings in terms of the mechanism through which the alterative pathway of complement is initiated are discussed.

Anilino Naphthalenesulfonates↗

PubMed1990

Regulatory system of guinea-pig complement C3b: two factor I-cofactor proteins on guinea-pig peritoneal granulocytes.

Complement factor I is a plasma protease serving for proteolytic inactivation of C3b together with its cofactor. We have identified two factor I-cofactor activities in solubilized extracts of guinea-pig peritoneal granulocytes using guinea-pig factor I (Igp) and fluorescent-labeled methylamine-treated guinea-pig C3 (f-C3(MA)gp). One of these eluted from a chromatofocusing column between pH 7.6-7.1, and the other at about pH 5.7. These two cofactor fractions both interacted with Igp and, to a lesser degree, with human factor I (Ihu) on C3(MA)gp cleaving it into an inactive C3bi analogue, but did not cleave methylamine-treated human C3 (C3(MA)hu) together with Igp or Ihu. These factors are therefore species specific. The neutral and acidic fractions with cofactor activity contained C3(MA)gp-binding proteins with a doublet of 55 kDa and 42 kDa, and a singlet of 160 kDa, respectively, on SDS-PAGE. These proteins may be membrane cofactor protein (MCP) and C3b/C4b receptor (CR1) of guinea-pigs.

Animals↗

PubMed2005

Hemolytic uremic syndrome: an example of insufficient complement regulation on self-tissue.

Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS is classified as either diarrhea associated, most commonly caused by infection with Escherichia coli O157, or the less common atypical HUS (aHUS), which may be familial or sporadic. Approximately 50% of patients with aHUS have mutations in one of the complement control proteins: factor H, factor I, or membrane cofactor protein (MCP). These proteins regulate complement activation through cofactor activity, the inactivation of C3b by limited proteolytic cleavage, a desirable event in the fluid phase (no target) or on healthy self-tissue (wrong target). Complement activation follows the endothelial cell injury that characterizes HUS. This disease represents a model of what takes place when inappropriate complement activation occurs on self-tissues due to the presence of mutated complement regulatory proteins. Screening for mutations in factor H, factor I, or MCP is expensive and time consuming. One approach is to perform antigenic screening for factor H and factor I deficiency and to look for low levels of MCP (CD46) expression by flow cytometry. Complement regulatory protein deficiency impacts treatment decisions as patients with aHUS have a recurrence rate in renal transplants of approximately 50%, whereas those with factor H mutations have an even higher risk (approximately 80%). By contrast, MCP deficiency can be corrected in part by a renal allograft. However, caution in the use of live-related donations is needed because of the high rates of incomplete penetrance of the described mutations.

Complement Activation↗

PubMed1989

Killing of human tumor cells by antibody C3b conjugates and human complement.

To potentiate the lytic action of complement on tumor cells, we have constructed heteroconjugates composed of monoclonal antibody and of the human C3b component of complement. The conjugates were formed efficiently using the heterobifunctional cross-linking reagent SPDP. The monoclonal antibody-C3b conjugate promoted the killing of K562 tumor cells by normal human serum. Treatment of the tumor cells with the monoclonal antibody and normal human serum resulted in 10-15% lysis. However, following pretreatment of the cells with antibody-C3b conjugates, their lysis by normal human serum increased to 70%. The conjugate activated selectively the alternative pathway of complement and the C3b component in the conjugate was highly resistant to cleavage and inactivation by the complement regulatory proteins Factors H and I. These results suggest that the coupling of C3b molecules to monoclonal antibodies anti-unique tumor antigens produces a potent complement-activating reagent which may act specifically on tumor cells and promote cancer therapy.

Antibodies, Monoclonal↗

PubMed2002

Variola virus immune evasion design: expression of a highly efficient inhibitor of human complement.

Variola virus, the most virulent member of the genus Orthopoxvirus, specifically infects humans and has no other animal reservoir. Variola causes the contagious disease smallpox, which has a 30-40% mortality rate. Conversely, the prototype orthopoxvirus, vaccinia, causes no disease in immunocompetent humans and was used in the global eradication of smallpox, which ended in 1977. However, the threat of smallpox persists because clandestine stockpiles of variola still exist. Although variola and vaccinia share remarkable DNA homology, the strict human tropism of variola suggests that its proteins are better suited than those of vaccinia to overcome the human immune response. Here, we demonstrate the functional advantage of a variola complement regulatory protein over that of its vaccinia homologue. Because authentic variola proteins are not available for study, we molecularly engineered and characterized the smallpox inhibitor of complement enzymes (SPICE), a homologue of a vaccinia virulence factor, vaccinia virus complement control protein (VCP). SPICE is nearly 100-fold more potent than VCP at inactivating human C3b and 6-fold more potent at inactivating C4b. SPICE is also more human complement-specific than is VCP. By inactivating complement components, SPICE serves to inhibit the formation of the C3/C5 convertases necessary for complement-mediated viral clearance. SPICE provides the first evidence that variola proteins are particularly adept at overcoming human immunity, and the decreased function of VCP suggests one reason why the vaccinia virus vaccine was associated with relatively low mortality. Disabling SPICE may be therapeutically useful if smallpox reemerges.

Amino Acid Sequence↗