Enhancement of anti-DIII antibodies by the C3d derivative P28 results in lower viral titers and augments protection in mice

West Nile virus (WNV) is a single-stranded positive polarity enveloped RNA virus and member of the Flavivirus genus of the Flaviviridae family. The genome (11 kb) encodes for three structural proteins (Capsid [C] [1], pre-membrane [prM] that is cleaved to form a mature membrane [M] [2] and Envelope [E] [1]) and seven nonstructural gene products (NS1, 2A, 2B, 3, 4A, 4B and 5). WNV is transmitted by mosquitoes and causes morbidity and mortality in birds, horses, and humans. Since 1999, there have been over 29,000 cases that reached clinical attention and resulted in greater than a thousand deaths http://www.cdc.gov/ncidod/dvbid/westnile/surv&control.htm webcite within the United States as reported to the Centers for Disease Control and Prevention. As the geographic distribution of this virus continues to expand, na？ve human populations are put at greater risk, making the need for a licensed vaccine and/or antiviral treatment pressing [3].The host immune response is critical for limiting virus spread and disease. Results from genetically engineered mice indicate that both the innate (e.g., interferon) and the adaptive (B and T cells) immune responses control WNV infection [4]. The production of antibodies is essential to protection against WNV infection [5], and passive antibody transfer of anti-WNV neutralizing antibodies can prevent or treat lethal infection [6]. The primary target of the neutralizing antibody response is the E protein, which is the most accessible structural glycoprotein on the surface of the virion [7]. Structural analysis of the soluble ectodomain of flavivirus E proteins reveals three domains [8,9]. Domain I is an 8-stranded β-barrel that participates in the conformational changes associated with the acidification of the endosome. Domain II, which contains 12 β-strands, has important roles in dimerization, trimerization, and virus-mediated fusion [10-12]. Domain III adopts an immunoglobulin-like fold that contains the most distal projecting loops