Novel Hiv Neutralizing Antibodies Selected from Phage Display Libraries

Neutralizing antibodies play a major role in host defense against viral infections. Passive administration of antibodies specific for HIV-1 can protect monkeys from infections mediated by the HIV-1 envelope glycoprotein (Env) in a concentration dependent manner (Shibata et al., 1999; Baba et al., 2000; Ruprecht et al., 2001; Xu et al., 2002; Veazey et al., 2003; Burton, 2002; Ferrantelli and Ruprecht, 2002; Mascola et al., 1999; Mascola et al., 2000; Mascola, 2002; Parren et al., 2001). In some of these experiments human monoclonal antibodies (hmAbs) were used that exhibit potent and broad HTV neutralizing activity in vitro (Burton, 1997; Burton, 2002; Ferrantelli and Ruprecht, 2002). Recent clinical trials found that two of these broadly HIV neutralizing hmAbs (nhmAbs), 2F5 and 2G12, could produce a modest decrease in viral load without side effects in humans (Armbruster et al., 2002; Stiegler et al., 2002). However, the potency of 2F5 and 2G12 used in combination in this clinical trial was not sufficient to reduce the HIV-1 plasma RNA levels to the low levels observed after treatment with HAART (Stiegler et al., 2002). Increases in the potency of the currently available broadly HTV nhmAbs and the development of new neutralizing hmAbs might be helpful here although problems associated with neutralization escape are likely to be severe in any attempts to use antibodies therapeutically. Importantly, finding immunogens that are able to elicit broadly HIV nhmAbs could be facilitated by the exploration of the interaction of these antibodies with the Env-an approach known as “retrovaccinology” (Burton, 2002). However, only a few broadly cross-reactive HTV nhmAbs have been identified to date and efforts to use mimetics of their epitopes or portions of the epitopes as immunogens are ongoing but of limited success so far (Zwick et al., 2001a). The identification of new broadly cross-reactive HIV nhmAbs and their conserved epitopes is therefore of obvious importance for the development of effective HIV vaccines.