Neutralizing Epitopes of HIV-1

Ideally, a vaccine against human immunodeficiency virus type 1 (HIV-1) would induce neutralizing antibody levels which would provide sterilizing immunity. The levels of antibody required however may not be achievable by vaccination (Gauduin et al., 1997; Parren et al., 1997; Moore and Burton, 1999; Shibata et al., 1999). Nevertheless, neutralizing antibody responses albeit of lesser, but still significant potency, will likely be essential in an HIV-1 vaccine in combination with broadly active cellular responses (Burton and Moore it et al., 1998). The necessity or benefit of stimulating B cells that produce neutralizing antibodies has been clearly established in murine infection models with retroviruses and other RNA viruses (Planz et al., 1997; Baldridge et al., 1997; Dittmer et al., 1998; Parren et al., 1999; Dittmer et al., 1999a; Dittmer et al., 1999b). Effective vaccines have been developed against a number of viral diseases mostly by using empirical methods. Many of these vaccines, including those against smallpox, measles and polio, consist of live attenuated viruses. Live attenuated viruses have consistently provided protection against infection with simian immunodeficiency virus (SIV) and SIV/HIV-1 chimeras in non-human primates. Serious safety concerns exist however which preclude the use of such vaccines in humans (Ezzel, 1997; Baba et al., 1999). The immune correlates of protection against infection of macaque monkeys by live attenuated SIV have not been clearly defined and the role of antibodies and cytotoxic T-lymphocytes (CTL) have been questioned (Stott and Schild, 1996; Stebbings et al., 1998). Protection against SHIV (SIV/HIV chimeras expressing HIV-1 envelope glycoprotein) by vaccination with attenuated SIV argues against a role of antibodies (Shibata et al., 1997; Wyand et al., 1999). A series of elegant experiments in which protective immune responses against the Friend retroviral complex were dissected however have shown that T cells (CD4+ and CD8+) and B cells are required to act in concert to achieve protection against pathogenic challenge in mice vaccinated with an attenuated retrovirus (Dittmer et al., 1999a). Furthermore, whereas CTL were required to protect against lethal infection, neutralizing antibody responses appeared necessary to prevent persistent infection (Dittmer et al., 1999b). Understanding neutralization of HIV-1 primary isolates is important for a knowledge-based approach for the development of a vaccine against HIV-1. Here we review HIV-1 neutralizing antibodies and their epitopes.