HIV vaccine design: the neutralizing antibody conundrum.

A brief historical overview of anti-HIV vaccine approaches The identification of the human immunodeficiency virus as the causative agent of AIDS [1–4] was followed by intensive efforts to develop a vaccine against this pathogen. Initial vaccine approaches aimed at the elicitation of anti-viral neutralizing antibodies (NAbs). The sole target of anti-HIV NAbs is the viral envelope glycoprotein (Env), which is comprised of two non-covalently associated subunits: a transmembrane subunit (gp41) and an extracellular subunit (gp120). The functional unit of the HIV Env is a trimer of gp120/gp41 heterodimers. Various recombinant forms of Env have been tested as vaccines to elicit NAbs. Such proteins are immunogenic and they do elicit anti-HIV antibody responses that can neutralize laboratory-adapted HIV-1 isolates, or unusually easy to-neutralize circulating primary isolates. Numerous animal studies and a few clinical trials with recombinant gp120 proteins indicated however that such constructs inefficiently elicit NAbs against a wide range of circulating primary HIV-1 isolate with more typical HIV neutralization phenotypes [5] (and also see reviews [6,7]). In fact, for many years it was thought that NAbs against primary HIV-1 isolates are very rarely developed even during natural HIV-1 infection and that it would therefore be extremely difficult to elicit such antibodies by immunization. As a result, the HIV vaccine field focused on the development of T cell-based vaccines, since HIV-specific CD8+ T cell responses can control viral replication during infection [8,9].