Humoral immunity arising after primary infection with HIV-1 may not prevent progression to AIDS (R. A. Koup et al., Nature, 370:416 (1994); R. A. Koup et al., J. Virol. 68:4650-5 (1994)). However, it is likely that humoral immunity can prevent infection if an individual has high-titered neutralizing antibodies prior to exposure to the virus. This concept is largely supported by passive immunization studies in which chimps were transfused with neutralizing anti-V3 monoclonal antibodies or pooled, high-titered neutralizing antisera around the time of challenge with cell-free virus (E. A. Emini et al., Nature: 355:728-30 (1992); R. Shibata et al., Nat. Med., 5:204-10 (1999)). Protection was obtained in both sets of studies, indicating that humoral immunity can be protective provided the right antibodies are present in sufficient titers at the time of challenge or shortly thereafter.
Additional studies suggest that humoral immunity can be protective against HIV-1. For example, passive immunization using the SCID-hu mouse system have shown that human monoclonal antibodies specific for the CD4 binding domain of gp120 can prevent infection (M. C. Gauduin et al., Nat. Med., 3: 13 89-93 (1997); P. W. Parren et al., AIDS, 9:F 1-6 (1995)). It has been further shown that passive transfer of a bivalent CD4-Ig “immunoadhesin,” a chimera made between CD4 and the human IgG2 heavy chain, can protect in the HIV-1 chimp challenge system (J. W. Eichberg et al., AIDS Rex Hum. Retroviruses, 8: 15 15-9 (1992); R. H. Ward et al., Nature, 352:434-6 (1991)). Additionally, neutralizing antibodies correlate strongly with protective immunity against SIV (J. L. Heeney et al., Proc. Natl. Acad. Sci. U.S.A., 95: 10803-8 (1998)). Still further, passive transfer studies in rhesus macaques showed that high-titered chimp antibodies specific for the HIV-1DH12 isolate, provided sterilizing immunity in rhesus macaques against SHIVDH12 if a sufficient concentration of the antibodies was used (R. Shibata et al., Nat. Med., 5:204-10 (1999)). Aso, passive-transfer experiments in rhesus macaques using HIVIg, 2G12, and 2F5 demonstrated 50% better protection in recipient groups compared to non-recipient controls against challenge with SHIV-89.6P (Mascola et al., J. Virol., 73:4009-18 (1999)).
These studies support the idea that immunization strategies which elicit persistent, high-titered (or highly effective) neutralizing antibody responses of broad specificity may be protective. A successful strategy to reach this goal has been elusive. The subunit formulations of recombinant monomeric or oligomeric HIV envelope that have been tested elicit neutralizing responses against a narrow range of isolates (J. P. Moore et al., AIDS, 9:S117-136 (1995); Q. J. Sattentau, Curr. Opin. Immunol., 8:540-5 (1996); R. Wyatt et al., Science, 280:1884-8 (1998)).