Passive administration of specific antibody can protect against disease caused by viruses such as polio, measles, rubella, varicella, hepatitis A and hepatitis B. While antibody alone may not protect against HIV-1 infection, the investigators hypothesize that pre-existing antibody in systemic and mucosal compartments may be an important component of protection against transmission of HIV-1. The lack of an animal challenge model for HIV-1 that readily supports replication of primary isolates and simulates the physiology of sexual HIV-infection has made it difficult to perform passive transfer studies that would elucidate humoral correlates of protection. An additional obstacle is that few available antibodies appear capable of potent neutralization of primary HIV-1 isolates. The investigators have recently demonstrated that three antibody reagents (a polyclonal HIVIG and human Mabs 2F5 and 2G12) each neutralize primary HIV-1 strains and together, display synergistic neutralizing activity. They propose to study the efficacy of passive administration of these antibodies (alone or in combination) in preventing macaque infection by a SHIV containing the HIV-1 envelope of a primary isolate (SHIV-89.6). Experiments will include intravenous and intravaginal challenge, and in-vivo protection will be correlated to measured levels of serum and mucosal HIV-specific antibody. Particular emphasis will be placed on the intravaginal challenge system as a model of sexual transmission of HIV-1. The main objectives are to evaluate the protective efficacy of passively transferred antibody and to understand the humoral immune correlates of protection. In addition, since genital tract dendritic cells are likely initial targets of HIV-1 infection, the investigators will perform neutralizing antibody assays using skin and blood derived dendritic cells as targets of HIV-1 infection.
Specific Aim 1. Develop in-vitro assays that can measure antibody-mediated virus neutralization from serum and muscosal specimens using human dendritic cells as targets of HIV-1 infection.
Specific Aim 2. Evaluate the in-vivo efficacy of passive administration of anti-HIV-1 antibody combinations in protection of rhesus macaques against intravenous and muscosal SHIV challenge.
Specific Aim 3. Correlate in-vivo protection from SHIV challenge with serum and muscosal antibody levels.
| Mascola, John R; Lewis, Mark G; VanCott, Thomas C et al. (2003) Cellular immunity elicited by human immunodeficiency virus type 1/ simian immunodeficiency virus DNA vaccination does not augment the sterile protection afforded by passive infusion of neutralizing antibodies. J Virol 77:10348-56 |
| Kim, J H; Mascola, J R; Ratto-Kim, S et al. (2001) Selective increases in HIV-specific neutralizing antibody and partial reconstitution of cellular immune responses during prolonged, successful drug therapy of HIV infection. AIDS Res Hum Retroviruses 17:1021-34 |
| Mascola, J R; Lewis, M G; Stiegler, G et al. (1999) Protection of Macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J Virol 73:4009-18 |
| Frankel, S S; Steinman, R M; Michael, N L et al. (1998) Neutralizing monoclonal antibodies block human immunodeficiency virus type 1 infection of dendritic cells and transmission to T cells. J Virol 72:9788-94 |
