Identifizierung der Regulationsmechanismen von HIV-reaktiven Antikörpern während der humanen B-Zell Entwicklung
Final Report Abstract
Human monoclonal antibodies to HIV can neutralize a broad range of viral isolates and protect non-human primates against infection. These antibodies neutralize HIV by targeting one of several different epitopes on the viral spike and therefore are of great importance for HIV-1 vaccine design. bNAbs are found in only a fraction of patients and more importantly it takes several years until they develop. A possible explanation for this long period of time between HIV-1 infection and the presence of bNAbs might result from requirement of many mutations in the so called framework regions of the antibody that is more resistant to the acquisition of mutations. Previous work showed that although antibodies can put selective pressure on the virus in passive transfer experiments, they do not suppress infection due to rapid mutation of HIV-1 and selection of antibody resistant variants. However, these experiments were performed before the recent discovery of more potent and broader anti-HIV-1 antibodies and their improvement by structure based rational design. We have re-examined passive transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody mono-therapy by specific mutation of antibody target sites, combinations of monoclonal antibodies control HIV-1 infection in hu-mice. Moreover, combinations of antibodies led to persistent viremic control up to an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies have longterm effects on the control of HIV-1 infection in hu-mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals.
Publications
- (2012) Broad neutralization by a combination of antibodies to the CD4 binding site and a new conformational epitope on the HIV envelope protein. J Exp Med, 209(8):1469-79
Klein F, Gaebler C, Mouquet H, Sather N, Lehmann C, Scheid JF, Kraft Z, Liu Y, Pietzsch J, Hurley A, Feizi T, Morris L, Walker BD, Fätkenheuer G, Seaman MS, Stamatatos L, Nussenzweig MC
(See online at https://doi.org/10.1084/jem.20120423) - (2012). HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature, 492(7427):118-22
Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF, Bournazos S, Mouquet H, Spatz LA, Diskin R, Abadir A, Zang T, Dorner M, Billerbeck E, Labitt RN, Gaebler C, Marcovecchio P, Incesu RB, Eisenreich TR, Bieniasz PD, Seaman MS, Bjorkman PJ, Ravetch JF, Ploss A, Nussenzweig MC
(See online at https://doi.org/10.1038/nature11604)
