C4: Einfluss der N-Glycosylierung der Hüllproteine der HIVSubtypen A, B und C auf die Infektiosität und die Interaktion mit viralen Rezeptoren und Glycoproteinen auf Zellmembranen
Binding of HIV-1 gp120 to the coreceptor molecules CCR5 or CXCR4 is necessary for infection of CD4+ cells. During binding the V3 loop region, a heavily glycosylated hypervariable domain of the gp120 protein, interacts with the N-terminal region of the coreceptors. In this project we investigate the role of the V3 loop based N-glycans for CCR5 and CXCR4 interaction. Besides their role for coreceptor binding, the V3 loop based N-glycans are shielding the V3 loop against neutralizing antibodies. Thus, V3 based N-glycans might have two functions (i) masking the V3 loop to prevent binding of neutralizing antibodies and (ii) modulation of the gp120--coreceptor interaction.
To investigate the role of N-glycans in the V3 loop region we constructed mutants of R5, X4 and R5X4 tropic HIV-1 strains differing in the presence of N-glycosylation sites. First results demonstrated that those mutants lacking carbohydrates g15, a glycosylation site within the V3 loop, showed markedly higher infectivity for CXCR4+ cells. In addition, the lack of the g15 N-glycan promotes sensitivity against neutralizing antibody. In contrast, mutants containing g15 were resistant to antibody neutralization and showed lower infectivity rates on CXCR4+ cells. Thus N-glycans play a pivotal role in the interaction of HIV with its cellular receptors and in the defense against neutralizing antibodies.
Contact:
Dr. Michael SchreiberAddress:
Bernhard-Nocht-Institut für Tropenmedizin
Bernhard-Nocht-Str. 74
20359 Hamburg
Telefon: 040-42818 461
Telefax: 040-42818 378
E-Mail: Michael.Schreiber@bni.uni-hamburg.de
http://www.bni.uni-hamburg.de/