118 The dense glycan shield on the HIV envelope: the Achilles heel of the virus?

The envelope gp120 of HIV contains an unusual high amount of N-glycans that serves as a dense shield to hide immunogenic epitopes on gp120 against the immune system. There exists a wide variety of glycan-binding agents with different specificities to recognize carbohydrate moieties present on the HIV envelope. Several of the carbohydrate-binding agents (CBA) are potent inhibitors of at least 4 different pathways of HIV to infect virus-susceptible cells and to be transmitted to virus-exposed individuals. These CBAs have been demonstrated (1) to inhibit cell-free virus infection of CD4+ T-lymphocytes and macrophages, (2) to block syncytia formation between persistently HIV-infected (gp120-expressing) cells and uninfected cells, (3) to prevent virus capture by DC-SIGN-expressing cells and (4) to block transmission of DC-SIGN-captured virus particles to uninfected CD4(+) T-lymphocytes. CBAs represent the only agents reported to be able to concomitantly interact with these 4 processes, which can be advantageous from a microbicide perspective. Interestingly, CBA drug pressure in cell culture forces the virus to select for mutant variants that have multiple N-glycan deletions in their envelope, and thus, to uncover immunogenic epitopes on gp120. Accumulation of such envelope mutations compromises the infectivity of the virus. Several gp120 antibodies show a markedly increased activity against such mutant viruses. CBAs may, therefore, represent an entirely novel therapeutic concept in that they inhibit virus entry into its susceptible cells, and prevent DC-SIGN-directed virus transmission, but in addition, they may trigger the host immune system as soon as drug-related (N-glycan) mutations appear in the viral envelope.