Abstract
Broad and potent neutralizing llama single domain antibodies (VHH) against HIV-1 targeting the CD4 binding site (CD4bs) have previously been isolated upon llama immunization. Here we describe the epitopes of three additional VHH groups selected from phage libraries. The 2E7 group binds to a new linear epitope in the first heptad repeat of gp41 that is only exposed in the fusion-intermediate conformation. The 1B5 group competes with co-receptor binding and the 1F10 group interacts with the crown of the gp120 V3 loop, occluded in native Env. We present biophysical and structural details on the 2E7 interaction with gp41. In order to further increase breadth and potency, we constructed bi-specific VHH. The combination of CD4bs VHH (J3/3E3) with 2E7 group VHH enhanced strain-specific neutralization with potencies up to 1400-fold higher than the mixture of the individual VHHs. Thus, these new bivalent VHH are potent new tools to develop therapeutic approaches or microbicide intervention.
Highlights
AIDS remains one of the largest global health problems and annually an estimated 1.8 million people die an AIDS related death
We have selected over 100 different HIV-1 neutralizing VHH starting with various immune libraries (Most important data summarized in Figures 1 and 2) [15,16,17,21,26]
Preliminary evidence indicated that a number of the selected VHH do not compete with J3 or 3E3 [19]
Summary
AIDS remains one of the largest global health problems and annually an estimated 1.8 million people die an AIDS related death. The variable domains of the heavy chain of heavy chain only antibodies (VHH) derived from llamas or other Camelidae may be better alternatives, as they can be produced relatively cheaply in microorganisms like bacteria or yeast [13] and are often stable at high temperatures [14]. This is predominantly related to their small size, which is a 10-fold smaller than that of a conventional antibody. Their small size and more than average length of CDR 3 allows them to bind to recessed epitopes, like the CD4 binding site (CD4bs) of HIV-1
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