Background:  After crossing monolayer mucosa, HIV-1 particles may directly infect target cells or be taken up by dendritic cells (DC) via DC-SIGN for further eventual trans-infection. The involvement of this mechanism in the selection of specific viral strains remains unclear. Our hypothesis is that, upon selection by DC-SIGN, expansion of viral quasi-species occurs, leading to the colonization of other lymphoid tissues including GALT. We have studied the behavior of different HIV-1 Env sequences in the multi-step process of the DC-SIGN transmission pathway taking in consideration the homo/heterosexual routes of contamination and the variety of sub-types.

Methods:  We used HIV-1 sequences from 17 acute infection samples before seroconversion, covering 6 different subtypes (10 B, 2 CRF02-AG, 1 K/J, 2 G, 1 F1, and 1 CRF01-AE) and homosexual (7) and heterosexual (10) routes. The env gene of 2 clones/sample was tested for its fusion capacity and selectively expressed at the surface of pseudoparticles. All our assays were normalized upon gp120 quantity allowing the specific study of the glycoprotein functionality in the different interactions with DC-SIGN, represented by binding, internalization and transmission.

Results:  Differences between Env proteins in fusion, binding, internalization, and transmission capacities were observed independently of the contamination routes and the subtypes. These differences were also observed within 1 sample, highlighting that only a specific viral strain could be transmitted via this route. Binding to DC-SIGN did not involve systematically internalization, suggesting that transmission may occur without internalization. When pseudo-particles were internalized, about 50% remained in the cytoplasm and 50% within vesicles reducing viral degradation, except for 2 clones which pseudo-particles were mainly found within vesicles. Of these 2 clones, 1 showed resistance to high concentration of lactoferrin, whereas the binding of the others was inhibited, and was also the 1 at best transmitted to indicator cells.

Conclusions:  There are inter- and intra-sequence variations in the behavior of gp120 from acute infection in the interactions with DC-SIGN, suggesting that selection of a specific viral strain among a quasi-species may occur at different steps. This study has allowed us to select 2 clones of interest:  1 with a high affinity to DC-SIGN without internalization, and 1 efficiently transmitted and with a high resistance to potential microbicides.