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    • Previously the N glycan in V of

    2021-06-10

    Previously, the N-glycan in V3 of HXB2, HXB10, LAI and BRU strains was reported to be dispensable for their infectivity to T cell lines, although detailed growth kinetics and experimental conditions were not described 4, 5, 6, 7, 8. The experiments appear to have been done by infection initiated with only a single virus dose that was not specified clearly. We have to note that differences between the wild-type and mutant viruses were not observed with higher input virus doses, suggesting that the effect of glycan removal would essentially be small in a single step replication, and become appreciable only after numerous rounds of replication. Even though small to a single replication cycle, the contribution of the glycan would be great enough to in vivo pathogenesis which involves persistence of highly active viral replications for a long period. It was previously noted that the N-glycosylation site in V3 is less conserved among T-tropic isolates than among M-tropic isolates [5]. This is apparently paradoxical if the N-glycan is important for CXCR-4- but not CCR-5-dependent entry as proposed in this study. However, inspection of V3 sequences revealed that the loss of the N-glycan is closely associated with a basic amino wnt substitution at the 11th position. Furthermore, the basic amino acid substitution at the 11th position in NL43HNT partially but significantly restored the infectious capacity. Therefore, the N-glycan in V3 seems to be dispensable only in the particular context of the peptide backbone, and plays an important role for CXCR-4-dependent membrane fusion when the 11th position of V3 is occupied by a non-basic residue. On the other hand, removal of the N-glycan from the V3 loop was reported to increase V3-specific antigenicity 5, 6, 7, 8. We could confirm this since the NL43HNT showed increased sensitivity to the V3-specific neutralizing monoclonal antibody 902 (data not shown). Back et al. [5]further raised the view that the N-glycan protects the V3 loop from attack by antibodies and hence is dispensable in patients with compromised immunity. However, in view of our present data showing a functional requirement of the glycan, the situation does not appear to be that simple. Their view may be applicable only to M-tropic strains whose N-glycan in V3 does not appear to be functionally important. The V3 loop was suggested to be involved in the gp120-co-receptor interaction 40, 41. Our present study demonstrated that there is a strain-specific requirement of the V3 glycan for this interaction. It is interesting but difficult to explain why and how the V3 glycan contributes to the infection process dependent on CXCR-4 but not CCR-5. It was previously reported that a subtle charge change in V3 of the T-tropic HIV-1 strain SF2 caused a drastic reduction of viral replicating capability in T cell lines, whereas the corresponding charge change in the M-tropic strain SF162 did not affect macrophage tropism [18]. It is thus possible that the V3 of T-tropic strains should be structurally more stringent for co-receptor recognition than that of M-tropic strains, and therefore the removal of N-glycan from the former could make an impact on virus-co-receptor interaction and infectivity. The N-glycan on V3 is supposed to be a complex type and thus negatively charged [1]. A single N-linked sugar chain possesses a molecular mass of 2000–3000. These physical and structural properties may somehow be required for V3 to fully interact with CXCR-4. However, the sugar chain may not be directly involved in the interaction, since a basic amino acid substitution at a nearby site partially compensated for the loss of the glycan. It is puzzling if the presence of a negative charge (in the glycan) and a basic amino acid substitution for a neutral nearby residue are both factors leading to upregulation of CXCR-4-dependent fusion. Increase of hydrophilicity is a common feature shared by both. V3 glycosylation and the basic amino acid substitution may thus facilitate V3 exposure for better interaction with CXCR-4. In any case, a basic amino acid substitution at the 11th position appears to be an apt change in vivo for this particular N-glycan-negative virus to acquire a sufficiently high infectivity or for the virus to evade clearance due to infectivity reduction caused by spontaneous removal of the glycan.