Abstract
The third variable region (V3) of the human immunodeficiency virus type 1 (HIV-1) envelope gp120 subunit participates in determination of viral infection coreceptor tropism and host humoral immune responses. Positive charge of the V3 plays a key role in determining viral coreceptor tropism. Here, we examined by bioinformatics, experimental, and protein modelling approaches whether the net positive charge of V3 sequence regulates viral sensitivity to humoral immunity. We chose HIV-1 CRF01_AE strain as a model virus to address the question. Diversity analyses using CRF01_AE V3 sequences from 37 countries during 1984 and 2005 (n = 1361) revealed that reduction in the V3's net positive charge makes V3 less variable due to limited positive selection. Consistently, neutralization assay using CRF01_AE V3 recombinant viruses (n = 30) showed that the reduction in the V3's net positive charge rendered HIV-1 less sensitive to neutralization by the blood anti-V3 antibodies. The especially neutralization resistant V3 sequences were the particular subset of the CCR5-tropic V3 sequences with net positive charges of +2 to +4. Molecular dynamics simulation of the gp120 monomers showed that the V3's net positive charge regulates the V3 configuration. This and reported gp120 structural data predict a less-exposed V3 with a reduced net positive charge in the native gp120 trimer context. Taken together, these data suggest a key role of the V3's net positive charge in the immunological escape and coreceptor tropism evolution of HIV-1 CRF01_AE in vivo. The findings have molecular implications for the adaptive evolution and vaccine design of HIV-1.
Highlights
The third variable region (V3) of human immunodeficiency virus type 1 (HIV-1) envelope gp120 subunit participates in determination of viral infection coreceptor tropism [1,2]
We demonstrate by combining bioinformatics, experimental, and protein modelling approaches that the reduction in net positive charge of HIV-1 CRF01_AE V3 sequence reduces viral sensitivity to humoral immunity and simultaneously confers viral chemokine receptor 5 (CCR5) tropism
A previous case study has suggested that a group of CRF01_AE V3 sequences for the viral CCR5 tropism is resistant to the selective force for amino acid variation [29,30]
Summary
The third variable region (V3) of human immunodeficiency virus type 1 (HIV-1) envelope gp120 subunit participates in determination of viral infection coreceptor tropism [1,2]. It is usually composed of 35 amino acids, which form a loop-like structure on the gp120 monomer [3,4]. The V3 and the conserved outer domain of gp120 create the binding surface for viral infection coreceptors after the binding of gp120 to the primary infection receptor CD4 [4,5] These interactions and successive conformational changes of gp120 are essential in rendering the initially occluded hydrophobic domain of the envelope gp subunit available to fusion with cellular plasma membrane. The two most common types of infection coreceptors in humans are the CC chemokine receptor 5 (CCR5)
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