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Conformational properties of the third variable loop of HIV-1AD8 envelope glycoprotein in the liganded conditions.

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Takeda S, Takizawa M, Miyauchi K, Urano E, Fujino M, Murakami T, Murakami T, Komano J,


Takeda S, Takizawa M, Miyauchi K, Urano E, Fujino M, Murakami T, Murakami T, Komano J, (click to view)

Takeda S, Takizawa M, Miyauchi K, Urano E, Fujino M, Murakami T, Murakami T, Komano J,

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Biochemical and biophysical research communications 2016 5 10() pii 10.1016/j.bbrc.2016.05.051

Abstract

The conformational dynamics of the HIV-1 envelope glycoprotein gp120 and gp41 (Env) remains poorly understood. Here we examined how the V3 loop conformation is regulated in the liganded state using a panel of recombinant HIV-1NL4-3 clones bearing HIV-1AD8 Env by two experimental approaches, one adopting a monoclonal neutralizing antibody KD-247 (suvizumab) that recognizes the tip of the V3 loop, and the other assessing the function of the V3 loop. A significant positive correlation of the Env-KD-247 binding was detected between the liganded and unliganded conditions. Namely, the mutation D163G located in the V2 loop, which enhances viral susceptibility to KD-247 by 59.4-fold, had little effect on the sCD4-induced increment of the virus-KD-247 binding. By contrast, a virus with the S370N mutation in the C3 region increased the virus-KD-247 binding by 91.4-fold, although it did not influence the KD-247-mediated neutralization. Co-receptor usage and the susceptibility to CCR5 inhibitor Maraviroc were unaffected by D163G and S370N mutations. Collectively, these data suggest that the conformation of the liganded V3-loop of HIV-1AD8 Env is still under regulation of other Env domains aside from the V3 loop, including V2 and C3. Our results give an insight into the structural properties of HIV-1 Env and viral resistance to entry inhibitors by non-V3 loop mutations.

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