Estimating the Threshold Surface Density of Gp120-CCR5 Complexes Necessary for HIV-1 Envelope-Mediated Cell-Cell Fusion

by Shiva Naresh Mulampaka, Narendra M. Dixit

Reduced expression of CCR5 on target CD4⁺ cells lowers their
susceptibility to infection by R5-tropic HIV-1, potentially preventing
transmission of infection and delaying disease progression. Binding of the HIV-1
envelope (Env) protein gp120 with CCR5 is essential for the entry of R5 viruses
into target cells. The threshold surface density of gp120-CCR5 complexes that
enables HIV-1 entry remains poorly estimated. We constructed a mathematical
model that mimics Env-mediated cell-cell fusion assays, where target
CD4⁺CCR5⁺ cells are exposed to effector
cells expressing Env in the presence of a coreceptor antagonist and the fraction
of target cells fused with effector cells is measured. Our model employs a
reaction network-based approach to describe protein interactions that precede
viral entry coupled with the ternary complex model to quantify the allosteric
interactions of the coreceptor antagonist and predicts the fraction of target
cells fused. By fitting model predictions to published data of cell-cell fusion
in the presence of the CCR5 antagonist vicriviroc, we estimated the threshold
surface density of gp120-CCR5 complexes for cell-cell fusion as ∼20
µm⁻². Model predictions with this
threshold captured data from independent cell-cell fusion assays in the presence
of vicriviroc and rapamycin, a drug that modulates CCR5 expression, as well as
assays in the presence of maraviroc, another CCR5 antagonist, using sixteen
different Env clones derived from transmitted or early founder viruses. Our
estimate of the threshold surface density of gp120-CCR5 complexes necessary for
HIV-1 entry thus appears robust and may have implications for optimizing
treatment with coreceptor antagonists, understanding the non-pathogenic
infection of non-human primates, and designing vaccines that suppress the
availability of target CD4⁺CCR5⁺ cells.

For the full article visit: Estimating the Threshold Surface Density of Gp120-CCR5 Complexes
Necessary for HIV-1 Envelope-Mediated Cell-Cell Fusion
Syndicated from:PLoS ONE

Article is licensed under a Creative Commons Attribution License.