Charge Discriminates Coreceptor Selectivity for HIV-1

We have performed physicochemical and statistical analysis of a large dataset of sequences of the V3 loop of the glycoprotein gp120 from HIV-1 strains with known coreceptor selectivity, derived from patient data. The entry of HIV-1 into host cells is mediated by the interaction of the V3 loop of gp120 and coreceptors CCR5 and CXCR4 on host cell surfaces, with the aid of viral protein gp41 and cell receptor CD4. The choice of CCR5 for viral entry is associated with the asymptomatic cell infection, whereas the choice of CXCR4 is associated with progression to disease. Given the sequence and structural variability of the V3 loop, we have searched for persistent physicochemical properties that may be mediators of coreceptor selectivity and binding using the Los Alamos HIV Databases [1]. Our electrostatic analysis demonstrates that charge is the dominant factor that mediates coreceptor selectivity, other factors being the N6XT/SX9 glycosylation motif and the 11/24/25 rule. We have examined amino acid propensities for each position of the V3 loop sequence and identified key amino acids and positions that may affect the coreceptor choice. We have studied the conformational variability of the V3 loop, using molecular dynamics simulations, and identified persistent intramolecular interactions that may be important for maintaining the electrostatic profile of the V3 loop that facilitates coreceptor binding. We have used a statistical model to estimate the probability for coreceptor selectivity, as a function of charge and presence or absence of glycosylation motif and 11/24/25 rule. We present an integrated predictive scheme of coreceptor selectivity and binding, which may be useful in estimating disease progression, and perhaps aiding in tailoring the selection of anti-HIV drugs for individual patients.[1] http://www.hiv.lanl.gov/content/index.