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Binding thermodynamics of the N-terminal peptide of the CCR5 coreceptor to HIV-1 envelope glycoprotein gp120.

ABSTRACT: The initial events of HIV-1 cell infection involve the sequential binding of the viral envelope glycoprotein gp120 to the cellular CD4 receptor and the coreceptor, usually CCR5 or CXCR4. Binding to the coreceptor triggers the chain of events that culminates with the entry of the virus into the cell. In this process, the interaction of gp120 with the tyrosine-sulfated N-terminus of CCR5 is critical; however, this interaction has never been characterized at a quantitative or thermodynamic level. Here, we present the first thermodynamic analysis of the interaction of gp120 with the N-terminal peptide of the CCR5 coreceptor. Microcalorimetric titrations demonstrate that measurable binding of S22 peptide, a 22-amino acid tyrosine-sulfated peptide corresponding to the CCR5 N-terminus, requires prior binding of CD4 to gp120. The S22 peptide binds to the gp120-CD4 complex with a binding affinity of 4.5 x 10(5) M(-1) (K(d) = 2.2 microM) in an enthalpically and entropically favorable process. An identical peptide lacking the sulfated tyrosine residues is unable to bind the gp120-CD4 complex. These results indicate that the sulfated tyrosines contribute close to -3.5 kcal/mol to the Gibbs energy of binding. Furthermore, the S22 peptide is a competitive inhibitor of the 17b HIV-1 neutralizing antibody, which is known to bind to the CCR5 coreceptor site in gp120. Together, these results point toward compounds containing sulfated aromatic groups as potential inhibitors of viral entry. In analogy to existing inhibitors that bind to the CCR5 coreceptor directly, these compounds will accomplish the same result by binding to the coreceptor site in gp120.

SUBMITTER: Brower ET

PROVIDER: S-EPMC2700308 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Binding thermodynamics of the N-terminal peptide of the CCR5 coreceptor to HIV-1 envelope glycoprotein gp120.

Brower Evan T ET Schön Arne A Klein Jeffrey C JC Freire Ernesto E

Biochemistry 20090201 4

The initial events of HIV-1 cell infection involve the sequential binding of the viral envelope glycoprotein gp120 to the cellular CD4 receptor and the coreceptor, usually CCR5 or CXCR4. Binding to the coreceptor triggers the chain of events that culminates with the entry of the virus into the cell. In this process, the interaction of gp120 with the tyrosine-sulfated N-terminus of CCR5 is critical; however, this interaction has never been characterized at a quantitative or thermodynamic level. H ...[more]

PMID: 19170639

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Project description:Adequate information on the precise molecular and biological composition of the viral strains that establish HIV infection in the human host will provide effective means of immunization against HIV infection. In an attempt to identify the transmitted founder (TF) virus and differentiate the biological properties and infectious potential of the TF virus from those of the population of the early transmitted viruses, 250 patient-derived gp120 envelope glycoproteins were cloned in pMN-K7-Luc-IRESs-NefΔgp120 to obtain chimeric viruses. Samples were obtained from eight infants who had recently become infected with HIV through mother-to-child transmission (MTCT) and two adults who acquired infection through the heterosexual route and were in the chronic stage of infection. Among the 250 clones tested, 65 chimeric viruses were infectious, and all belonged to HIV-1 subtype C. The 65 clones were analyzed for molecular features of the envelope, per-infectious-particle infectivity, coreceptor tropism, drug sensitivity, and sensitivity to broadly neutralizing antibodies. Based on genotypic and phenotypic analysis of the viral clones, we identified 10 TF viruses from the eight infants. The TF viruses were characterized by shorter V1V2 regions, a reduced number of potential N-linked glycosylation sites, and a higher infectivity titer compared to the virus variants from the adults in the chronic stage of infection. CXCR6 coreceptor usage, in addition to that of the CCR5 coreceptor, which was used by all 65 chimeric viruses, was identified in 13 viruses. The sensitivity of the TF variants to maraviroc and a standard panel of neutralizing monoclonal antibodies (VRC01, PG09, PG16, and PGT121) was found to be much lower than that of the virus variants from the adults in the chronic stage of infection.IMPORTANCE Tremendous progress has been made during the last three and half decades of HIV research, but some significant gaps continue to exist. One of the frontier areas of HIV research which has not seen a breakthrough yet is vaccine research, which is because of the enormous genetic diversity of HIV-1 and the unique infectious fitness of the virus. Among the repertoire of viral variants, the virus that establishes successful infection (transmitted founder [TF] virus) has not been well characterized yet. An insight into the salient features of the TF virus would go a long way toward helping with the design of an effective vaccine against HIV. Here we studied the biological properties of recently transmitted viruses isolated from infants who acquired infection from the mother and have come up with unique characterizations for the TF virus that establishes infection in the human host.

Dataset Information

Binding thermodynamics of the N-terminal peptide of the CCR5 coreceptor to HIV-1 envelope glycoprotein gp120.

Publications

Binding thermodynamics of the N-terminal peptide of the CCR5 coreceptor to HIV-1 envelope glycoprotein gp120.

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