Structural studies of antibodies and CD4-mimetic compounds that influence HIV-1 Env conformation
EMSL Project ID
51196
Abstract
The HIV-1 envelope glycoprotein (Env), a homotrimer of gp120-gp41 heterodimers, changes its conformation to mediate fusion of the host and viral membrane bilayers, the first step in infection that allows entry of the viral RNA into the host cell cytoplasm. The fusion process is initiated by interactions between the Env gp120 subunit and the host receptor CD4, resulting in conformational changes that reveal the binding site for a host coreceptor. Since Env-mediated fusion represents the first step in HIV-1 infection, vaccines or targeted small-molecule and antibody therapies to disrupt the mechanism of viral entry are ideal. In this proposal, we will structurally characterize conformational changes in Env trimers upon binding to antibodies and CD4-mimetic compounds, which act as entry inhibitors. By doing so, we will address two questions in the HIV field relevant to the basic understanding of viral fusion mechanisms and the design of next-generation therapeutics: 1) What interactions between gp120 and CD4-mimetic compounds induce Env conformational changes, and how does that compare to CD4-bound states? and, 2) What is the mechanism that governs Env conformational changes induced by antibodies binding distal to the CD4-binding site? Elucidating these structures will favorably impact the HIV field and enable key translationally-relevant advances in anti-HIV therapies by 1) analyzing functional differences between CD4, CD4-mimetic compounds, and antibodies that induce Env conformational changes leading to Env-mediated fusion; 2) defining the structural effects of entry inhibitors on Env trimers; and 3) guide the rational design of improved therapies targeting the entry process.
Project Details
Start Date
2019-11-10
End Date
2020-08-10
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Jette C., C. Barnes, S. Kirk, B. Melillo, A.B. Smith III, and P. Bjorkman. "Cryo-EM structures of HIV-1 trimer bound to CD4-mimetics BNM-III-170 and M48U1 adopt a CD4-bound open conformation." Nature Communications