Blocking of HIV-1 Infectivity by a Soluble, Secreted Form of the CD4 Antigen

Abstract

The initial event in the infection of human T lymphocytes, macrophages, and other cells by human immunodeficiency virus (HIV-1) is the attachment of the HIV-1 envelope glycoprotein gp120 to its cellular receptor, CD4. As a step toward designing antagonists of this binding event, soluble, secreted forms of CD4 were produced by transfection of mammalian cells with vectors encoding versions of CD4 lacking its transmembrane and cytoplasmic domains. The soluble CD4 so produced binds gp120 with an affinity and specificity comparable to intact CD4 and is capable of neutralizing the infectivity of HIV-1. These studies reveal that the high-affinity CD4-gp120 interaction does not require other cell or viral components and may establish a novel basis for therapeutic intervention in the acquired immune deficiency syndrome (AIDS).

Nef Stimulates Human Immunodeficiency Virus Type 1 Replication in Primary T Cells by Enhancing Virion-Associated gp120 Levels: Coreceptor-Dependent Requirement for Nef in Viral Replication

“…Nef-defective virions contained higher levels of CD4 than wild-type HIV-1. Infection by HIV-1 laboratory strains (predominately X4 tropic) is more susceptible to inhibition by sCD4 than are HIV-1 primary isolates (which are normally R5 tropic) (21,49,62). We hypothesized that virion-associated CD4 more potently inhibits infection by X4-tropic viruses, thereby preferentially inhibiting replication of nef-defective X4-tropic replication.…”

A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

“…Early efforts to block HIV-1 entry to cells focused on using sCD4 to inhibit virus infection (29,30). Although sCD4 demonstrated efficacy against many laboratory strains, it exhibited poor activity against primary isolates (31), which may have contributed to disappointing results in clinical trials (31,32).…”

Distinct modulatory effects of bryostatin 1 and staurosporine on the biosynthesis and expression of the HIV receptor protein (CD4) by T cells.

“…A substantial number of studies have previously shown that CD4 is the major receptor for human immunodeficiency virus (HIV) Smith et al, 1987;Lifson et al, 1988), the causative agent of the acquired immunodeficiency syndrome (AIDS) (Fauci, 1988). Infection of T cells with HIV is known to involve the binding of the viral envelope glycoprotein (gpl 20) to CD4 Smith et aL, 1987;Lifson et al, 1988). Thus anti-CD4 monoclonal antibodies and synthetic CD4 oligopeptides have recently been used to map the virus binding site on the CD4 molecule.…”