Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies

Abstract

Functional impairment and selective depletion of CD4+ T cells, the hallmark of AIDS, are at least partly caused by human immunodeficiency virus (HIV-1) type 1 binding to the CD4 molecule and infecting CD4+ cells. It may, therefore, be of therapeutic value to target an antiviral agent to CD4+ cells to prevent infection and to inhibit HIV-1 production in patients' CD4+ cells which contain proviral DNA. We report here that HIV-1 replication in normal primary CD4+ T cells can be inhibited by pokeweed antiviral protein, a plant protein of relative molecular mass 30,000, which inhibits replication of certain plant RNA viruses, and of herpes simplex virus, poliovirus and influenza virus. Targeting pokeweed antiviral protein to CD4+ T cells by conjugating it to monoclonal antibodies reactive with CD5, CD7 or CD4 expressed on CD4+ cells, increased its anti-HIV potency up to 1,000-fold. HIV-1 replication is inhibited at picomolar concentrations of conjugates of pokeweed antiviral protein and monoclonal antibodies, which do not inhibit proliferation of normal CD4+ T cells or CD4-dependent responses. These conjugates inhibit HIV-1 protein synthesis and also strongly inhibit HIV-1 production in activated CD4+ T cells from infected patients.

Pokeweed Antiviral Protein Inhibits Brome Mosaic Virus Replication in Plant Cells

“…Since its initial description as an antiviral agent against tobacco mosaic virus (1), PAP has been demonstrated to reduce the propagation of several plant and animal viruses, including potato virus X, HIV, and influenza (2)(3)(4). It therefore holds promise as a broad-spectrum antiviral agent.…”

Isolation and characterization of pokeweed antiviral protein mutations in Saccharomyces cerevisiae: identification of residues important for toxicity.

“…Studies that compare the relative antiviral properties of a number of RIPs showed that all of the RIPs tested had antiviral activity, but none was as effective as PAP (4). PAP has been shown to inhibit infection of both Vero and HeLa cells by herpes simplex virus (5) and to inhibit human immunodeficiency virus 1 (HIV-1) replication in T cells and macrophages infected in vitro at concentrations that do not inhibit cellular protein synthesis (6). A number of recent studies have shown that conjugating PAP with monoclonal antibodies dramatically increases its potency against cells infected with HIV and human cytomegalovirus (7).…”

Cell surface receptor directed targeting of toxin to human malaria parasite, Plasmodium falciparum

“…That targeted toxins represent a rational approach to cytocidal therapy in certain infectious diseases, envisaged earlier, has indeed been attested to, by the success of anti CD4-toxin and CD4-toxin conjugates for combating human immunodeficiency virus [12,13]. Moreover, such hybrid molecules prepared by chemical conjugation, linked to either antireceptor antibodies or ligands, have been demonstrated to selectively kill cells, displaying the complementary determinants (antigen or receptor) on their surfaces [14].…”