Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4+ cells by monoclonal antibodies.
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.
Zarling
J M
JM
Oncogen, Seattle, Washington 98121.
Moran
P A
PA
Haffar
O
O
Sias
J
J
Richman
D D
DD
Spina
C A
CA
Myers
D E
DE
Kuebelbeck
V
V
Ledbetter
J A
JA
Uckun
F M
FM
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D000922:Immunotoxins; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D054789:Ribosome Inactivating Proteins, Type 1; D014779:Virus Replication / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000998:Antiviral Agents; D015704:CD4 Antigens; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein