Rationale for the Use of Immunotoxins in the Treatment of HIV-infected Humans

Abstract

The first step in the replication of human immunodeficiency virus (HIV) is selective binding of the envelope glycoprotein (gp120) to CD4 receptors on T cells or macrophages. After penetration in these cells, the genome of the virus is integrated in the human genome. HIV-infection causes depletion of CD4-positive cells resulting in a severe immunosuppression. It is believed that eliminating HIV-infected cells is crucial in limiting further reduction of CD4-positive cells and thus, preventing disease progression. The most commonly used drugs, such as zidovudine (AZT), appeared to be not completely effective. Therefore many investigators are searching for alternative treatment modalities. The use of immunotoxins (ITs) to eliminate HIV-infected cells is discussed. ITs are chimeric molecules in which cell-binding ligands are coupled to toxins and can specifically eliminate undesired cells. The cell-binding carriers of anti-HIV ITs have been directed against different regions of the HIV envelope glycoprotein (gp120 and gp41) and surface antigens (e.g CD4, CD25). The ITs have been composed of different ribosome-inactivating proteins (RIPs) like pokeweed antiviral protein (PAP), Pseudomonas exotoxin (PE), Diphtheria toxin (DT), or ricin. In in vitro studies, several of these ITs have been shown to be effective and specific in killing acute and persistently HIV-infected cells. The ITs were effective at concentrations (ID50 range from 10(-9) M to 10(-12) M) that were not toxic to uninfected cells or cells without the antigen. The IT CD4(178)PE40, a fusion protein directed against the CD4 binding site of gp120, has been investigated in two in vivo trials. The results were disappointing considering the antiviral activity in vitro. This was thought to be due to the rapid clearance of the IT and the differential resistance of clinical HIV isolates. Use of a panel of ITs is likely to be more effective because multiple approaches cover the intrinsic variability of HIV and the presence of IT-resistant or latently infected cells, as well as the blocking presence of neutralizing anti-HIV antibodies and the immunogenicity of most ITs. It may be possible to control the virus completely with a panel of ITs in combination with other antiviral or immunosuppressive agents such as RT inhibitors (e.g AZT), interferon alpha, or cyclosporine. More research will be necessary to develop such a combined therapy.