Therapeutic potential of neutralizing antibodies in the treatment of HIV-1 infection

Abstract

In 1981 unusual cases of severe immune deficiency were reported. Two years later the cause of the acquired immuno- deficiency syndrome (AIDS) was identified: a retrovirus, designated the human immunodeficiency virus (HIV), that caused a loss of important immune functions leading to a dramatic vulnerability to a variety of bacterial, viral and fungal infections. The finding that the presence of neutral- izing antibodies correlated with the disease status suggested that infusion with hyperimmune plasma and human HIV- specific immunoglobulin (HIVIG) obtained from chronically HIV-1-infected asymptomatic donors may be of benefit to patients. However, early clinical studies were disappointing. No clear benefits were found for the majority of patients treated. 1 The introduction of highly active antiretroviral therapy (HAART) in 1996 caused great excitement. HAART drugs inhibit viral replication within infected cells by interfering with two crucial viral enzymes: reverse transcriptase and pro- tease. The initial hope that HIV could be eradicated in patients undergoing several years of HAART was not fulfilled and it became clear that HAART had major drawbacks. The high degree of severe side effects, short drug half-life, persistent viral reservoirs and the increasing prevalence of drug- resistant viruses underscored the need for additional thera- peutic approaches against HIV-1. Drugs that prevent viral replication at earlier steps such as virus entry into target cells and integration of the viral genome into the host genome are the focus of current drug development. Fusion inhibitors such as the T20 peptide, which prevents conformational changes in the viral membrane necessary for virus entry, are currently in clinical development. 2 However, T20 has to be injected daily owing to its short half-life, and induces adverse reactions at the site of administration. During the last decade several human monoclonal anti- bodies (hmAbs) were established to have an unusually high antiviral potential against HIV-1. The hmAbs neutralize the virus by binding to conserved epitopes of the proteins gp120 (antibodies 2G12, 3,4 IgG1b12 5 ) or gp41 (2F5, 6 4E10 7 ) representing 'natural' entry inhibitors with half-lives 50- 100 times longer than fusion inhibitor peptides. These anti- bodies inhibit replication of the majority of primary isolates with high potency. 8 Moreover, there is evidence that these antibodies are capable of lysing virus particles and infected cells by antibody-dependent cellular cytotoxicity (ADCC) and complement activation. 4,9 Although the high antiviral potential of these antibodies has been demonstrated in vitro, their usefulness for in vivo application was doubted by many. The unsatisfying results in HIVIG studies and the difficulties in hmAb large-scale technology were major hurdles for the development of antibody therapy.