MODULATING APOPTOSIS WITH TAT ANTIBODIES

Tat antibodies are detected in the serum of HIV-infected patients, and a number of short linear Tat epitopes recognized by IgM or IgG patients’ antibodies have been characterized in several regions of the protein.^58-62 Independent groups showed that, in contrast to antibodies to Env, Nef, and Gag, the level of Tat antibodies is elevated in long-term non- or slow-progressors and is low in fast progressors; their decline in asymptomatic individuals would be related to the imminence of acquired immunodeficiency syndrome (AIDS).^62-66 It was also reported that the presence of Tat natural IgM antibodies in normal individuals (and chimpanzees, but not in other primates and mice) and reacting with functional Tat regions might have some influence on the course of AIDS pro- gression.^64,67 Taken together, this body of evidence suggests that immunization with Tat or Tat fragments might block certain extracellular deleterious functions of Tat and, consequently, may considerably delay the emergence and spread of infection.

B cell epitopes important for Tat neutralization were located in the N-terminus and the basic region of the Tat protein.^60-62,74-78 These regions of Tat, in particular, the basic region, are relatively well conserved among all viral subtypes, except for the O subtype.^42,79 Recently, we showed that only sera-containing antibodies reacting with both regions were able to inhibit extracellular Tat- dependent transactivation in vitro.⁸⁰ This feature was found in mice, rabbits, macaques, and humans vaccinated with recombinant or synthetic Tat, Tat toxoid, and Tat peptides. Furthermore, human monoclonal antibodies as well as human single-chain fragment variable (scFv) antibodies specific for Tat were found to modulate HIV-1 replication in infected cell cultures.

Specific antibodies generated in rabbits and macaques against Tat peptides were also shown to inhibit Tat-induced apoptosis of T cells. This was demonstrated, for example, with OKT3-activated Jurkat T cells.⁴² Such antibodies, either produced actively by vaccinated individuals or adminis­trated passively at the very beginning of infection, might play a critical role in controlling Tat- induced death of uninfected cells. They might hamper the effect of Tat on critical immune cells and particularly on dendritic cells that are targeted and activated by Tat.^82,83 Several independent clinical trials have demonstrated the safety of Tat toxoid,^84-86 and Ensoli and colleagues recently started preventive and therapeutic phase I clinical trials in Italy to evaluate the effectiveness of a Tat-based vaccine strategy.⁸⁷ Intense research is also devoted to the production of Tat-specific human intrabodies that may be useful for passive immunization.^81,88,89