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antibodies and HIV treatment

Human immunodeficiency virus (HIV) is one of the leading causes of death in the world. In 2003 alone, there were approximately 37 million adults and 2.5 million children under the age of 15 who were infected, while approximately 4.2 million adults and 700,000 children were newly infected^[1]. The only treatment currently available against HIV is HAART (highly active antiretroviral therapy), which requires greater than 90% adherence for the rest of the infected individual's life as well as costs of around $1500 per month^[1]. Several new treatments are currently in research, however. These include treatments in which plant-produced pokeweed antiviral protein (PAP), gp120, Tat, and Cyanovirin-N are used to inhibit HIV infection. This review will focus on PAP since it is the most relevant to antibodies and immunotherapy.

Pokeweed antiviral protein inhibits protein translation

PAP is a protein that is found naturally in the roots and leaves of the pokeweed plant, Phytolacca americana ^[2,3]. It functions to inactivate prokaryotic and eukaryotic ribosomes by removing a specific adenine residue from the larger rRNA to generate a depurinated ribosome no longer capable of binding to the elongation factor 2 (EF-2)-GTP complex. This step is crucial to protein synthesis by allowing the translocation of the nascent protein polypeptide from one site in the ribosome to another^[2,3]. The current hypothesis is that PAP is released into the plant cell cytoplasm during mechanical disruption of the plant cell wall, such as during vector innoculation or viral infection, and thereafter inhibits viral growth^[3]. In the animal cell, however, evidence suggests that the inhibition of viral growth by PAP is through some mechanism other than that of protein synthesis: PAP's inhibition of viral growth far surpasses its ability to inhibit protein synthesis^[3].

PAP inhibits many viruses when conjugated with monoclonal antibodies

PAP has been made in transgenic potato and tobacco plants^[2,3]. In these plants, PAP has been shown to be an effective antiviral compound against poliovirus, herpes simplex virus, cytomegalovirus, influenza virus and HIV-1^[2]. This broad-spectrum effect of PAP makes it a particularly strong candidate for the production of a microbicide that can protect individuals against the more common sexually transmitted diseases (STDs). Rajamohan et al. found that PAP conjugation to monoclonal antibodies that recognize CD4, CD5 or CD7 antigens on the surface of lymphocytes was crucial to its inhibition of HIV-1 development in CD4+ cells infected with HIB-1. They found the same result in activated T-cells from asymptomatic HIV-1-seropositive donors as well.

Animal models and human epithelial cell systems show that PAP is relatively safe

Research within the last five years has shown some tentative evidence for the safety of PAP use inside the body: PAP can protect against HIV infection without affecting the motility or function of sperm in mice and humans^[4,5]; it does not cause cytotoxicity or the development of lesions in mouse, human and rabbit vaginal epithelium ^[4,5,6], but there was mild to moderate vaginal irritation in rabbits^[6]. Therefore current research suggests that PAP is a good candidate for use as a microbicide, but requires careful monitoring to prevent irritation.

Conclusion

There have been several advancements in HIV research within the last decade. In particular, the production of PAP in transgenic potatoes and tobacco plants represents a promising alternative in HIV anti-viral therapy. Key to PAP's activity, however, seems to be its function in relation to its presentation on antibodies. However, there are several other developments in anti-HIV therapy that were not covered in this report. For example, Cyanovirin-N molecule is another potentially useful microbicide that inhibits HIV entry into epithelial cells by binding to the viral gp120 cell surface protein and preventing its interaction with epithelial cell receptors^[7]. As well, Tat protein^[8] and gp120^[9] that are produced in transgenic spinach and gp120, respectively, have been used as antigens in vaccines to induce host immune response against the virus. It can be seen that there are many potential HIV treatments in development along with PAP.

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