Immunotherapy for Infectious Diseases

INTRODUCTION
From: Immunotherapy for Infectious Diseases
Edited by: J. M. Jacobson © Humana Press Inc., Totowa, NJ
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Gene Therapy for HIV-1 Infection
Ralph Dornburg and Roger J. Pomerantz
Since the discovery that AIDS is caused by a retrovirus, HIV-1, enormous efforts
have been made to develop new drugs that will combat this infectious disease. Although
new conventional drugs have been found to block the replication of this virus efficiently,
new mutant strains continuously arise, which escape the inhibitory effect of
such drugs. Furthermore, since HIV-1 integrates its genome into that of the host cell,
dormant viruses persist in infected individuals over long periods. Thus, great efforts are
currently being made in many laboratories to develop alternative genetic approaches to
inhibit the replication of this virus. With growing insight into the mechanism and regulation
of HIV-1 replication, in the past decade, many strategies have been developed
and proposed for clinical application to block HIV-1 replication inside the cell. Such
strategies use either antiviral RNAs or proteins (for some recent reviews, see refs. 1–4).
Antiviral strategies that employ RNAs have the advantage that they are less likely to
be immunogenic than protein-based antiviral agents. However, protein-based systems
have been engineered using inducible promoters that only become active upon HIV-1
infection. Although such antivirals have been proved to be very effective in vitro, their
beneficial effect in vivo is very difficult to evaluate and still remains to be shown. In
particular, the long latent period from infection to the onset of AIDS (up to 10 years
or longer) makes it very difficult to evaluate the efficacy of a new drug.
Another obstacle is the transduction of therapeutic genes into the patient’s immune
cells. Although a large variety of gene transfer tools exist, which allow efficient transduction
of genes in tissue culture, it becomes more and more evident that ex vivo transduced
cells do not survive long in vivo. No efficient gene delivery tools are available at this point
that would allow robust delivery to the actual target cell in vivo. This chapter summarizes
experimental genetic approaches toward blocking HIV-1 replication and current gene
delivery techniques for transducing therapeutic genes into the precise target cells.
HIV-1 LIFE-CYCLE AND POTENTIAL
TARGETS FOR GENETIC ANTIVIRALS
HIV-1 primarily infects and destroys cells of the human immune system, in particular
CD4� T-lymphocytes and macrophages. The destruction of such cells leads to a
severe immunodeficiency, e.g., the inability to fight other infectious agents or tumor