Immunotherapy for Infectious Diseases

Gene Therapy for HIV-1 Infection 239
Fig. 1. Life cycle of HIV-1, which is similar to that of all retroviruses studied. HIV-1 attaches
to the target cell mainly by binding to the CD4 molecule. After fusion of the viral and cellular membranes,
retroviral core particles are released into the cytoplasm. The RNA genome is converted into
a double-stranded DNA by the viral reverse transcriptase (RT) and ribonuclease H (RNaseH) and
actively transported into the nucleus, probably aided by the viral protein Vpr. The viral DNA is
integrated into the genome of the host cell by the viral integrase (in). The integrated DNA form of
the virus is called the provirus. In contrast to other retroviruses, transcription and RNA splicing of
the provirus is regulated by viral accessory proteins. For example, the viral protein Tat must bind
to a specific sequence in the HIV genome (termed TAR) to enable highly efficient transcription of
the provirus. Rev is required to control RNA splicing and the transport of RNAs into the cytoplasm.
Finally, in the cytoplasm, virus core particles are assembled by encapsidating full-length genomic
viral RNAs (recognized by specific encapsidation sequences). At the cell membrane, virus particle
assembly is completed by the interaction of the core with the viral membrane proteins, and new
particles “bud” (are released) from the infected cell. For more details regarding regulatory proteins,
see also Figure 5. Env, envelope; ER, endoplasmatic reticulum.
fourth criteria, is that the antiviral agent has to be tolerated by the immune system. It
would not make much sense to endow immune cells with an antiviral agent that elicits
an immune response against itself, leading to the destruction of the HIV-1-resistant
cell after a short period.