Delivery of novel macromolecular drugs against HIV-1.
The development of new low molecular weight drugs against human immunodeficiency virus Type 1 (HIV-1) targets other than reverse transcriptase (RT) and protease, such as the integrase and the envelope glycoprotein, is likely to take many years. Macromolecular drugs, including antisense oligonucleotides, ribozymes, RNA decoys and transdominant mutant proteins, may be able to interfere with a relatively large number of viral targets, thereby decreasing the likelihood of the emergence of drug-resistant strains. It may also be relatively easy to alter the sequence of some of the macromolecular drugs to counter emerging drug-resistant viruses. The delivery of antisense oligonucleotides and ribozymes to HIV-1 infected or potentially infectable cells by antibody-targeted liposomes, certain cationic lipid formulations and pH-sensitive liposomes results in significant anti-HIV-1 activity. These carriers not only facilitate cytoplasmic delivery but also protect the drugs from nuclease digestion. Delivery of therapeutic genes (another form of macromolecular drug) to target cells is an important challenge of gene therapy. Following delivery by a viral vector, sufficient levels of gene expression must be maintained over an extended period of time to have therapeutic activity. Robust expression of therapeutically useful ribozymes, antisense, decoys and aptamers can be achieved by the use of Pol III expression systems. Moloney murine leukaemia virus- (MoMuLV), adeno-associated virus (AAV)-, or HIV-derived vectors expressing a variety of therapeutic genes have been used successfully to inhibit HIV-1 replication in cultured cells.
Düzgünes
N
N
Department of Microbiology, School of Dentistry, University of the Pacific, 2155 Webster Street, San Francisco, CA 94115, USA. nduzgune@sf.uop.edu
Simões
S
S
Konopka
K
K
Rossi
J J
JJ
Pedroso de Lima
M C
MC
D019380:Anti-HIV Agents / Q000008:administration & dosage*; D004267:DNA Viruses / Q000235:genetics; D005822:Genetic Vectors; D015497:HIV-1; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D012328:RNA Viruses / Q000235:genetics; D016337:RNA, Catalytic / Q000008:administration & dosage
D019380:Anti-HIV Agents; D016376:Oligonucleotides, Antisense; D016337:RNA, Catalytic