ABSTRACT
An antisense oligodeoxynucleotide against the human immunodeficiency virus type 1 (HIV-1) Rev response element, a ribozyme complementary to the HIV-1 5'-LTR, and the reverse transcriptase inhibitors 9-(2-phosphonylmethoxyethyl) adenine (PMEA) and (R)-9-(2-phosphonylmethoxypropyl)-adenine (PMPA) inhibited virus replication in monocyte-derived macrophages more effectively when delivered in pH-sensitive liposomes compared to the free drugs.
Subject(s)
Adenine/analogs & derivatives , Adenine/administration & dosage , Anti-HIV Agents/administration & dosage , HIV-1/drug effects , Macrophages/virology , Oligonucleotides, Antisense/administration & dosage , Organophosphonates , Organophosphorus Compounds/administration & dosage , RNA, Catalytic/administration & dosage , Virus Replication/drug effects , Adenine/pharmacokinetics , Anti-HIV Agents/pharmacokinetics , Genes, env/genetics , HIV-1/physiology , Humans , Hydrogen-Ion Concentration , Liposomes , Macrophages/metabolism , Oligonucleotides, Antisense/genetics , Organophosphorus Compounds/pharmacokinetics , Tenofovir , Thionucleotides/administration & dosageABSTRACT
During the past decade major advances have been made in combating HIV infection and reducing the incidence of AIDS in the western world. Despite optimism about such progress, there is accumulating evidence to suggest that new forms of therapy may be necessary to combat viral resistance to current drugs as well as to provide alternatives to life-long drug use. Genetic forms of therapy are considered to be an important alternative to current drug therapy. One therapeutic agent that can be tailored to inhibit viral infection is catalytic RNA or ribozymes. These RNAs can be engineered to site-specifically cleave targeted RNAs, thereby minimizing cellular toxicity associated with conventional drugs. A potential advantage of ribozymes over other forms of genetic therapy aside from target specificity is their potential for interfering with different stages of the viral life cycle. Ribozymes can be designed and expressed to interfere with viral entry, messenger RNA function and viral packaging. For the two simplest ribozyme motifs, the hammerhead and hairpin, there are hundreds of potential sites along the viral genome. Combinatorial use of ribozymes allows multiple HIV-1 sequences to be attacked simultaneously, thereby circumventing viral resistance through mutation. Ribozymes can also be designed to inhibit expression of cellular targets, which are required for HIV-1 infection. The successful applications of ribozymes against HIV-1 in preclinical settings has now set the stage for their testing in patient trials and several first phase clinical trials are currently underway.