INHIBITION OF CLINICAL HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) TYPE-1 ISOLATES IN PRIMARY CD4(-LYMPHOCYTES BY RETROVIRAL VECTORS EXPRESSING ANTI-HIV GENES() T)

Gene therapy may be of benefit in human immunodeficiency virus type 1 (HIV-1)-infected individuals by virtue of its ability to inhibit virus replication and prevent viral gene expression. It is not known whethe r anti-HIV-1 gene therapy strategies based on antisense or transdomina nt HIV-1 mutant proteins can inhibit the replication and expression of clinical HIV-1 isolates in primary CD4(+) T lymphocytes. We therefore transduced CD4(+) T lymphocytes from uninfected individuals with retr oviral vectors expressing either HIV-1-specific antisense-TAR or antis ense-Tat/Rev RNA, transdominant HIV-1 Rev protein, and a combination o f antisense-TAR and transdominant Rev. The engineered CD4(+) T lymphoc ytes were then infected with four different clinical HIV-1 isolates. W e found that replication of all HIV-1 isolates was inhibited by all th e anti-HIV vectors tested. Greater inhibition of HIV-1 was observed wi th transdominant Rev than,vith antisense RNA. We hereby demonstrated e ffective protection by antisense RNA or transdominant mutant proteins against HIV-1 infection in primary CD4(+) T lymphocytes using clinical HIV-1 isolates, and this represents an essential step toward clinical anti-HIV-1 gene therapy.