Long-Term Inhibition of Clinical and Laboratory Human Immunodeficiency Virus Strains in Human T-Cell Lines Containing an HIV-Regulated Diphtheria Toxin A Chain Gene

Abstract

The human immunodeficiency virus (HIV) causes persistent infection of T cells. Chemotherapy for infection in humans may slow HIV-related disease progression, but it does not eradicate virus. Thus, other treatment modalities are warranted. We have previously demonstrated that the human T cell line H9, ordinarily permissive for HIV infection, may be protected against infection with the LAI strain of HIV by intracellular immunization with the gene encoding diphtheria toxin A chain (DT-A) under the control of HIV Tat and Rev. Cloned cells were protected for up to 6 days in vitro. We now report protection against the LAI laboratory isolate for up to 59 days, and against clinical HIV strains of differing phenotypic properties and cell tropisms for up to 59 days. In some cases, protection was complete in that no residual HIV was detected by HIV p24 antigen production, co-culture with parental H9 cells, or the polymerase chain reaction (PCR). CD4⁺ surface expression of DT-A transduced cloned H9 cells was similar to parental H9 in most cases. These results suggest that toxin gene therapy for HIV infection may ultimately be feasible. H9 cells transduced with an HIV-regulated DT-A chain gene exhibited long-term protection against laboratory and clinical HIV strains. HIV production was assayed by monitoring p24 levels over time, and by the sensitive PCR. The findings presented here support the notion that HIV-regulated toxin gene expression may be an effective gene therapy approach aimed at eradicating HIV-infected cells early in infection.