CD8+ T cells suppress human immunodeficiency virus replication by inhibiting viral transcription.
CD8+ cells from human immunodeficiency virus (HIV)-infected individuals suppress HIV replication in cultured CD4+ cells by a noncytolytic mechanism that involves a secreted CD8(+)-cell antiviral factor (CAF). The results of this study suggest that CD8+ cells, as well as CAF, arrest HIV replication at the level of viral transcription. Culturing naturally infected CD4+ cells actively producing HIV with autologous CD8+ cells or a 50% dilution of culture fluids from these cells results in a > 80% reduction in the number of cells expressing HIV antigens and RNA. This effect was observed within 2 days after exposure to CD8+ cells but required 6 days in the presence of CAF-containing culture fluids to reach the same extent of HIV suppression. Northern blot analysis of CD4+ cell extracts revealed that all viral RNA species (unspliced and single and double spliced) were reduced in quantity to a similar extent. CAF-containing culture fluids also had a direct inhibitory effect on HIV long terminal repeat (LTR)-driven transcription in HIV-infected 1G5 cells carrying an LTR-luciferase construct. Suppression of basal levels of LTR-driven transcription was not detected. Thus, the results suggest that the noncytolytic CD8+ cell antiviral activity observed in HIV infection exerts its effects, at least in part, by specifically interrupting HIV transcription. These findings could help in developing therapies for HIV infection.
Mackewicz
C E
CE
Cancer Research Institute, University of California, School of Medicine, San Francisco 94143-0128.
Blackbourn
D J
DJ
Levy
J A
JA
D000998:Antiviral Agents / Q000494:pharmacology; D015152:Blotting, Northern; D016827:CD8 Antigens / Q000032:analysis / Q000096:biosynthesis* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002460:Cell Line; D002478:Cells, Cultured; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D016325:HIV Long Terminal Repeat; D054303:HIV Reverse Transcriptase; D006679:HIV Seropositivity / Q000276:immunology*; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D012326:RNA Splicing; D012367:RNA, Viral / Q000032:analysis / Q000096:biosynthesis; D018894:Reverse Transcriptase Inhibitors; D013601:T-Lymphocytes; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D016827:CD8 Antigens; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase