CD8+ T-cell-induced inhibition of retroviral replication is mediated at the transcriptional level.

Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.

CD8+ T-cell-induced inhibition of retroviral replication is mediated at the transcriptional level.

Symp Nonhum Primate Models AIDS. 1990 Nov 28-30;8:43 (abstract no. 27). Unique Identifier : AIDSLINE PRIM8/900027
Powell JD; Bednarik DP; Folks TM; Jehuda-Cohen T; Villinger F; McClure HM; Ansari AA; Department of Pathology, Emory University School of Medicine,; Atlanta, GA 30322

Abstract: There is increasing evidence that CD8+ T cells play a crucial role in controlling HIV infection in vivo. Via et al. (Immunology Today, 11(7):250) propose that the clinical transition from the asymptomatic to disease state may be secondary to the quantitative loss of such CD8+ cells. Previously, our laboratory has shown that CD8+ T cells from not only seropositive but also seronegative sooty mangabeys have the ability to inhibit SIV replication in vitro. Since sooty mangabeys are naturally infected with SIVsmm and do not succumb to the sequela of SIV infection, they provide a unique model to examine effector mechanisms potentially responsible for the maintenance of the asymptomatic state. Toward this goal, B cells from a seropositive sooty mangabey were EBV transformed and then transfected with a human CD4 gene. These cells, termed FEcl, were shown to stably express CD4 on their cell surface and are replication-competent for SIV. Autologous lymphocytes are able to inhibit not only SIV replication in the FEcl cells but also the replication of HIV-1 and HIV-2. Utilizing a dual chamber culture system, it was found that inhibition of viral replication was mediated by a soluble factor. Parallel studies examining viral replication and CTL activity in PBMC from the FEc monkey showed marked inhibition of viral replication in the absence of significant cytotoxic activity. Whereas such data do not rule out the role of CTL activity in inhibiting viral replication, they do suggest that an additional mechanism may be involved. As such, Fecl cells were transiently transfected with an LTR-driven CAT reporter gene. It was found that autologous CD8+ T cells markedly inhibited CAT activity, suggesting that inhibition of viral replication in this model must occur at the level of transcription. Furthermore, co-transfection of the FEcl cell line with an LTR-driven tat plasmid and LTR-CAT was able to quantitatively mitigate the suppressive effect. Thus, transcriptional inhibition appears to be directed at cellular mechanisms of viral replication. Using an LTR-driven CAT plasmid with a mutation at the nFkB binding site completely inhibited CAT activity in these cells. Indeed, gel retardation assays confirm the presence of nFkB binding proteins in the FEcl cells. Taken together, these data demonstrate the ability of CD8+ T cells to inhibit nFkB-driven viral replication. Currently, experiments are underway to (i) identify the soluble factor(s) responsible for this effect, (ii) identify the specific sub-lineage of CD8+ T cells involved, (iii) provide a detailed characterization of the molecular mechanism of nFkB inhibition. This model accentuates the ability of the virus to usurp the activation machinery of immunologically relevant cells and the potential role for CD8+ T cells in regulating this axis.

Keywords: Animal Antigens, CD4/GENETICS Binding Sites Cell Line Cell Transformation, Viral Chloramphenicol Acetyltransferase/METABOLISM CD4-Positive T-Lymphocytes/METABOLISM Disease Models, Animal *DNA Replication DNA, Viral/*BIOSYNTHESIS Genes, Viral Herpesvirus 4, Human/PHYSIOLOGY HIV Enhancer HIV-1/GROWTH & DEVELOPMENT HIV-2/GROWTH & DEVELOPMENT Macaca Mutation Repetitive Sequences, Nucleic Acid Simian Acquired Immunodeficiency Syndrome/GENETICS SIV/*GROWTH & DEVELOPMENT/GENETICS T-Lymphocytes, Cytotoxic/METABOLISM T-Lymphocytes, Suppressor-Effector/*METABOLISM/MICROBIOLOGY Transcription, Genetic Transfection Virus Replication/*GENETICS ABSTRACT
910730
M9170967

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