Suppression of Activation of the Human Immunodeficiency Virus Long Terminal Repeat by CD8⁺T Cells Is Not Lentivirus Specific

Abstract

CD8+ T lymphocytes of HIV-1-infected individuals can efficiently suppress HIV-1 replication in CD4+ T lymphocytes. To elucidate the molecular events underlying this suppression, we have used the HIV-1 LTR directing the chloramphenicol acetyltransferase gene (CAT) in transient transfection assays using human Jurkat T cells. In addition to supernatants of patient CD8+ T lymphocytes (CD4+ > 350/microliters), supernatant of a T cell clone derived by Herpesvirus saimiri (HVS)-mediated transformation of CD8+ T lymphocytes of a patient demonstrating inhibition of virus replication were examined. Similar levels of inhibition of LTR-mediated gene expression in response to Tat or mitogenic activation with phorbol ester and calcium ionophore were observed by supernatants of both sources. The inhibitory effect of CD8+ T lymphocytes was not exclusive to lentiviral LTRs since transcription of both the HTLV-I LTR and RSV LTR in response to mitogen was effectively inhibited. In examination of the influence of CD8+ T cell-derived supernatant on NF kappa B-mediated activation, a dimer of the HIV-1 NF kappa B elements directing CAT was markedly inhibited by supernatants of both patient CD8+ lymphocytes and the HVS-derived CD8+ clone. Thus the inhibitory nature of CD8+ T lymphocytes appears not to be specific to lentiviral promoters and may mediate an inhibitory effect via the NF kappa B element.

Initiation of Human Immunodeficiency Virus Type 1 (HIV-1) Transcription is Inhibited by Noncytolytic CD8+ Suppression

“…CD8 + T cells from asymptomatic HIV-1 infected individuals could inhibit both basal and Tat mediated transcription and other work further substantiated these findings [19,20]. Importantly, these affects on viral gene expression were also observed and confirmed using a primary lymphocyte culture in an ongoing cycle of viral replication where potent suppression of CXCR4-tropic viruses was shown not to involve entry or reverse transcription [21].…”

CD8+T cell-mediated enhancement of tumour necrosis factor-alpha (TNF-α) production and HIV-1 LTR-driven gene expression in human monocytic cells is pertussis toxin-sensitive

“…We previously reported that while CD8 þ T cell supernatants suppress HIV-1 LTR-mediated gene expression in Jurkat T cells [18,19], an opposite effect was observed on gene expression in monocytic cells [22]. …”

“…In addition to inhibition of HIV-1 replication in CD4 þ T cells and T cell lines, CD8 þ T cells mediate inhibition of LTR-directed gene expression in T cell lines [17][18][19][20][21]. We previously reported on the opposite effects of CD8 þ T cells on gene expression in T cells versus monocytic cells [22].…”

The CD8+cell noncytotoxic anti-HIV response can be blocked by protease inhibitors

“…It does not directly inactivate HIV but blocks virus transcription (12,13,29). The amount of CAF in CD8 ϩ cell culture fluids is low (e.g., 4 units͞ml in which 1 unit is 50% inhibition of HIV replication), and thus it is difficult to isolate CAF from the serum-or protein-containing media in which CD8 ϩ cells must be grown (4).…”

“…CNAR appears to be mediated by the secretion of a soluble CD8 ϩ cell antiviral factor (CAF), which, as observed with CNAR, blocks HIV transcription (8,12,13). CAF in culture fluids can be measured by culturing acutely infected CD4 ϩ cells in the continual presence of the CD8 ϩ cell supernatant.…”