T Cell-Derived Suppressive Activity: Evidence of Autocrine Noncytolytic Control of HIV Type 1 Transcription and Replication

Abstract

The ability of CD8+ T lymphocytes to suppress the transcription and replication of HIV-1 is well documented. We have demonstrated that the factor(s) responsible for the suppression of HIV-1 LTR-mediated gene expression are not the CC chemokines RANTES, MIP-1alpha, and MIP-1beta. Interestingly, these and other chemokines and cytokines are produced by both CD8+ and CD4+ T lymphocytes. On the presumption that CD4+ T lymphocytes may also be able to modulate HIV-1 expression in vitro we assessed the LTR-modulatory effects of a panel of culture supernatants derived from stimulated CD4+ T lymphocytes from HIV-positive patients and uninfected controls. Supernatants of both CD4+ and CD8+ T cells mediated a suppression of LTR-driven gene expression in Jurkat T cells and an enhancement of gene expression in U38 monocytic cells. On the basis of these results, and using a herpesvirus saimiri (HVS)-transformed CD4+ T lymphocyte clone (HVSCD4), we demonstrate that both suppressive and enhancing effects are dose dependent. Furthermore, we have shown that supernatants of both HVSCD4 and HVSCD8 cells suppress LTR-mediated gene expression and HIV-1 replication in transfected/infected T cells. In U1 monocytic cells, supernatants of both CD4+ and CD8+ lymphocytes from an HIV-1-infected individual enhanced LTR-mediated gene expression, HIV-1 replication, and TNF-alpha production. However, only these effects as induced by CD8+ T cells were sensitive to the G protein inhibitor pertussis toxin. These results indicate that factors produced by both CD4+ and CD8+ T cells exert dichotomous effects on HIV-1 gene expression and replication in T cells and monocytes.

Noninfectious papilloma virus–like particles inhibit HIV-1 replication: implications for immune control of HIV-1 infection by IL-27

“…Here, we have identified that IL-27 is a novel antiviral cytokine. A number of soluble anti-HIV factors have been identified from tissue culture supernatants, [11][12][13][14][15] and it has been proposed that HIV replication might be immunologically controlled by soluble factors. 65 Understanding the mechanism of IL-27-mediated HIV inhibition may delineate an invaluable insight into immunologic control of HIV replication and possible strategies for therapeutic invention.…”

“…[11][12][13][14][15] For example, secretion of anti-HIV ␤-chemokines and CD8 antiviral factor (CAF) from human T-lymphotropic virus (HTLV)-type 1 and herpes virus saimiri-infected cell line have been described. [11][12][13][14][15] Although a combination of antibodies and suppressive factors was able to reverse the inhibitory activity of CAF, complete reversal of HIV-1 suppression was not observed, suggesting that additional unknown suppressive factors were involved. 16 Certain microbial organisms elicit immune responses that reduce clinical HIV-1 infection presumably through the induction of soluble suppressive factors.…”

A Soluble Factor Secreted by an HIV-1-Resistant Cell Line Blocks Transcription through Inactivating the DNA-Binding Capacity of the NF-κB p65/p50 Dimer

“…Although much of this interest was dedicated to studying the antiviral responses of CD8 T lymphocytes, it has been well known that some infected individuals mount vigorous HIV-1-specific CD4 T cells responses, resulting in the elaboration of IFN-␥ and antiviral ␤-chemokines (12). Furthermore, a number of studies suggested that CD4 T cells mediated the secretion of unidentified protein factor(s), acting after virus entry to restrict virus replication (10,(13)(14)(15).…”

CAF-Mediated Human Immunodeficiency Virus (HIV) Type 1 Transcriptional Inhibition Is Distinct from α-Defensin-1 HIV Inhibition

“…However, several studies have shown that these ␤-chemokines cannot entirely account for CAF-mediated antiviral effects, particularly since CAF can inhibit the replication of HIV-1 strains that use CXCR4 and not CCR5 for entry (1,20,28,29,36). Furthermore, CAF can prevent HIV-1 replication postentry (6,10,23,25,29,41). In addition to the ␤-chemokines, a number of other soluble factors including interleukin-16, interferons, macrophage-derived chemokines, antithrombin III, and most recently ␣-defensins 1 to 3, may contribute to CAF activities (17,49; reviewed in reference 40).…”

“…Several independent reports have shown that CAF can inhibit HIV-1 RNA transcription, particularly at the step of long terminal repeat (LTR)-driven gene expression (6,10,23,25), although this is not the only step in the virus life cycle inhibited by CAF. Previously, we demonstrated that CAF inhibits HIV-1 replication and LTR activation through activation of STAT1 (signal transducers and activators of transcription) (3).…”