We have previously characterized a model for immune activation of HIV-1 in which viral proteins as well as infectious virus are induced in HIV-1 transgenic mice by infection with intracellular protozoan and bacterial pathogens commonly encountered by AIDS patients. Viral expression in this system appears to be restricted in situ and in vitro to antigen presenting cells (APC) with T cells failing to respond even after polyclonal stimulation. In the past year?s work we explored the mechanism underlying this T cell unresponsiveness. Simultaneous treatment of spleen cultures with polyclonal T cell activators was found to inhibit LPS induced p24 expression suggesting that activated T cells produce a factor that suppresses viral replication. Using isolated cell populations it was shown that CD4+ T lymphocytes and to a lesser extent CD8+ T lymphocytes are suppressive and that viral expression by purified B cells is inhibited by this mechanism. By means of transwell experiments we demonstrated that suppression of B cell p24 production by CD4+ T cells does not require cell contact while CD8 mediated suppression is contact- dependent. Indeed, supernatants of activated T lymphocytes could suppress LPS induced virus production by whole spleen cells or purified B cells. Additional studies using supernatants generated from knock-out mice failed to reveal a role for down-regulatory cytokines in HIV suppression. Moreover, the suppressive factor was shown to be both heat resistant and protease insensitive. 0ne possibility is that the synthesis of this factor by T lymphocytes results in autocrine inhibition of virus production by the same cell population. Attempts to study the above mechanism at the transcriptional level were hampered by our inability to detect elevated gag or env mRNA in LPS stimulated spleen cells or purified splenic B and T cell populations in vitro. This difficulty may reflect unconventional message processing or indicate that the regulation of virus production in our model can occur at the translational level.
