Analysis of HIV-specific CD8+ T cells from HIV-infected donors revealed that TRAF1 expression was specifically reduced in these cells from chronically infected donors but not from recently infected donors or virus controllers. Further studies confirmed that TRAF1 expression levels decrease in HIV-specific CD8+ T cells over time and negatively correlate with viral load and the expression of programmed cell death 1 (PD1), which is a negative regulator of T cell function. Forced knockdown of TRAF1 expression in CD8+ T cells from virus controllers using small interfering RNA led to defective virus control of infected CD4+ T cells by these CD8+ T cells ex vivo. This defect could be overcome by simultaneous knockdown of the pro-apoptotic molecule BCL2-interacting mediator of cell death (BIM; also known as BCL2L11), which is known to be downmodulated in a TRAF1-dependent manner. Loss of TRAF1 expression was also found to impair the proliferation of HIV-specific CD8+ T cells in response to 4-1BB ligand (4-1BBL; also known as TNFSF9), the receptor for which signals through TRAF1.
The authors similarly observed a selective loss of TRAF1 expression in virus-specific CD8+ T cells from mice infected with an LCMV strain that establishes a chronic infection, but not from mice infected with an acute LCMV strain. In addition, a role for TRAF1-dependent, 4-1BBL-mediated signalling in the control of early infection is consistent with the finding that 4-1BBL-deficient mice generated low numbers of virus-specific CD8+ T cells and had high viral loads early after infection with LCMV, but not at later stages of the infection.
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