Comment on Muthumani et al, page 2059
The accessory HIV-1 protein Nef can activate a proapoptotic pathway via the activation of the p38 MAP kinase. Accumulating evidence links p38 MAP kinase to AIDS pathogenesis.
Human immunodeficiency virus-1 (HIV-1) uses a plethora of mechanisms to subvert the immune response, mainly by triggering the apoptotic decay of immune cells.1 Cell death not only occurs in HIV-1–infected cells as a consequence of the cytopathic effect (in cis) but also affects noninfected bystander cells (in trans).1
In an elegant paper in this issue of Blood, Muthumani and colleagues unravel a novel pathway through which HIV-1 can trigger bystander cell killing. The accessory protein Nef is one of the rare HIV-1–encoded gene products that can inhibit apoptosis in infected cells, thus enhancing the possibility of the virus to replicate in a cell whose life is prolonged. Simultaneously, Nef stimulates the expression of CD95 ligand (CD95L, FasL), a cell surface–anchored protein that can bind in trans to CD95 (Fas), a death receptor expressed on the plasma membrane of activated lymphocytes. Thus, Nef-elicited CD95L may trigger the death of uninfected CD95+ cytotoxic lymphocytes (CTLs) that interact with CD95L+ HIV-1–infected cells. Specifically, Muthumani et al show that HIV-1–infected activated macrophages can trigger the death of primary CD8+ CTLs in a CD95-dependent fashion. This effect is obtained when macrophages are infected with a pseudotyped HIV-1 derivative in which the HIV-1 env gene has been replaced by the vesicular stomatitis virus G (VSV-G) envelope, yet disappears upon deletion of nef from the viral genome, thus implicating Nef and not Env in the proapoptotic effect. In a transgenic mouse model, Nef (without other HIV-1 genes) is sufficient to cause an immunodeficiency syndrome, even in animals genetically deficient for CD95 or CD95L.2 This suggests that the CD95/CD95L system is dispensable for Nef-dependent AIDS pathogenesis in vivo, perhaps because it is backed up by other proapoptotic mechanisms such as other death receptors and their ligands.FIG1
Of most importance, however, Weiner et al show that p38 mitogen-activated protein (MAP) kinase is activated by Nef and that inhibition of this kinase by chemical inhibitors, dominant-negative p38 mutants, or small-interfering RNA abolishes CD95L induction by Nef. Thus, p38 inhibition can abolish CTL bystander killing by HIV-1–infected macrophages. Although Nef is sufficient to induce p38 activation, Nef-deficient HIV-1 still elicits partial p38 activation. Indeed, the HIV-1 envelope glycoprotein complex (gp120/gp41) anchored in the plasma membrane or its soluble derivative gp120 has been known to trigger p38 activation in trans, either through the induction of cell fusion or through signaling mediated by the CXC receptor 4 (CXCR4) chemokine receptor.3 Once activated by an upstream kinase such as MAP kinase kinase 3 (MKK3), p38 then can trigger the expression of proapoptotic proteins through the action of transcription factors, namely AP1 (a heterodimer of c-Jun and c-Fos) or p53, the latter being a direct target of p38-mediated phosphorylation.3 This appears to be context dependent, because p38 activated in cis (by Nef) leads to AP1 activation (with consequent CD95L expression), presumably without p53 activation because Nef can bind and neutralize p53. However, p38 activated in trans (by gp120/gp41 or gp120) causes nuclear factor κB (NF-κB) and p53 activation, thereby triggering the intrinsic pathway of apoptosis (see the figure).
Of note, the activating phosphorylation of p38 has been observed in peripheral mononuclear cells and lymph node biopsies from untreated HIV-1–infected donors, correlating with viral load.3 p38 activation has also been found in the brain of patients with HIV-1–associated encephalopathy, specifically in multinucleated giant cells,4 making it a possible surrogate marker of disease progression as well as a prospective therapeutic target. ▪