AUTOLOGOUS CELL-MEDIATED KILLING VIA THE RELEASE OF SOLUBLE FACTORS

Cytotoxic HIV Proteins

Env

The influence of HIV on the extrinsic pathways of cell death has been reported both in productively infected cells and in bystander cells. Cross-linking of CD4⁺ T cells by gp120 activates the Fas-FasL pathway¹⁷ and induces T cell apoptosis (Figure 15.2).

As disease progresses, HIV-1 infected patients show a loss of NK cytotoxic function and a gradual loss of CD4⁺ T cells and NK cells. A concomitant killing in vitro of both gp120-coated CD4⁺ peripheral blood lymphocytes and NK cells has been observed in the antibody-dependent cell-mediated cytotoxicity (ADCC) system.⁸⁴

The envelope gp120_SF2 and SDF-1 differ in the cell type on which they stimulate CXCR4 to induce neuronal apoptosis, but both ligands use the p38 MAPK pathway for death signaling.

via activation of chemokine receptors on M0∕microglia, whereas SDF-1 may act directly on neurons or astrocytes.⁸⁵

Nef, Tat, Vpr

Nef-expressing T cells coexpress FasL,⁸⁶ thereby becoming potential killers of uninfected Fas- expressing T cells. Similarly, Tat, which is secreted by infected cells, upregulates Fas and FasL on uninfected cells and enhances their susceptibility to Fas-mediated apoptosis.⁶³,⁸⁷ Recently, soluble Nef protein was shown to trigger apoptosis of CD4⁺ T cells via stimulation of CXCR4.⁸⁸ Synthetic Vpr induces apoptosis via a direct effect on the mitochondrial permeability transition pore, resulting in the mitochondrial release of apoptogenic proteins such as cytochrome c (Figure 15.2).^89-91

Cytotoxic Factors

Neuronal apoptosis within the central nervous system is a characteristic feature of AIDS dementia, and it represents a common mechanism of neuronal death induced by neurotoxins, e.g., glutamate, released from HIV-infected M0. The V-melhyl-D-asparlale (NMDA) glutamate receptor/Bcl-2- regulated apoptotic pathway contributes significantly to HIV∕M0-induced neuronal apoptosis, and Bcl-2 family proteins protect neurons against the spectrum of primary HIV-1 isolates.⁹² An unusual syncytium-inducing HIV-1 primary isolate from the central nervous system that is restricted to CXCR4 replicates efficiently in M0 and induces neuronal apoptosis via the release of soluble factors.⁹² Primary HIV-1 (BaL)-infected monocytes produce a 66 kDa protein (FLJ21908) that can be detected in brain and lymph tissue from HIV-1-infected patients who suffer from AIDS dementia. Supernatants from these cells induce apoptosis in PBMC, CD4⁺ T cells, CD8⁺ T cells, and B cells.⁹³ Administration of lipopolysaccharide (LPS) to HIV-1-infected huPBMC-NOD-SCID (human PBMC into nonobese diabetic severe combined immunodeficient) mice induces infiltration of HIV- 1-infected human cells in the perivascular region of the brain, and neuronal apoptosis is found in M0-tropic but not T cell-tropic HIV-1-infected brains. The apoptotic neurons were frequently colocalized with the HIV-1-infected M0 that expressed TRAIL. Administration of a neutralizing antibody against TRAIL but not TNF-α or FasL blocked the neuronal apoptosis in the HIV-1-infected brain. These results strongly suggest a critical contribution of TRAIL expressed on HIV-1-infected M0 to neuronal apoptosis.⁹⁴ Also, focal inflammation in brain tissue with HIV-1 encephalitis may upregulate neuronal fractalkine levels, which, in turn, may be a neuroimmune modulator recruiting peripheral M0 into the brain.⁹⁵