Functional Synergy between CD40 Ligand and HIV-1 Tat Contributes to Inflammation: Implications in HIV Type 1 Dementia

Abstract

HIV type 1 (HIV-1)-associated dementia (HAD) is believed to occur due to aberrant activation of monocyte-derived macrophages and brain-resident microglial cells by viral proteins as well as by the proinflammatory mediators released by infected cells. To investigate the inflammatory aspects of the disease, we examined the levels of soluble CD40L (sCD40L) in paired samples of plasma and cerebrospinal fluid obtained from 25 HIV-infected individuals. A significantly higher level of sCD40L was detected in both cerebrospinal fluid and plasma from HIV-infected patients with cognitive impairment, compared with their nonimpaired counterparts. The contribution of sCD40L to the pathogenesis of HAD was then examined by in vitro experiments. rCD40L synergized with HIV-1 Tat to increase TNF-α release from primary human monocytes and microglia, in an NF-κB-dependent manner. The mechanistic basis for this synergism was attributed to a Tat-mediated up-regulation of CD40 in monocytes and microglia. Finally, the CD40L-mediated increase in TNF-α production by monocytes was shown to be biologically important; immunodepletion experiments revealed that TNF-α was essential for the neurotoxic effects of conditioned medium recovered from Tat/CD40L-treated monocytes. Taken together, our results show that CD40 signaling in microglia and monocytes can synergize with the effects of Tat, further amplifying inflammatory processes within the CNS and influencing neuronal survival.

Flipping the switches: CD40 and CD45 modulation of microglial activation states in HIV associated dementia (HAD)

“…Upregulation of CD40 expression has been detected on microglia of HIV-1-infected brain tissues [28]. CD40L was also shown to potentiate the ability of HIV-1 Tat to activate monocytes and microglia leading to the overproduction of inflammatory proteins such as cytokines and chemokines [122]. …”

“…Furthermore HAART is unable to modulate blood brain barrier (BBB) leakage and inflammation in HAD patients [29,123] in part because it does not reduce the elevated levels of CD40 ligand (CD40L) found in the plasma and CSF of HIV-1-infected patients [122,124]. In further confirmation, other systems [125-127] have shown high levels of sCD40L can modulate CNS inflammation at the level of the BBB.…”

“…Further assays from the same study showed CD40L synergized with HIV-1 Tat to increase TNF-α release from primary human monocytes and microglia, in an NF-κB-dependent manner [122]. …”

HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity

“…Williams et al 69 have reported that the interplay of TNFa and HIV-1 leads to enhanced expression of toxic chemokines. Sui et al 70 have shown that the HIV protein influences neuronal survival by increasing in TNFa production. Intrathecal administration of soluble gp120 induces neuropathic pain and proinflammatory cytokine release in the spinal cord.…”

Role of Tat Protein in HIV Neuropathogenesis

“…The epitope of Tat that induces TNF-a is different from the one that causes neurotoxicity (Buscemi et al 2007). Tat-induced TNF-a can mediate neurotoxicity (New et al 1998;Shi et al 1998;Sui et al 2007). MCP-1/ CCL-2 is a highly potent chemoattractant for monocytes.…”