Immunomodulatory Role of Complement Proteins in the Neuropathology Associated with Opiate Abuse and HIV-1 Co-Morbidity

Abstract

The complement system which is a critical mediator of innate immunity plays diverse roles in the neuropathogenesis of HIV-1 infection such as clearing HIV-1 and promoting productive HIV-1 replication. In the development of HIV-1 associated neurological disorders (HAND), there may be an imbalance between complement activation and regulation, which may contribute to the neuronal damage as a consequence of HIV-1 infection. It is well recognized that opiate abuse exacerbates HIV-1 neuropathology, however, little is known about the role of complement proteins in opiate induced neuromodulation, specifically in the presence of co-morbidity such as HIV-1 infection. Complement levels are significantly increased in the HIV-1-infected brain, thus HIV-induced complement synthesis may represent an important mechanism for the pathogenesis of AIDS in the brain, but remains underexplored. Anti-HIV-1 antibodies are able to initiate complement activation in HIV-1 infected CNS cells such as microglia and astrocytes during the course of disease progression; however, this complement activation fails to clear and eradicate HIV-1 from infected cells. In addition, the antiretroviral agents used for HIV therapy cause dysregulation of lipid metabolism, endothelial, and adipocyte cell function, and activation of pro-inflammatory cytokines. We speculate that both HIV-1 and opiates trigger a cytokine-mediated pro-inflammatory stimulus that modulates the complement cascade to exacerbate the virus-induced neurological damage. We examined the expression levels of C1q, SC5b-9, C5L2, C5aR, C3aR, and C9 key members of the complement cascade both in vivo in post mortem brain frontal cortex tissue from patients with HAND who used/did not use heroin, and in vitro using human microglial cultures treated with HIV tat and/or heroin. We observed significant expression of C1q and SC5b-9 by immunofluorescence staining in both the brain cortical and hippocampal region in HAND patients who abused heroin. Additionally, we observed increased gene expression of C5aR, C3aR, and C9 in the brain tissue of both HIV-1 infected patients with HAND who abused and did not abuse heroin, as compared to HIV negative controls. Our results show a significant increase in the expression of complement proteins C9, C5L2, C5aR, and C3aR in HIV transfected microglia and an additional increase in the levels of these complement proteins in heroin-treated HIV transfected microglia. This study highlights the a) potential roles of complement proteins in the pathogenesis of HIV-1-related neurodegenerative disorders; b) the combined effect of an opiate, like heroin, and HIV viral protein like HIV tat on complement proteins in normal human microglial cells and HIV transfected microglial cells. In the context of HAND, targeting selective steps in the complement cascade could help ameliorating the HIV burden in the CNS, thus investigations of complement-related therapeutic approaches for the treatment of HAND are warranted.

Loss of regulation of complement C5 activation in HIV associated Preeclampsia

“…We also demonstrate that HIV status did not affect serum C2 expression at term, albeit with an upregulated trend. These results are similar to that of Mahajan et al (2017) who reported in vitro studies of HIV-1 infected astrocytic cell lines and primary astrocytes a significant enhancement of C2 and C3 expression [62]. Huson et al (2015) reported increased C3 and C1q-C4 levels in asymptomatic patients with HIV infection compared to healthy controls [31].…”

“…These results are similar to that of Mahajan et al . (2017) who reported in vitro studies of HIV-1 infected astrocytic cell lines and primary astrocytes a significant enhancement of C2 and C3 expression [62]. Huson et al .…”

Emerging Roles of Complement Protein C1q in Neurodegeneration

“…C1q is considered to be beneficial for eliminating aggregated proteins following the activation of the complement factor by low levels of aggregates. However, when the complement factor is chronically activated, it can harm the CNS due to activated microglia and pro-inflammatory cytokines [79, 80]. In the CNS, many components of the immune system are locally produced.…”

HIV Tat causes synapse loss in a mouse model of HIV‐associated neurocognitive disorder that is independent of the classical complement cascade component C1q

“…In contrast, the reports on C3 levels in the CSF of HIV+ patients have been mixed with some studies showing increased levels (Jongen et al., 2000) and others decreased levels (Reboul et al, 1989; Rozek et al, 2007) that likely reflect the complex interplay between increased expression and enhanced activation/degradation of C3. Within brain parenchyma, multiple complement transcripts are up-regulated in patients with HIV-1 encephalitis (Gelman et al, 2012; Mahajan et al, 2017), a neuropathologic entity that occurs infrequently since the advent of cART. Whether aberrant complement deposition represents a penultimate step in synapse removal associated with HIV infection remains an essential unanswered question because synaptic architecture and function are the key pathologic substrates for HAND.…”