Mechanisms of HIV Neuropathogenesis: Role of Cellular Communication Systems

Abstract

Background: One of the major complications of Human Immunodeficiency Virus (HIV) infection is the development of HIV-Associated Neurocognitive Disorders (HANDs) in approximately 50-60% of HIV infected individuals. Despite undetectable viral loads in the periphery owing to anti-retroviral therapy, neuroinflammation and neurocognitive impairment are still prevalent in HIV infected individuals. Several studies indicate that the central nervous system (CNS) abnormalities observed in HIV infected individuals are not a direct effect of viral replication in the CNS, rather these neurological abnormalities are associated with amplification of HIV specific signals by unknown mechanisms. We propose that some of these mechanisms of damage amplification are mediated by gap junction channels, pannexin and connexin hemichannels, tunneling nanotubes and microvesicles/exosomes.

Objective: Our laboratory and others have demonstrated that HIV infection targets cell to cell communication by altering all these communication systems resulting in enhanced bystander apoptosis of uninfected cells, inflammation and viral infection. Here we discuss the role of these communication systems in HIV neuropathogenesis.

Conclusion: In the current manuscript, we have described the mechanisms by which HIV "hijacks" these host cellular communication systems, leading to exacerbation of HIV neuropathogenesis, and to simultaneously promote the survival of HIV infected cells, resulting in the establishment of viral reservoirs.

Fig. 1. Probenecid: A key component regulating intercellular communication as well as anti-retroviral availability

Probenecid, a pannexin channel blocker, has been extensively used along with anti-retrovirals during the treatment of HIV infection. Blocking pannexin channels by probenecid leads to inhibition of ATP release and further activation of purinergic receptors, thereby decreasing ATP-induced neurotoxicity. In addition to its effects on pannexin channels, probenecid leads to decreased renal clearance of anti-retrovirals, causing increased drug exposure. On the other hand, p-glycoproteins have been known to cause active efflux of anti-retrovirals from the cells, leading to lesser efficacy of these drugs. Probenecid, via possible interactions with p-glycoproteins, has been shown to enhance the clinical effects of Tenofovir, Zalcitabine and Zidovudine by limiting their renal tubular secretion. Although blocking pannexin channels by probenecid may lead to lesser ATP-induced neurotoxicity, increased levels of anti-retroviral may be toxic to cells. Hence, clinical usage of probenecid may be critically determined to achieve lesser anti-retroviral toxicity.

Fig. 2. Model of HIV CNS infection

HIV enters the CNS early during the course of HIV infection. CD14⁺ CD16⁺ subset of monocytes are susceptible to HIV infection. This monocyte population (CD14⁺ CD16⁺) contributes to the development of HAND as they promote viral seeding into the brain and manifestation of neuroinflammation. Neuroinvasion by HIV infected CD14⁺ CD16⁺ monocytes is further promoted by expression of various junctional adhesion molecules on the transmigrating monocytes. The transmigration of HIV infected monocytes into the brain leads to alteration of brain homeostasis and results in further spread of the virus to macrophages, microglia as well as astrocytes. The release of viral as well as inflammatory mediators from infected cells results in further activation of non-infected cells, leading to neuroinflammation, neuronal compromise and establishment of viral reservoirs.

Fig. 3. Cell-cell communication systems and spread of toxic stimuli during HIV infection

HIV “hijacks” the intercellular communication systems (Gap junctions, hemichannels, tunneling nanotubes) to transfer toxic stimuli from infected cells to adjacent uninfected cells. This allows the virus to evade the immune system as well as results in the spread of toxic metabolites (ATP, small molecules, glutamate) to the uninfected cells. A- Gap junction channels, composed of connexin proteins, allows HIV infected astrocytes to transfer toxic/apoptotic signals to physically adjacent cells (endothelial cells, astrocytes, neurons). B- Unopposed hemichannels, composed of connexins as well as pannexins, results in transfer of toxic signals, such as ATP, into the extracellular space which may further lead to activation of purinergic receptors on nearby uninfected cells and promote neuroinflammation as well as neuronal compromise. C- Tunneling nanotubes act as a long-range communication system between infected and uninfected cells and may assist in transfer of viral particles as well as viral proteins, successfully evading the host immune response. D- Exosomes contribute to HIV pathogenesis by aiding in transfer of HIV virions/viral components such as viral RNA and viral proteins from infected to uninfected cells.