HIV immune complexes prevent excitotoxicity by interaction with NMDA receptors.

PURPOSE: Human immunodeficiency virus-1 (HIV)-associated neurocognitive disorder (HAND) is a neurodegenerative disease for which there is no available neuroprotective therapy. Viral proteins, such as Tat, have been implicated as agents of neurotoxicity via multiple mechanisms, including effects by directly binding to the NMDA receptor. We evaluated the ability of the immune response against Tat to modulate neurotoxicity at glutamate receptors. METHODS: Neurotoxicity was measured in primary neuronal-glial cultures and in hippocampal slice cultures. We used immunoprecipitation experiments to demonstrate interaction between Tat, NMDA receptor, and anti-Tat antibody. Using known structures of Tat and NMDA receptors, we developed a model of their interactions. RESULTS: Antibodies to Tat attenuated Tat-mediated neurotoxicity. Interestingly, Tat immune complexes also blocked neurotoxicity caused by NMDA receptor agonists but not kainate/AMPA receptor agonists. Neither Tat nor antibody alone blocked the excitotoxic effect, nor did an unrelated antigen-antibody complex. The protective effect of the Tat immune complexes was also lost when Tat was modified by nitrosylation or by using a deletion mutant of Tat. CONCLUSIONS: The ability of viral immune complexes to interact with NMDA receptors and prevent excitotoxicity represents a novel host defense mechanism. Host immune responses may influence host susceptibility to various effects of viral proteins, modulating HIV complications, such as onset of HAND. These observations provide rationale for development of vaccine therapies targeting Tat for prevention of HAND.

Developments in HIV neuropathogenesis.

Despite the fact that neurons are rarely infected by the human immunodeficiency virus (HIV), neuronal loss is common in patients with HIV infection, likely due to the effects of viral proteins and inflammatory mediators on these cells. Despite the widespread use of highly active antiretroviral therapy (HAART), at least in developed nations, cognitive impairment and other neurological complications of HIV infection persist with devastating personal and socioeconomic consequences. Fortunately, we have made important advances in recent years in defining the molecular mechanisms by which HIV infection targets the nervous system for damage. Such understanding has opened numerous therapeutic options, which are only now beginning to be exploited. This review will highlight the current state of thought regarding the neuropathogenesis of HIV infection. It will summarize the most recent research looking at the roles of both viral and host factors in mediating HIV-induced neurological disease. Utilizing this knowledge base, a framework will be outlined for current and future therapeutic trials to prevent or improve neurological complications of HIV infection.

HIV-associated neurocognitive disorders: Five new things.

HIV-associated neurocognitive disorders (HAND) remain an important cause of cognitive dysfunction. Current nomenclature for HAND includes HIV-associated dementia and milder forms known as asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND). ANI and MND remain highly prevalent despite combined antiretroviral therapy (cART). These mild forms of HAND must be diagnosed through neuropsychological testing. If a patient has HAND, it remains unclear whether using a cART regimen with theoretically superior CNS penetration improves the prognosis. Nevertheless, a CNS penetration effectiveness score for antiretrovirals is available. Other factors to consider when diagnosing and treating HIV infection and HAND include the HIV clade or subtype. Data suggest that HAND occurs more often in association with certain clades, and higher vigilance for cognitive dysfunction may be recommended. Finally, comorbidities, such as diseases associated with advanced age, other infections, and drug abuse, need to be considered as cofactors for cognitive dysfunction and treated accordingly.

Developing neuroprotective strategies for treatment of HIV-associated neurocognitive dysfunction.

Important advances have been made in recent years in identifying the molecular mechanisms of HIV neuropathogenesis. Defining the pathways leading to HIV dementia has created an opportunity to therapeutically target many steps in the pathogenic process. HIV itself rarely infects neurons, but significant neuronal damage is caused both by viral proteins and by inflammatory mediators produced by the host in response to infection. Highly active antiretroviral therapy (HAART) does not target these mediators of neuronal damage, and the prevalence of HIV-associated neurocognitive dysfunction has actually been rising in the post-HAART era. This review will briefly summarize our current understanding of the mechanisms of HIV-induced neurological disease, and emphasize translation of this basic research into potential clinical applications.

Ceftriaxone protects against the neurotoxicity of human immunodeficiency virus proteins.

Human immunodeficiency virus (HIV) proteins Tat and gp120 have been implicated in the pathogenesis of HIV dementia by various mechanisms, including down-regulation of excitatory amino acid transporter-2 (EAAT2), which is responsible for inactivation of synaptic glutamate. Recent work indicates that beta-lactam antibiotics are potent stimulators of EAAT2 expression. The authors treated mixed human fetal neuronal cultures with recombinant gp120 or Tat, in the presence or absence of ceftriaxone, and determined neurotoxicity by measuring mitochondrial membrane potential and neuronal cell death. Ceftriaxone produced dose-dependent attenuation of the neurotoxicity and neuronal cell death caused by both viral proteins. This study demonstrates that this class of drugs may have therapeutic efficacy in HIV dementia.

Viruses and the brain: from inflammation to dementia.

Many viruses cause encephalitis, but understanding the mechanisms by which viral infection leads to encephalopathy or dementia remain elusive. In many cases, inflammation generated by the host's attempt to combat the infection is itself implicated as a primary factor in causing neuronal dysfunction or degeneration. In this review, we outline the current state of knowledge regarding the pathophysiology of CNS (central nervous system) injury in viral infection. We focus our review on the neuropathogenesis of HIV type 1 (HIV-1)-associated dementia, because, within this class of infection, it is the best studied. We will also discuss the key similarities and differences in the pathological mechanisms of other important viral encephalitides. Understanding these mechanisms should ultimately enable development of immunomodulatory therapies for treating these infections, as well as other neuro-inflammatory conditions.

Pseudomonas aeruginosa infective endocarditis presenting as bacterial meningitis.

Pseudomonas aeruginosa is a rare cause of infective endocarditis. The case of community-acquired P. aeruginosa infective endocarditis reported here is the first described in the literature to present as bacterial meningitis. Furthermore, new risk factors for P. aeruginosa infective endocarditis, including mitral annular calcification and re-use of insulin syringes, are proposed. Treatment of P. aeruginosa infective endocarditis complicated by bacterial meningitis is discussed.