Cerebral complement activation in AIDS

Neurological symptoms among HIV-1-infected patients are rather frequent. The most prominent infection- associated complex of neurological dysfunctions is the AIDS dementia complex (ADC) with cognitive, motor and behavioural symptoms. Although the symptoms of ADC are severe and widespread neuroinflammation and - degeneration are found, only a small part of the brain cells is infected. For that reason it is supposed that neurological damage is an indirect effect with induction of a harmful mediator substance rather than a direct effect of viral infection of the cells. Several intriguing hints from literature and previous own results suggest that complement as a central part of the innate brain immunity might also be a mediator of HIV-induced neurodegeneration. It is known that HIV activates the classical pathway of the complement cascade independently of the presence of antibodies, and an association of chronic complement activation to neurodegeneration has already been established for diseases like Alzheimer`s disease and multiple sclerosis. Furthermore, since complement activation products activate microglial cells and astrocytes, enhance the synthesis of pro-inflammatory cytokines and induce neuronal apoptosis, HIV-induced complement activation can contribute to the processes of neuroinflammation, microgliosis and reactive astrocytosis, which are typical findings in ADC. In addition, our previous work showed that HIV highly upregulates the expression of some complement factors in astrocytes, thus providing the basis of these complement effects. Our aim is to analyse cerebral complement synthesis and activation in humans and, as an appropriate animal model, in monkeys during infection with HIV or SIV, respectively, and to establish a correlation between complement and neurological damage. This project can give important insights into the mechanism of HIV/SIV-associated brain pathogenesis and, moreover, this knowledge might help to design a new therapeutic approach for the treatment of ADC by modulating the extent of HIV/SIV-induced complement activation in the brain. For this project we could gain two different collaboration partners who will provide precious and rare investigation material which enables us to to answer these questions both in a monkey model and in HIV-infected patients.

HIV-infected patients suffer from a variety of neurological dysfunctions with partly severe cognitive, motor and behavioural symptoms. The high percentage of AIDS patients with viral penetration within the CNS and subsequent neuronal damage indicates a profound failure of the antiviral immune defence of the brain. The precise mechanism of HIV-induced cerebral inflammation and neurodegeneration is not known. The fact that only a small part of the brain cells is infected implies the involvement of a soluble factor which is produced during infection and exerts neurotoxic effects. Complement is a central immune system of the CNS which might play a role both in protective and harmful processes. Its primary aim is to opsonize invading pathogens and infected cells, thus targeting them for phagocytosis. Furthermore, it harbors the capacity to induce direct lysis and to attract peripheral immune cells into the brain. Thus it represents a putative therapeutic target aiming to support complement activation and effectiveness. However, this powerful weapon with its capacity to promote inflammation and destruction of infected cells is also supposed to participate in neurogeneration, as shown for diseases like Multiple Sclerosis and Alzheimer. Therefore it might also represent a potentially destructive brain component. Normal complement levels in the cerebrospinal fluid (CSF) are low. We could show both in cell culture and in a monkey model that different brain cell types react on viral infection with a dramatic increase of complement synthesis. Samples from HIV-infected patients confirmed the result that stimulation of complement production represents an early defence mechanism of the brain. This increase in complement levels reflects an increase in antimicrobial capacity of the complement system. CSF from uninfected persons with normal complement levels was not able to target invading pathogens for phagocytosis and to induce the oxidative burst, a destruction program within the phagocytes. Consequently, the amount of viable pathogens could not be diminished by incubation in normal CSF. In contrast inflammatory CSF from patients with cerebral HIV infection and increased concentrations of complement efficiently opsonized pathogens for phagocytosis, induced a significant oxidative burst and reduced the viability of pathogens. However, the efficiency of serum with its high complement levels could not be reached, indicating additional complement increase as putative therapeutic target. On the other hand, immunohistochemical staining in brain sections derived from HIV-infected patients revealed indications that complement might also contribute to neuronal loss, implying that such a therapeutic approach should strictly weigh the balance between beneficial and harmful effect.