HIV Neuropathogenesis

HIV – associated dementia (HIVD), as the commonest cause of dementia in people ages less than 40, is a major clinical problem. Its prevalence has continued to rise in Australia despite the introduction of highly active antiretroviral therapy (HAART). The requirements for the development of HIVD are immunosuppression, loss of macrophage regulation, infection of central nervous system (CNS) microglia and macrophages with a neurovirulent HIV strain, restricted HIV infection of astrocytes, and astrocyte cell death; all of which lead to a neurotoxic intracellular milieu.

The use of HAART to control viral replication both systemically and centrally, has a major impact on this cascade. However those patients who have persistently elevated levels of HIV replication, due either to resistant virus or the inability to tolerate HAART, are at high risk of developing cognitive dysfunction. In addition there is a subgroup of patients with ongoing HIV replication in the CNS despite systemic virological control who are also at risk. Our understanding of the control of excessive microglial and macrophage activation or a diminution of astrocyte and neuronal apoptosis could have benefits in the treatment of these patients.

Peripheral neuropathy is another very common and disabling neurological complication of HIV infection, with limited treatment options. This may occur as a consequence of the direct effects of viral replication. However, controlling viral replication with HAART has not reduced the incidence of neuropathy, with the toxic effects of antiretrovirals now contributing to peripheral nerve damage. Mitochondrial dysfunction as well as macrophage activation are thought to play significant roles in the pathogenesis of this condition.

There are a number of similarities and parallels in the pathogenesis of HIVD and peripheral neuropathy. A better understanding of these may lead to novel therapies with improved efficacy against nervous system disease compared with simply controlling viral replication.