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Most studies consider the induction of innate immune responses such as cytokines, chemokines, oxidative stress, and proteases to be detrimental to the neuron. This concept has been applied to most neurodegenerative diseases, including HIV-associated cognitive impairment (Fig. 1). However there are reasons to believe that in the setting of viral infections, such responses may not always be hostile to the host. Organisms that lack a cellular immune response often use such innate immune responses to protect themselves from invading pathogens. For example, plants, without a specific adaptive immune system, may use metalloproteinases, along with other innate defense mechanisms, to combat infection. For example, the metallo-proteinases-2 gene of the soybean, Glycine max, is upregulated in response to a variety of infections (1). Thus in circumstances where the cellular immune responses fail to control the pathogen such as persistent HIV infection of the CNS, the innate immune responses get activated. For example, it has been shown that matrix matal-loproteinases (MMP), which are a family of structurally similar, zinc-containing endopeptidases, that are known to be increased in patients with HIV dementia can cleave the Tat protein of HIV and thus inactivate it and prevent the protein from causing neurotoxicity or from transactivating the HIV genome (2). Similarly, oxidative stress may be an attempt by the host to cause inactivation of viral proteins by modification by free radicals, nitric oxide, or reactive aldehydes released by lipid peroxidation. However, these types of offensive mechanisms are nonspecific and can result in damage to the host cells (Fig. 1). This is particularly true when there is a chronic activation of the innate immune responses. Considering the same example of MMPs, it has been shown that these molecules can enzymatically degrade the extracellular matrix proteins and can thus disrupt the blood-brain barrier and neuronal synapses (3-6). MMPs can also cleave other host proteins, such as chemokines (7), and these cleavage products can cause neurotoxicity. Further, MMPs may directly interact with integrin receptors on neurons, and initiate a cascade of events leading to neuronal cell death (8).

Further, innate immune responses may interact with one another. MMPs can become nitrosylated and persist in a hyperactive state, perhaps contributing to neurotoxicity under conditions of oxidative stress (9). Autopsy studies also confirm elevated levels of inducible nitric oxide synthase (iNOS) in patients with HIV dementia (10-11). iNOS is present in macrophages and microglia and its levels

Activated macrophage

Reactive oxygen species and NO

Reactive oxygen species and NO

Proteases

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