NeuroHIV and Chemokine Receptors
Despite the benefits of current antiretroviral treatments, the neurological complications of HIV infection remain an important and unmet medical and social need. Drug abusers, particularly injection drug users, represent a significant group of HIV-infected patients. These individuals, whose adherence to antiretroviral therapy is generally poor, often present with a more dramatic progression to AIDS and neuroAIDS. Opiates can accelerate HIV neuropathology by acting on immune and neural cells; however, the mechanisms involved are unclear. Characterization of these mechanisms will yield new insights for the development of neuroprotective therapies in HIV patients.
The neurological complications of HIV include a large spectrum of sensory, motor and cognitive problems caused by neuronal and glial alterations in the peripheral and central nervous system. HIV enters the brain early in the course of infection through the passage of infected mononuclear cells into the perivascular space and infects macrophages and microglia. However, neurodegeneration likely results from the interplay of viral and cellular factors in the CNS with systemic components of neuroinflammation occurring over a longer period of time. Neuronal damage and loss derive from a complex series of events implicating both neuronal and non-neuronal cells. To date, the molecular mechanisms leading to CNS injury and the viral factors involved in neuronal death are still undefined. Although Highly Active Antiretroviral Therapy (HAART) has reduced the incidence of HIV-associated dementia, it does not provide complete protection from dementia or other minor neurological complications of AIDS. These neurological manifestations remain an important complication of HIV infection that interfere with patients’ daily activities, and also represent an independent risk factor for mortality.
According to current models, CNS injury is mainly caused by the release of neurotoxic factors by immune-activated and HIV-infected macrophages and microglia. These toxins may include the HIV envelope proteins, gp120 and gp41, other viral proteins, and various cellular products, which are able to induce neuronal injury, dendritic and synaptic damage, as well as neuronal and glial apoptosis. One well-studied viral protein with reported neurotoxic effects in vitro and in vivo is the HIV-1 envelope protein gp120, which normally mediates binding of HIV to target cells via CD4 and a chemokine receptor. In vitro, gp120 is able to induce apoptosis of neurons both in the presence and in the absence of glia and microglia. Transgenic mice expressing gp120 in the brain manifest neuropathological features similar to those observed in AIDS patients. Thus, both direct and indirect mechanisms may be responsible for the neuronal damage/death associated with HIV-1 infection. Existing evidence supports both mechanisms although the molecular details have just started to be unraveled.
The interaction of gp120 with target cells is mediated by chemokine receptors (namely CCR5 and CXCR4), a family of G-protein coupled receptors that regulate important physiological processes, such as activation and migration of leukocytes, neuronal development and organogenesis. Studies from several laboratories including ours have demonstrated that neurons and glia cells normally express chemokine receptors, which activate different signaling pathways in both cell types. Research over the last few years has indeed shown that — besides their traditional role in neuroinflammation — chemokines are involved in a number of neuronal and glial functions, from proliferation, survival, and differentiation to migration and neurotransmission. Thus, alteration of their function may contribute to different neuropathologies, such as neuroAIDS and cancer.
By characterizing the cellular and environmental factors that modulate the interaction of chemokines with their cognate receptors, we aim to gain insights into innovative therapeutic approaches against HIV neuropathology and, possibly, other neurological disorders. The ultimate goal is to design and adopt strategies that promote the neuroprotective actions of homeostatic chemokines.