Human Immunodeficiency Virus (HIV) does not only impact the immune system, but it is also associated with neurocognitive disorders that lead to a spectrum of cognitive, motor, and mood problems. These HIV-associated neurocognitive disorders (HAND) are seen in many HIV patients with about 30-50% suffering from at least a mild form of the disorder. Some side effects of HAND include difficulty with attention, concentration, memory, and slowed movements. Many factors can contribute to the development and severity of HAND including age and comorbidities. Scientists at San Diego BioMed are concentrating on how these contributing factors impact HAND to understand where therapies need to be targeted.

STUDY

HIV-Associated Neurocognitive Disorders (HAND) – The Marcondes Group

While the Central Nervous System (CNS) is susceptible to inflammation, it also contributes to the inflammatory processes that are initiated by local and peripheral insults. Glia cells, microglia, and astrocytes are early responders to HIV infection. In response to infection, they quickly modify the production of inflammatory mediators, cytokines, free radical, and neurotrophic factors. Glial cells enhance the recruitment of peripheral immune and inflammatory cells which further activate glial cells, reducing the function and viability of neurons. This negatively impacts cognitive function, behavior, body temperature, and circadian rhythm.

Viral infections of the CNS, including HIV, modulate the activity of glial cells and the immune environment leading to the production of acute and chronic neurological symptoms. Within the first few weeks of infection, HIV, carried by white blood cells known as macrophages, cross the blood-brain barrier and enter the CNS. Once in the brain, HIV quickly infects microglia and perivascular macrophages. The result is extremely damaging. Moreover, neither HAND nor neuroAIDS, two neurological disorders caused by HIV damage, are controlled by antiretroviral therapies.

The Marcondes group is looking at two factors that can aggravate CNS function in HIV-infected individuals – aging and drug abuse. Aging can aggravate neurological outcomes and CNS dysfunction in HIV-infected individuals. The Marcondes group is testing the hypothesis that HIV triggers mechanisms that are common to and accelerate the aging process. Ongoing research examines the changes that are induced in cells in the CNS by HIV-infection and that are also present in aging uninfected cells.

Another factor that can aggravate CNS function during HIV infection is drug use. A drug of particular concern is methamphetamine, which is cheap, highly addictive, and its use is rapidly increasing. There is substantial overlap between the epidemiology of methamphetamine abuse and HIV infection. The Marcondes lab has shown that methamphetamine use increases the abundance and activation of HIV target cells in the CNS, increasing the HIV reservoir and aggravating inflammatory pathology.

Dr. Marcondes’ research focuses on how methamphetamine modulates infiltrating macrophages and glial cells to become inflammatory and support HIV productive infection. Methamphetamine might act directly through the induction of second messengers which are intended to activate and amplify signaling pathways, inducing a cellular response.

In addition to this, the Marcondes group studies other deleterious consequences of methamphetamine including its ability to increase the core body temperature, often resulting in lethal hyperthermia. This condition involves free radicals in peripheral thermogenic sites, including brown adipose tissue. The Marcondes group is studying how the oxidative stress-mediated mechanisms that affect body temperature modify thermogenetic programs.