Glutamate metabolism and HIV-associated neurocognitive disorders.

HIV-1 infection can lead to neurocognitive impairment collectively known as HIV-associated neurocognitive disorders (HAND). Although combined antiretroviral treatment (cART) has significantly ameliorated HIV's morbidity and mortality, persistent neuroinflammation and neurocognitive dysfunction continue. This review focuses on the current clinical and molecular evidence of the viral and host factors that influence glutamate-mediated neurotoxicity and neuropathogenesis as an important underlying mechanism during the course of HAND development. In addition, discusses potential pharmacological strategies targeting the glutamatergic system that may help prevent and improve neurological outcomes in HIV-1-infected subjects.

Impact of Depression and Inflammation on the Progression of HIV Disease.

The human immunodeficiency virus type 1 (HIV-1) epidemic has negatively affected over 40 million people worldwide. Antiretroviral therapy (ART) has improved life expectancy and changed the outcome of HIV-1 infection, making it a chronic and manageable disease. However, AIDS and non-AIDS comorbid illnesses persist during the course of infection despite the use of ART. In addition, the development of neuropsychiatric comorbidities (including depression) by HIV-infected subjects significantly affects quality of life, medication adherence, and disease prognosis. The factors associated with depression during HIV-1 infection include altered immune response, the release of pro-inflammatory cytokines, and monoamine imbalance. Elevated plasma pro-inflammatory cytokine levels contribute to the development of depression and depressive-like behaviors in HIV+ subjects. In addition, comorbid depression influences the decline rates of CD4+ cell counts and increases plasma viral load. Depression can manifest in some subjects despite their adherence to ART. In addition, psychosocial factors related to stigma (negative attitudes, moral issues, and abuse of HIV+ subjects) are also associated with depression. Both neurobiological and psychosocial factors are important considerations for the effective clinical management of HIV and the prevention of HIV disease progression.

Envelope gene evolution and HIV-1 neuropathogenesis.

In the era of combined antiretroviral therapy (cART), HIV-associated neurocognitive disorders (HAND) account for 40 to 56% of all HIV+ cases. During the acute stage of HIV-1 infection (<6 months), the virus invades and replicates within the central nervous system (CNS). Compared to peripheral tissues, the local CNS cell population expresses distinct levels of chemokine receptors, which levels exert selective pressure on the invading virus. HIV-1 envelope (env) sequences recovered from the brains and cerebrospinal fluid (CSF) of neurocognitively impaired HIV+ subjects often display higher nucleotide variability as compared to non-impaired HIV+ subjects. Specifically, env evolution provides HIV-1 with the strategies to evade host immune response, to reduce chemokine receptor dependence, to increase co-receptor binding efficiency, and to potentiate neurotoxicity. The evolution of env within the CNS leads to changes that may result in the emergence of novel isolates with neurotoxic and neurovirulent features. However, whether specific factors of HIV-1 evolution lead to the emergence of neurovirulent and neurotropic isolates remains ill-defined. HIV-1 env evolution is an ongoing phenomenon that occurs independently of neurological and neurocognitive disease severity; thus HIV env evolution may play a pivotal and reciprocal role in the etiology of HAND. Despite the use of cART, the reactivation of latent viral reservoirs represents a clinical challenge because of the replenishment of the viral pool that may subsequently lead to persistent infection. Therefore, gaining a more complete understanding of how HIV-1 env evolves over the course of the disease should be considered for the development of future therapies aimed at controlling CNS burden, diminishing persistent viremia, and eradicating viral reservoirs. Here we review the current literature on the role of HIV-1 env evolution in the setting of HAND disease progression and on the impact of cART on the dynamics of viral evolution.