Adjunctive therapies for HIV-1 associated neurologic disease

Abstract

In the past decade we have seen a milder phenotype and decreased incidence of HIV-1 associated dementia (HAD), largely due to the widespread use of combination chemotherapy to reduce viral burden. However, the prevalence of neurologic disease in people living with HIV-1 has actually increased, raising significant concerns that new therapeutic strategies, directed at restoring neuronal and glial homeostasis and signaling in the central nervous system (CNS), as opposed to directly interfering with the life cycle of HIV-1, must be developed. In this review, we focus briefly on previous Phase 1 clinical trials for adjunctive (i.e., chemotherapeutic agents that do not have a primary antiretroviral mechanism of action) therapy in patients with HAD, followed by an overview of key molecular events in the neuropathogenesis of HAD, and then discuss in more detail our rationale for investigating the effects of therapeutic agents that restore impaired mitochondrial bioenergetics in the CNS. Specifically, we focus on agents that either work in part through K-ATP channels, present in both mitochondria and plasma membranes, and agents that work to weakly uncouple the respiratory capacity of the electron transport chain in mitochondria from ATP production. We propose these agents may be complementary to currently available antiretroviral agents and may significantly improve the capacity of CNS infected with HIV-1 to meet increased bioenergetic demands involved in normal synaptic communication.

Copolymer-1 Induces Adaptive Immune Anti-inflammatory Glial and Neuroprotective Responses in a Murine Model of HIV-1 Encephalitis

“…These factors include, but are not limited to, the HIV-1 proteins such as gp120 and tat, proinflammatory cytokines, arachidonic acid and its metabolites, quinolinic acid, and glutamate (42)(43)(44). Prior works performed in animal models and in humans have shown that adjunctive microglial immune modulatory drugs can affect HIV-1-associated cognitive decline (43,(45)(46)(47). Such neuroprotective therapies interrupt direct damage to neurons by attenuating the effects of macrophage activation.…”

Neuroimmunity and the Blood–Brain Barrier: Molecular Regulation of Leukocyte Transmigration and Viral Entry into the Nervous System with a Focus on NeuroAIDS

“…HAART has not been effective in reducing the prevalence of HIV-related neurodegenerative disease (see review by Perry et al 2005), suggesting the existence of a viral reservoir in the CNS. This was found in the two-virus model of NeuroAIDS; infected macaques treated with a compound incapable of crossing the BBB were found to have higher CNS viral loads than those that received a compound that could .…”

“…Therefore, the pharmaceutical focus should expand to include adjunctive therapies that may prevent HIV infection of immune cells that infiltrate the BBB, decrease neurocognitive impairment through neuronal protection, and target and control neurotoxic mediators of CNS inflammation (Lane et al 1996;Nuovo and Alfieri 1996;Gartner 2000;Diesing et al 2002;Perry et al 2005).…”

Feline Immunodeficiency Virus Neuropathogenesis: From Cats to Calcium

“…The actions of these substances lead to a toxic accumulation of intracellular calcium, oxidative stress, and generation of proapoptotic signals. Many of these pathways have been the target of therapeutic strategies designed to protect neurons (Perry et al 2005;Turchan et al 2003). Control of intracellular calcium has been an important focus of many of these efforts.…”