HIV-Associated Neurolocognitive Disorders (HAND), as well as peripheral neuropathy, affects a significant number of people with HIV. It may manifest mildly or progress to more serious conditions. These include peripheral nerve pain (neuropathy), coordination problems, cognitive and memory trouble to dementia—and this sometimes in spite of antiretroviral therapy.
Research is uncovering how this disease manifests—and some ideas about how to intervene. These data underscore aspects of HIV disease that contribute significantly to the progression of the disease, resulting in damage to the neurological system manifesting as cognitive defects and/or peripheral neuropathies. Part of what happens with HIV is that the body’s response is excessive, causing increased oxidative stress.
HIV proteins like tat can damage cells by inhibiting a regulator gene of redox reactions and detoxification known as nrf2. Normally, when this gene is induced (activated) in response to increased amounts of free radicals, it in turn activates other genes like SOD and catalase, the body’s system of transforming potentially damaging free radicals into water or other innocuous substances. This helps protect healthy cells–and often neurons, not infected by HIV directly, are damaged by the release of excessive amounts of free radicals.
Maintaining an appropriate redox balance is key, as these free radicals are also part of the bodies immune defenses that help to kill infected cells. One problem in HIV is that many cells that die, most CD4 T-lymphocytes and neurons, for example, aren’t infected. But they die due in part to oxidative stress
So what to do? There are data on ways to manage neuropathy, including using 3 grams per day of acetylcarnitine or the judicious use of Cannabis sativa. A drug derived from Tripterygium wilfordii called Celastrol has shown some early promise. In addition, the Men Who Have Sex with Men supplement can help! Woops, wrong acronym. MSM here represents methylsulfonylmethane, often used in formulae to help join function or on its own. Unfortunately, these are only animal studies so we don’t have information on how or if it will help in offsetting HIV-related cognitive disorder.
Could we ever get a clinical trial?
MSM ameliorates HIV-1 Tat induced neuronal oxidative stress via rebalance of the glutathione cycle.
HIV-1 Tat protein is a key neuropathological element in HIV associated neurogcognitive disorders (HAND); a type of cognitive syndrome thought to be at least partially mediated by increased levels of brain reactive oxygen species (ROS) and nitric oxide (NO). Methylsulfonylmethane (MSM) is a sulfur-containing compound known to reduce oxidative stress. This study was conducted to determine whether administration of MSM attenuates HIV-1 Tat induced oxidative stress in mouse neuronal cells. MSM treatment significantly decreased neuronal cell NO and ROS secretion. Further, MSM significantly reversed HIV-1 Tat mediated reductions in reduced glutathione (GSH) as well as HIV-1 Tat mediated increases in oxidized glutathione (GSSG). In addition, Tat reduced nuclear translocation of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), a key nuclear promoter of antioxidant activity, while MSM increased its translocation to the nucleus in the presence of Tat. These results suggest that HIV-1 Tat reduces the resiliency of neuron cells to oxidative stress which can be reversed by MSM. Given the clinical safety of MSM, future preclinical in vivo studies will be required to further confirm these results in effort to validate MSM as a neuroprotectant in patients at risk of, or who are already diagnosed with, HAND.
Toxicol Appl Pharmacol. 2014 Oct 1;280(1):42-52. doi: 10.1016/j.taap.2014.07.010. Epub 2014 Jul 23.
Celastrol ameliorates HIV-1 Tat-induced inflammatory responses via NF-kappaB and AP-1 inhibition and heme oxygenase-1 induction in astrocytes.
HIV-1 Tat causes extensive neuroinflammation that may progress to AIDS-related encephalitis and dementia. Celastrol possesses various biological activities such as anti-oxidant, anti-tumor, and anti-inflammatory activities. In this study, we investigated the modulatory effects of celastrol on HIV-1 Tat-induced inflammatory responses and the molecular mechanisms underlying its action in astrocytes. Pre-treatment of CRT-MG human astroglioma cells with celastrol significantly inhibited HIV-1 Tat-induced expression of ICAM-1/VCAM-1 and subsequent monocyte adhesiveness in CRT-MG cells. In addition, celastrol suppressed HIV-1 Tat-induced expression of pro-inflammatory chemokines, such as CXCL10, IL-8, and MCP-1. Celastrol decreased HIV-1 Tat-induced activation of JNK MAPK, AP-1, and NF-κB. Furthermore, celastrol induced mRNA and protein expression of HO-1 as well as Nrf2 activation. Blockage of HO-1 expression using siRNA reversed the inhibitory effect of celastrol on HIV-1 Tat-induced inflammatory responses. These results suggest that celastrol has regulatory effects on HIV-1 Tat-induced inflammatory responses by blocking the JNK MAPK-AP-1/NF-κB signaling pathways and inducing HO-1 expression in astrocytes.