White matter loss and oligodendrocyte dysfunction in HIV: A consequence of the infection, the antiretroviral therapy or both?

•White matter abnormalities are persistent in HIV+ individuals with HAND.•This may be due to HIV reservoirs in the CNS, side effects of antiretroviral compounds or both.•Some potential driving mechanisms of white matter damage include increased oxidative stress, activation of the unfolded protein response and/or dysregulation of lipid metabolism.•Evidence that HIV proteins and select antiretroviral agents damage oligodendrocytes, the myelin producing glia cells in the CNS, suggests multiple mechanisms underlie observed changes in white matter in patients living with HIV. While the severe cognitive effects of HIV-associated dementia have been reduced by combined antiretroviral therapy (cART), nearly half of HIV-positive (HIV+) patients still suffer from some form of HIV-Associated Neurocognitive Disorders (HAND). While frank neuronal loss has been dramatically reduced in HAND patients, white matter loss, including dramatic thinning of the corpus callosum, and loss of volume and structural integrity of myelin persists despite viral control by cART. It remains unclear whether changes in white matter underlie the clinical manifestation seen in patients or whether they are the result of persistent viral reservoirs, remnant damage from the acute infection, the antiretroviral compounds used to treat HIV, secondary effects due to peripheral toxicities or other associated comorbid conditions. Both HIV infection itself and its treatment with antiretroviral drugs can induce metabolic syndrome, lipodystrophy, atherosclerosis and peripheral neuropathies by increased oxidative stress, induction of the unfolded protein response and dysregulation of lipid metabolism. These virally and/or cART-induced processes can also cause myelin loss in the CNS. This review aims to highlight existing data on the contribution of white matter damage to HAND and explore the mechanisms by which HIV infection and its treatment contribute to persistence of white matter changes in people living with HIV currently on cART.