White Matter/Oligodendroglial Pathology
HIV can cause white matter damage (Gosztonyi et al. 1994; Langford et al. 2002; Xuan et al. 2013) even with less severe forms of HAND (Chen et al. 2009; Leite et al. 2013; Correa et al. 2015). Diffusion tensor magnetic resonance imaging (DTI) demonstrates white matter damage early in HAND (Ragin et al. 2004; Stubbe-Drger et al. 2012; Leite et al. 2013; Correa et al. 2015). White matter deficits are associated with cognitive impairment, including shortfalls in memory (Ragin et al. 2005), executive function (Correa et al. 2015), motor speed (Wu et al. 2006; Stubbe-Drger et al. 2012), and perhaps depression (Schmaal and van Velzen 2019). Preclinical studies in simian immunodeficiency virus- (SIV-) infected rhesus macaques (Marcario et al. 2008) and HIV-infected humanized mice (Boska et al. 2014) support the clinical findings. Injury to oligodendrocytes (OLs) can occur very early in the disease (see review, Liu et al. 2016b). Viral proteins, including Tat, gp120, and Nef, have been implicated in OL injury in vitro (Kimura-Kuroda et al. 1994; Bernardo et al. 1997; Radja et al. 2003; Nukuzuma et al. 2012; Zou et al. 2015), and in animal models in vivo (Radja et al. 2003; Hauser et al. 2009; Zou et al. 2015). Importantly, Tat has been detected in OLs in the brains of AIDS patients (Del Valle et al. 2000).
HIV likely damages OLs through both direct and indirect actions. OLs lack CD4, and reports of OL infection by HIV are variable (Esiri et al. 1991; Albright et al. 1996; Wohlschlaeger et al. 2009); thus, HIV infection of OLs is unlikely a major avenue of OL or white matter damage (discussed below). Alternatively, bystander damage to OLs through the production of “virotoxins” and “cellular toxins” (Nath 1999) by infected neighboring cells is more likely to be operative (Hauser et al. 2009; Zou et al. 2015; Jensen et al. 2019; Zou et al. 2019). ARVs also contribute to OL cytotoxicity (Jensen et al. 2015; Festa et al. 2019; Jensen et al. 2019). HIV-1 Tat directly induces damage in isolated OLs through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-D-aspartic acid (NMDA) receptor-dependent mechanisms (Zou et al. 2015) and is also associated with abnormal Kv1.3 activity (Liu et al. 2017). Immature OLs are preferentially targeted by Tat compared to differentiated OLs (Khurdayan et al. 2004; Hahn et al. 2012; Zou et al. 2015, 2019). While the reasons why immature OLs are more susceptible to Tat are unclear, unlike mature OLs, Tat preferentially upregulates GSK-3β signaling in undifferentiated OLs by inhibiting Ca2+/calmodulin-dependent protein kinase II β (CaMKIIβ) (Zou et al. 2019).
Opioid abuse by itself can result in demyelination, leukoencephalopathy, and lesions in white matter (Offiah and Hall 2008; Eran and Barak 2009; Morales Odia et al. 2010; Bora et al. 2012; Li et al. 2013), and the degree of myelin disruption correlates with the duration of opiate dependence (Ivers et al. 2018). Chronic oxycodone exposure in rats causes some axonopathies and reduces the size of axonal fascicles, decreases myelin basic protein levels, and causes the accumulation of amyloid-β precursor protein (APP) (Fan et al. 2018). Most preclinical studies have examined the effects of opioids and opioid receptor blockade on OL maturation and/or the timing of myelination (Hauser et al. 1993; Knapp et al. 1998; Stiene-Martin et al. 2001; Sanchez et al. 2008; Knapp et al. 2009; Vestal-Laborde et al. 2014). OLs can transiently express MORs and other opioid receptor types (Knapp et al. 1998; Tryoen-Toth et al. 2000; Knapp et al. 2001; Stiene-Martin et al. 2001). Selective MOR and possibly KOR activation can directly modulate the growth of OLs in vitro (Knapp and Hauser 1996; Knapp et al. 1998, 2001).
Despite long-standing evidence of white matter damage early during the infection even in asymptomatic PWH (Price et al. 1988; Gray et al. 1996; Chen et al. 2009; Stubbe-Drger et al. 2012; Jensen et al. 2019), few studies have examined how opiate exposure affects OLs and myelin in neuroHIV (Tables 1 and 2). Increased demyelination is reported in SIV-infected rhesus macaques chronically treated with morphine (4× daily, up to 59 weeks) (Marcario et al. 2008). Specifically, morphine-treated SIV macaques developed more subtle, focal, dysmyelinating lesions, with accumulations of macrophages in areas of myelin loss (Marcario et al. 2008), as well as accompanying gliosis (Marcario et al. 2008; Rivera-Amill et al. 2010a; Bokhari et al. 2011). Morphine exposure increased degeneration of OLs in Tat+ mice, which was accompanied by elevations in caspase-3 activation and TUNEL reactivity in OLs and reversible by naloxone or naltrexone, respectively (Hauser et al. 2009). Although OLs can express MOR both in vivo (Stiene-Martin et al. 2001) and in vitro (Hauser et al. 2009), it remains unclear the extent to which MOR activation in OLs directly mediates HIV pathogenesis.