Morphine Potentiates Neuropathogenesis of SIV Infection in Rhesus Macaques

Abstract

Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Opiates are well-known to modulate immune responses by preventing the development of cell-mediated immune responses. Their effect on the pathogenesis of HIV-1 infection however, remains controversial. Using the Simian Immunodeficiency Virus/macaque model of HIV pathogenesis, we sought to explore the impact of morphine on disease progression and pathogenesis. Sixteen Rhesus macaques were divided into 2 groups; 4 were administered saline and twelve others morphine routinely. Both groups of animals were then inoculated with SIVmacR71/17E and followed longitudinally for disease pathogenesis. The morphine group (M+V) exhibited a trend towards higher mortality rates and retardation in weight gain compared to the virus alone group. Interestingly, a subset of M+V animals succumbed to disease within weeks post-infection. These rapid progressors also exhibited a higher incidence of other end-organ pathologies. Despite the higher numbers of circulating CD4+ and CD8+T cells in the M+V group, CD4:CD8 ratios between the groups remained unchanged. Plasma and CSF viral load in the M+V group was at least a log higher than the control group. Similarly there was a trend toward increased virus build-up in the brains of M+V animals compared with controls. A novel finding of this study was the increased influx of infected monocyte/macrophages in the brains of M+V animals.

Chronic Inflammation and the Role for Cofactors (Hepatitis C, Drug Abuse, Antiretroviral Drug Toxicity, Aging) in HAND Persistence

“…These findings are consistent with studies demonstrating that treatment of SIV-infected rhesus macaques with selegiline, an inhibitor of dopamine catabolism through inhibition of MAO activity, or L-DOPA, the precursor of dopamine, resulted in elevated brain viral loads [73, 74]. In the SIV-macaque model, methamphetamine and opioid exposure increased both CSF/brain viral loads and macrophage influx into the CNS [75, 76]. In contrast, cocaine exposed SIV-infected macaques did not show elevated CNS viral replication or alterations in inflammatory markers; notably, the low dose cocaine-treated animals had significantly lower CSF viral RNA [77].…”

Enhanced Pulmonary Arteriopathy in Simian Immunodeficiency Virus–infected Macaques Exposed to Morphine

“…As reported earlier, no significant differences were found in the CD4 or CD8 counts or plasma viral load between the V and VM groups (18). However, in other studies of SIV/SHIV-infected macaques, exposure to chronic morphine had a significant and dramatic effect on viral replication in cerebral tissues, resulting in early mortality (29,30). Furthermore, no correlation was observed between the plasma viral load/CD4 count and the degree of pulmonary vascular remodeling in these groups, although the C088 macaque, with the most pronounced arteriopathy, had the lowest CD4 counts among all of the animals.…”

Effects of Morphine on Behavioral Task Performance in SIV-Infected Rhesus Macaques

“…Previous studies from our group have shown that morphine potentiates neuropathognesis in macaques infected with SIV mac R71/17E (Marcario et al, 2008; Bokhari et al, 2011). Such morphine mediated viral pathogenesis also resulted in alterations in brain stem responses and visual evoked potentials (Raymond et al, 1998; Cheney et al, 2008; Riazi et al, 2009).…”