Cocaine, crack, and methamphetamine are sympathomimetic stimulants that can acutely precipitate both physical and psychological changes such as hyperthermia, elevated blood pressure, decreased appetite, insomnia, enhanced sex drive, and feelings of euphoria (Makisumi et al., 1998; Irwin et al., 2007). Despite the potent effects of stimulants, relatively few investigations have examined the extent to which these substances are immunomodulatory (Kopnisky et al., 2007). In vitro data indicate that methamphetamine up-regulates human immunodeficiency virus (HIV) reverse transcriptase activity, promotes the expression of CC chemokine receptor 5 (CCR5), and inhibits the production of interferon–alpha in monocyte/macrophage cultures (Liang et al., 2008). In addition, a number of investigations have observed that administration of cocaine to rodents decreases the number of circulating lymphocytes (Pellegrino & Bayer, 1998). In one study that examined a murine model of acquired immune deficiency syndrome, retrovirus-infected mice that received cocaine injections displayed increases in thymus weight compared to uninfected mice that received saline injections. Retrovirus-infected mice that received cocaine also displayed greater reductions in T-helper (CD4+) count in the thymus compared to other retrovirus-infected mice that did not receive cocaine (Lopez et al., 1992). Bearing in mind the fact that the sympathetic nervous system innervates lymphoid organs such as the thymus (Nance & Sanders, 2007), these effects may reflect the influence of cocaine-induced sympathetic nervous system activation. These findings are further supported by investigations of the effects of cocaine infusion among HIV-negative individuals with cocaine dependence. Irwin and colleagues (2007) observed decrements in both resting and stimulated monocyte expression of tumor necrosis factor–alpha (TNF-α) as well as decreased circulating levels of its soluble receptor (sTNF-R75) among men that received cocaine versus a placebo. Interestingly, cocaine-dependent participants displayed enhanced autonomic nervous system activation which was, in turn, associated with lower resting and stimulated monocyte expression of TNF-α. In another study where individuals were administered cocaine, stimulated peripheral blood mononuclear cells (PBMCs) demonstrated in vitro changes that favored an enhanced cellular-immune response. These cocaine-induced changes in stimulated cytokine production included increases in interferon-gamma (IFN-γ) and concurrent decreases in interleukin-10 (Gan et al., 1998). Although the exact nature and clinical relevance of the acute immunologic effects of stimulants remains unclear, findings provide some preliminary indication that these substances may directly impair the capacity of the immune system to effectively manage chronic viral infections such as HIV.
Because stimulants activate the autonomic nervous system (ANS), it may represent an important pathway for any observed immunomodulatory effects. The physiologic effects of stimulants appear to be mediated by ANS activation (Irwin et al., 2007; Makisumi et al., 1998), resulting in the release of norepinephrine at nerve terminals. By binding with β2 receptors on the lymphocyte membrane, norepinephrine activates the G protein linked adenyl cyclase-cAMP-protein kinase A signaling cascade (Kobilka, 1992). Cellular changes of this nature are associated with in vitro decrements in IFN-γ and interleukin-10 during the eight days following HIV infection of PBMCs. This suppression of IFN-γ and interleukin-10 production, in turn, predicts elevations in HIV viral load over time (Cole et al., 1998). Bearing in mind that the lymphoid organs have been shown to be a primary site for HIV replication, sympathetic innervation of both primary and secondary lymphoid tissue may provide an ideal microenvironment for ANS activation to accelerate HIV replication. This is supported by data indicating that simian immunodeficiency virus replication is enhanced by 3.9-fold near catecholaminergic varicosities (Sloan et al., 2006). Lending further support to the role of ANS activation, another study observed that Individuals who displayed higher ANS activity at rest prior to beginning anti-retroviral therapy (ART) subsequently demonstrated poorer suppression of HIV viral load and decreased CD4+ cell reconstitution over a 3 to 11 month period (Cole et al., 2001). Taken together, there is burgeoning evidence for the role of ANS activation in hastened HIV disease progression (Cole, 2008).
Greater output of norepinephrine may partially explain observations that stimulant users on ART display a markedly elevated HIV viral load (Ellis et al., 2003). Even after accounting for higher rates of self-reported ART non-adherence, regular stimulant use (2–3 times per week or more) is independently associated with 50% higher HIV viral load (Carrico et al., 2007). In the context of chronic HIV infection, elevated viral load may lead to sustained activation of the cellular-immune response (Hunt et al., 2006) that could be further exacerbated by the capacity of stimulants to increase IFN-γ production in the periphery (Gan et al., 1998). This may result in both direct and indirect effects of stimulants on enhanced immune activation. The potential direct effects of stimulants on immune activation are further supported by an investigation with injecting heroin users where cocaine use was independently associated with higher levels of neopterin, even after accounting for HIV serostatus (Fuchs et al., 1987). Among HIV-positive persons, this may have important clinical implications because markers of immune activation such as neopterin have been shown to independently predict more rapid HIV disease progression (Mildvan et al., 2005).
Immune activation among stimulant users may also promote degradation of L-trypothphan, an essential amino acid that serves as the precursor for several important compounds such as serotonin (Schroecksnadel et al., 2006). IFN-γ directly increases neopterin production by activating monocytes/macrophages and it stimulates indoleamine-(2,3)-dioxygenase (IDO) to catabolize tryptophan via the kynurenine pathway. Thus, the kynurenine/tryptophan (kyn/trp) ratio provides an estimate of IDO activity that can be accelerated by IFN-γ (Schroecksnadel et al., 2006). This is supported by findings that tryptophan degradation is partially reversed following initiation of ART (Zangerle et al., 2002), possibly via decreased immune activation. Among HIV-positive persons, the clinical relevance of tryptophan degradation is supported by findings indicating that a higher kyn/trp ratio is associated with depression and impaired quality of life (Schroecksnadel et al., 2008). Taken together, stimulant use and ART non-adherence are important behavioral factors that may be independently associated with HIV disease markers. The goal of the present study was to examine if stimulant use and ART non-adherence are independently associated with immune activation and indices of tryptophan degradation.