Elsevier

Brain, Behavior, and Immunity

Volume 22, Issue 8, November 2008, Pages 1257-1262
Brain, Behavior, and Immunity

Stimulant use is associated with immune activation and depleted tryptophan among HIV-positive persons on anti-retroviral therapy

https://doi.org/10.1016/j.bbi.2008.07.010Get rights and content

Abstract

Cocaine, crack, and methamphetamine are stimulants that promote autonomic nervous system activation. Although these stimulants may have immunomodulatory effects, relatively few studies have examined this possibility. The present cross-sectional investigation utilized baseline data from 127 HIV-positive individuals on anti-retroviral therapy (ART) that were enrolled in a randomized controlled trial. The goal of this study was to examine whether stimulant use is independently associated with immune activation and indices of tryptophan degradation. Forty-four participants reported using stimulants 2–3 times a month or more (i.e., monthly stimulant use) and a sub-set of these (n = 27) reported using stimulants once a week or more (i.e., weekly stimulant use) during the past three months. These stimulant-using groups were compared to a group of participants who reported no stimulant use (n = 83) during the past three months. Results indicated that individuals who reported either monthly or weekly stimulant use displayed elevated neopterin, a measure of immune activation. Those who reported weekly stimulant use also displayed a markedly elevated HIV viral load and lower tryptophan levels. Even after controlling for self-reported ART non-adherence, weekly stimulant use was independently associated with higher neopterin, elevated HIV viral load, and lower tryptophan. To our knowledge, this is the first study to observe that stimulant use may independently promote immune activation and tryptophan degradation among HIV-positive persons on ART. Further research is needed to replicate these findings and examine the plausible bio-behavioral pathways that may account for the effects of stimulant use on HIV disease markers and depleted tryptophan.

Introduction

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-α 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 and 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 and 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-α (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-γ (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 8 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 3–11 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-tryptophan, 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.

Section snippets

Procedures

HIV-positive individuals in four U.S. cities (San Francisco, Los Angeles, Milwaukee, and New York City) were recruited from community agencies and medical clinics between July 2000 and January 2002 for a randomized behavioral prevention trial of an intervention designed to reduce HIV transmission risk. Detailed information regarding the methods and results of this trial have been published elsewhere (Carrico et al., in press, Healthy Living Project Team, 2007, Johnson et al., 2007). In total,

Participant characteristics

The mean age of participants was 43 (range: 20–64) years. The majority of participants were gay or bisexual men (74%). Other participants were women (13%) and heterosexual men (13%). The sample was relatively diverse with respect to ethnicity: 47% Caucasian, 33% African American, 9% Hispanic/Latino, 2% Asian/Pacific Islander, 1% Native American/Alaskan Native, and 8% of multi-cultural heritage. Most participants (65%) had completed at least some college. Individuals had been diagnosed with HIV

Discussion

Results of the present investigation lend support to a previous in vitro study which reported that stimulants may accelerate HIV viral replication in monocytes/macrophages (Liang et al., 2008). We have previously demonstrated that individuals who report using stimulants 2–3 times per week or more display a 50% higher HIV viral load, independent of self-reported ART non-adherence (Carrico et al., 2007). The present study replicated this finding utilizing a less stringent criterion for regular

Acknowledgments

Funding for this research was provided by the Until There’s A Cure Foundation (560 Mountain Home Road Redwood City, CA 94062-2515). Additional support was provided by a Ruth L. Kirschstein National Research Service Award (T32-MH019391).

References (33)

  • D.R. Bangsberg et al.

    Adherence–resistance relationships for protease inhibitors and non-nucleoside reverse transcriptase inhibitors explained by virological fitness

    AIDS

    (2006)
  • A.T. Beck et al.

    Comparison of the beck depression inventories-IA and -II in psychiatric outpatients

    J. Pers. Assess.

    (1996)
  • Carrico, A.W., Chesney, M.A., Johnson, M.O., Neilands, T.B., Remien, R.H., Rotheram-Borus, M.J., Wong, F.L., Healthy...
  • A.W. Carrico et al.

    Affect regulation, stimulant use, and viral load among HIV-positive persons on anti-retroviral therapy

    Psychosom. Med.

    (2007)
  • M.A. Chesney et al.

    Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: the AACTG adherence instruments. Patient care committee & adherence working group of the outcomes committee of the adult aids clinical trials group (AACTG)

    AIDS Care

    (2000)
  • S.W. Cole

    Psychosocial influences on HIV-1 disease progression: neural, endocrine, and virologic mechanisms

    Psychosom. Med.

    (2008)
  • Cited by (45)

    • Multi-omics study reveals associations among neurotransmitter, extracellular vesicle-derived microRNA and psychiatric comorbidities during heroin and methamphetamine withdrawal

      2022, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      Conversely, a significant increase in plasma dopamine but not platelet serotonin has been shown in heroin and cocaine addicts [10]. Stimulant abuse (e.g., methamphetamine) is associated with elevated immune activation and lower tryptophan [11], in line with the finding that decreased serum tryptophan, a precursor of serotonin, has been found in heroin treated rats [12]. Cumulating structural and functional brain changes, as well as neurocognitive deficits and emotional impairments in both heroin and methamphetamine dependent populations have been demonstrated in neuropsychological studies.

    • Minority stress and leukocyte gene expression in sexual minority men living with treated HIV infection

      2018, Brain, Behavior, and Immunity
      Citation Excerpt :

      Inflammation, in turn is an important predictor of other health conditions (e.g., high blood pressure; Chae et al., 2001) as well as greater risk for mortality for HIV-positive individuals (Tien et al., 2010) and among the general population (Kabagambe et al., 2011), while impaired immunity can increase vulnerability to disease. Sexual minority stress may also impact physiology through behavioral pathways, for example sexual minority stress is related to substance use (Hatzenbuehler et al., 2008; McCabe et al., 2010), which also impacts immune and inflammatory response (Cabral, 2006; Carrico et al., 2008; Cole et al., 1998; Pandrea et al., 2010; Sacerdote et al., 2012) and cardiovascular function (Darke et al., 2008; Lange and Hillis, 2001). In sum, while the exact mechanisms need further exploration, existing research on minority stress and chronic stress suggests that minority stress may be related to inflammation, as well as immune and cardiovascular function, which in turn may be related to poorer health outcomes observed among sexual minority people.

    • Overamped: Stimulant Use and HIV Pathogenesis

      2023, Current HIV/AIDS Reports
    View all citing articles on Scopus
    View full text