Impact of tobacco smoke in HIV progression: a major risk factor for the development of NeuroAIDS and associated CNS disorders

  • Aditya Bhalerao
  • Luca CuculloEmail author
Review Article



The advent of highly active antiretroviral therapy (HAART) and combined antiretroviral therapy (cART) has substantially increased the life expectancy of patients infected with human immunodeficiency virus (HIV). However, this has brought into sharp contrast the incidence of several non-acquired immunodeficiency syndrome (non-AIDS) diseases such as NeuroAIDS, which identifies a group of neurological disorders caused primarily by HIV-mediated damage to the central and peripheral nervous systems. Given the patients’ depleted immune condition, the use and abuse of drug and addictive substances such as tobacco smoking can further deteriorate their overall health and accelerate the progression and severity of the disease. In this review, we detail the pathogenesis, progression, and characteristics of HIV, and the impact of tobacco smoking as a risk factor for the progression of the disease to NeuroAIDS. This is a poorly understood aspect of HIV-related complications that needs to be addressed.

Subjects and methods

Review of theoretical approaches and knowledge synthesis.


Tobacco smoking is highly prevalent in HIV patients when compared to the general population. The oxidative damage and inflammatory stress caused by chronic smoking on the cerebrovascular system have been well established. Considering that HIV patients have an impaired immune system and smokers per se are more susceptible to viral and bacterial inflammatory neuropathologies than non-smokers, it is conceivable that tobacco smoking is a risk factor for the progression of HIV into NeuroAIDS and related neurological impairments.


Tobacco smoke (TS) may bring about a synergistic effect in the context of persistent inflammatory state and cerebrovascular damage which facilitate HIV infection and progression to NeuroAIDS when compared to non-smokers.


Blood–brain barrier Oxidative stress Inflammation Smoking Brain disorders Abuse Cognitive 



Acquired immunodeficiency syndrome


Activator protein 1


Antiretroviral therapy


Blood–brain barrier


Large conductance, Ca2 + --activated K+ Channels


Interleukin 8


High FOS-like antigen 1


High FOS-like antigen 2


Central nervous system


Oxidative stress




Acquired immunodeficiency syndrome


Human immunodeficiency virus


Highly active antiretroviral therapy


Combined antiretroviral therapy


AIDS dementia complex


HIV-associated cognitive–motor complex


HIV-associated neurocognitive disorders


C-reactive protein


Reactive oxygen species


Protein tyrosine kinases


Transforming growth factor type 1



This work was supported by the National Institutes of Health/ National Institute on Drug Abuse 2R01-DA029121-01A1 to Dr. Luca Cucullo.


A.B. prepared the draft of the manuscript, figure preparations. L.C. conceived the study, assisted with data interpretation, drafting of the manuscript, and preparation of the figures. L.C. also oversaw the research study and provided funding. Both authors reviewed the manuscript.

Compliance with ethical standards

Competing interests

The authors declare no competing interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by the author.


  1. Abbruscato TJ, Lopez SP, Mark KS, Hawkins BT, Davis TP (2002) Nicotine and cotinine modulate cerebral microvascular permeability and protein expression of ZO-1 through nicotinic acetylcholine receptors expressed on brain endothelial cells. J Pharm Sci 91:2525–2538. CrossRefGoogle Scholar
  2. Abbud RA, Finegan CK, Guay LA, Rich EA (1995) Enhanced production of human immunodeficiency virus type 1 by in vitro-infected alveolar macrophages from otherwise healthy cigarette smokers. J Infect Dis 172:859–863CrossRefGoogle Scholar
  3. Ambrose JA, Barua RS (2004) The pathophysiology of cigarette smoking and cardiovascular disease: an update. JACC 43(10):1731–1737.
  4. Ande A, McArthur C, Kumar A, Kumar S (2013) Tobacco smoking effect on HIV-1 pathogenesis: role of cytochrome P450 isozymes. Expert Opin Drug Metab Toxicol 9:1453–1464. CrossRefGoogle Scholar
  5. Ande A et al (2015) Effect of mild-to-moderate smoking on viral load, cytokines, oxidative stress, and cytochrome P450 enzymes in HIV-infected individuals. PLoS One 10(4):e0122402. CrossRefGoogle Scholar
  6. Antiretroviral Therapy Cohort Collaboration (2010) Causes of death in HIV-1–infected patients treated with antiretroviral therapy, 1996–2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis 50:1387–1396. CrossRefGoogle Scholar
  7. Atluri VSR (2016) Editorial: HIV and illicit drugs of abuse. Front Microbiol 7:221.
  8. Atluri VSR, Hidalgo M, Samikkannu T, Kurapati KRV, Jayant RD, Sagar V, Nair MPN (2015) Effect of human immunodeficiency virus on blood-brain barrier integrity and function: an update. Front Cell Neurosci 9:1–10. CrossRefGoogle Scholar
  9. Avison MJ, Nath A, Greene-Avison R, Schmitt FA, Greenberg RN, Berger JR (2004) Neuroimaging correlates of HIV-associated BBB compromise. J Neuroimmunol 157:140–146. CrossRefGoogle Scholar
  10. Banks WA, Robinson SM, Nath A (2005) Permeability of the blood–brain barrier to HIV-1 tat. Exp Neurol 193:218–227. CrossRefGoogle Scholar
  11. Banks WA, Ercal N, Otamis Price T (2006) The blood–brain barrier in NeuroAIDS. Curr HIV Res 4(3):259–266CrossRefGoogle Scholar
  12. Banzet N, Francois D, Polla BS (1999) TS induces mitochondrial depolarization along with cell death: effects of antioxidants. Redox Rep 4:229–236. CrossRefGoogle Scholar
  13. Barré-Sinoussi F, Ross AL, Delfraissy JF (2013) Past, present and future: 30 years of HIV research. Nat Rev Microbiol 11(12):877–878. CrossRefGoogle Scholar
  14. Bernhard D, Rossmann A, Wick G (2005) Metals in cigarette smoke. IUBMB Life 57:805–809. CrossRefGoogle Scholar
  15. Boelaert JR, Piette J, Weinberg GA, Sappey C, Weinberg ED (1996) Iron and oxidative stress as a mechanism for the enhanced production of human immunodeficiency virus by alveolar macrophages from otherwise healthy cigarette smokers. J Infect Dis 173:1045–1047CrossRefGoogle Scholar
  16. Burns DN et al (1996) Cigarette smoking, bacterial pneumonia, and other clinical outcomes in HIV-1 infection. Terry Beirn community programs for clinical research on AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 13:374–383CrossRefGoogle Scholar
  17. Centers for Disease Control and Prevention (2018) About HIV/AIDS, pp.2–3Google Scholar
  18. Chen YH, Chen SH, Jong A, Zhou ZY, Li W, Suzuki K, Huang SH (2002) Enhanced Escherichia coli invasion of human brain microvascular endothelial cells is associated with alternations in cytoskeleton induced by nicotine. Cell Microbiol 4:503–514CrossRefGoogle Scholar
  19. Chen HW, Chien ML, Chaung YH, Lii CK, Wang TS (2004) Extracts from cigarette smoke induce DNA damage and cell adhesion molecule expression through different pathways. Chem Biol Interact 150:233–241. CrossRefGoogle Scholar
  20. Circu ML, Aw TY (2010) Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 48:749–762. CrossRefGoogle Scholar
  21. Cohen MS, Shaw GM, McMichael AJ, Haynes BF (2011) Acute HIV-1 infection. N Engl J Med 364:1943–1954. CrossRefGoogle Scholar
  22. Cole SB, Langkamp-Henken B, Bender BS, Findley K, Herrlinger-Garcia KA, Uphold CR (2005) Oxidative stress and antioxidant capacity in smoking and nonsmoking men with HIV/acquired immunodeficiency syndrome. Nutr Clin Pract 20:662–667. CrossRefGoogle Scholar
  23. Colles SM, Maxson JM, Carlson SG, Chisolm GM (2001) Oxidized LDL-induced injury and apoptosis in atherosclerosis. Potential roles for oxysterols. Trends Cardiovasc Med 11:131–138CrossRefGoogle Scholar
  24. Conley LJ, Bush TJ, Buchbinder SP, Penley KA, Judson FN, Holmberg SD (1996) The association between cigarette smoking and selected HIV-related medical conditions. AIDS 10:1121–1126Google Scholar
  25. Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study Group et al (2010) Factors associated with specific causes of death amongst HIV-positive individuals in the D:a:D study. AIDS 24:1537–1548. Google Scholar
  26. Deeks SG, Phillips AN (2009) HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ (Online) 338:288–292. Google Scholar
  27. DeMarini DM (2004) Genotoxicity of TS and TS condensate: a review. Mutat Res 567:447–474. CrossRefGoogle Scholar
  28. Earla R, Ande A, McArthur C, Kumar A, Kumar S (2014) Enhanced nicotine metabolism in HIV-1-positive smokers compared with HIV-negative smokers: simultaneous determination of nicotine and its four metabolites in their plasma using a simple and sensitive electrospray ionization liquid chromatography–tandem mass spectrometry technique. Drug Metab Dispos 42:282–293. CrossRefGoogle Scholar
  29. Elzi L et al (2006) A smoking cessation programme in HIV-infected individuals: a pilot study. Antivir Ther 11:787–795Google Scholar
  30. Eugenin EA, Clements JE, Zink MC, Berman JW (2011) Human immunodeficiency virus infection of human astrocytes disrupts blood–brain barrier integrity by a gap junction-dependent mechanism. J Neurosci 31:9456–9465. CrossRefGoogle Scholar
  31. Feldman JG et al (2006) Association of cigarette smoking with HIV prognosis among women in the HAART era: a report from the women’s interagency HIV study. Am J Public Health 96:1060–1065. CrossRefGoogle Scholar
  32. Fowles J, Dybing E (2003) Application of toxicological risk assessment principles to the chemical constituents of cigarette smoke. Tob Control 12(4):424–430. CrossRefGoogle Scholar
  33. Girdhar G, Xu S, Jesty J, Bluestein D (2008) In vitro model of platelet–endothelial activation due to cigarette smoke under cardiovascular circulation conditions. Ann Biomed Eng 36:1142–1151. CrossRefGoogle Scholar
  34. Hasnis E, Bar-Shai M, Burbea Z, Reznick AZ (2007) Mechanisms underlying cigarette smoke-induced NF-kappaB activation in human lymphocytes: the role of reactive nitrogen species. J Physiol Pharmacol 58(Suppl 5):275–287Google Scholar
  35. Hawkins BT, Abbruscato TJ, Egleton RD, Brown RC, Huber JD, Campos CR, Davis TP (2004) Nicotine increases in vivo blood–brain barrier permeability and alters cerebral microvascular tight junction protein distribution. Brain Res 1027:48–58. CrossRefGoogle Scholar
  36. Hernandez-Vargas EA, Middleton RH (2013) Modeling the three stages in HIV infection. J Theor Biol 320:33–40. CrossRefGoogle Scholar
  37. Hossain M et al (2009) TS: a critical etiological factor for vascular impairment at the blood–brain barrier. Brain Res 1287:192–205. CrossRefGoogle Scholar
  38. Hossain M, Mazzone P, Tierney W, Cucullo L (2011) In vitro assessment of tobacco smoke toxicity at the BBB: do antioxidant supplements have a protective role?. BMC Neurosci 12:92.
  39. Howard G et al (1998) Cigarette smoking and progression of atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study. JAMA 279:119–124CrossRefGoogle Scholar
  40. Iles K, Poplawski NK, Couper RT (2001) Passive exposure to TS and bacterial meningitis in children. J Paediatr Child Health 37:388–391CrossRefGoogle Scholar
  41. Jin M et al (2012) A LC-MS/MS method for concurrent determination of nicotine metabolites and role of CYP2A6 in nicotine metabolism in U937 macrophages: implications in oxidative stress in HIV + smokers. J NeuroImmune Pharmacol 7:289–299. CrossRefGoogle Scholar
  42. Kaisar MA, Prasad S, Cucullo L (2015) Protecting the BBB endothelium against cigarette smoke-induced oxidative stress using popular antioxidants: are they really beneficial? Brain Res 1627:90–100. CrossRefGoogle Scholar
  43. Kaisar MA et al (2017) Offsetting the impact of smoking and e-cigarette vaping on the cerebrovascular system and stroke injury: is metformin a viable countermeasure? Redox Biol 13:353–362. CrossRefGoogle Scholar
  44. Kaisar MA, Sivandzade F, Bhalerao A, Cucullo L (2018) Conventional and electronic cigarettes dysregulate the expression of iron transporters and detoxifying enzymes at the brain vascular endothelium: in vivo evidence of a gender-specific cellular response to chronic cigarette smoke exposure. Neurosci Lett 682:1–9. CrossRefGoogle Scholar
  45. Kalra R, Singh SP, Savage SM, Finch GL, Sopori ML (2000) Effects of cigarette smoke on immune response: chronic exposure to cigarette smoke impairs antigen-mediated signaling in T cells and depletes IP3-sensitive ca(2+) stores. J Pharmacol Exp Ther 293:166–171Google Scholar
  46. Kumar S, Rao P, Earla R, Kumar A, City K, City K (2015) Drug–drug interactions between anti-retroviral therapies and drugs of abuse in HIV systems expert opinion on drug metabolism and. Toxicology 11:343–355. Google Scholar
  47. Lane HC (2010) Pathogenesis of HIV infection: total CD4+ T-cell pool, immune activation, and inflammation. Top HIV Med 18:2–6Google Scholar
  48. Liu G et al. (2006) Metal exposure and Alzheimer’s pathogenesis. J Struct Biol 155(1):45–51. CrossRefGoogle Scholar
  49. Lopez S et al (2004) Mitochondrial effects of antiretroviral therapies in asymptomatic patients. Antivir Ther 9:47–55Google Scholar
  50. Maartens G, Celum C, Lewin SR (2014) HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet 384:258–271. CrossRefGoogle Scholar
  51. Masubuchi T et al (1998) Smoke extract stimulates lung epithelial cells to release neutrophil and monocyte chemotactic activity. Am J Pathol 153:1903–1912. CrossRefGoogle Scholar
  52. Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3:e442. CrossRefGoogle Scholar
  53. Mazzone P, Tierney W, Hossain M, Puvenna V, Janigro D, Cucullo L (2010) Pathophysiological impact of cigarette smoke exposure on the cerebrovascular system with a focus on the blood–brain barrier: expanding the awareness of smoking toxicity in an underappreciated area. Int J Environ Res Public Health 7(12):4111–4126. CrossRefGoogle Scholar
  54. McMullen CB, Fleming E, Clarke G, Armstrong MA (2000) The role of reactive oxygen intermediates in the regulation of cytokine-induced ICAM-1 surface expression on endothelial cells. Mol Cell Biol Res Commun 3:231–237. CrossRefGoogle Scholar
  55. McRae M (2016) HIV and viral protein effects on the blood–brain barrier. Tissue Barriers 4:e1143543. CrossRefGoogle Scholar
  56. Miller ER 3rd, Appel LJ, Jiang L, Risby TH (1997) Association between cigarette smoking and lipid peroxidation in a controlled feeding study. Circulation 96:1097–1101CrossRefGoogle Scholar
  57. Naik P, Sajja RK, Prasad S, Cucullo L (2015) Effect of full flavor and denicotinized cigarettes exposure on the brain microvascular endothelium: a microarray-based gene expression study using a human immortalized BBB endothelial cell line. BMC Neurosci 16:38. CrossRefGoogle Scholar
  58. National Institute on Drug Abuse (2012) How does drug abuse affect the HIV epidemic?Google Scholar
  59. Nordskog BK, Blixt AD, Morgan WT, Fields WR, Hellmann GM (2003) Matrix-degrading and pro-inflammatory changes in human vascular endothelial cells exposed to cigarette smoke condensate. Cardiovasc Toxicol 3:101–117CrossRefGoogle Scholar
  60. Önen NF, Overton TE (2011) A review of premature frailty in HIV-infected persons; another manifestation of HIV-related accelerated aging. Current Aging Science 4:33–41. CrossRefGoogle Scholar
  61. Pacek LRC, Cioe PA (2015) Tobacco use, use disorders, and smoking cessation interventions in persons living with HIV. Curr HIV/AIDS Rep 12(4):413–420. CrossRefGoogle Scholar
  62. Pal D, Kwatra D, Minocha M, Paturi DK, Budda B, Mitra AK (2011) Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals. Life Sci 88:959–971. CrossRefGoogle Scholar
  63. Peluffo G, Calcerrada P, Piacenza L, Pizzano N, Radi R (2009) Superoxide-mediated inactivation of nitric oxide and peroxynitrite formation by TS in vascular endothelium: studies in cultured cells and smokers. Am J Physiol Heart Circ Physiol 296:H1781–H1792. CrossRefGoogle Scholar
  64. Pendyala G, Want EJ, Webb W, Siuzdak G, Fox HS (2007) Biomarkers for neuroAIDS: the widening scope of metabolomics. J Neuroimmune Pharmacol 2(1):72–80 CrossRefGoogle Scholar
  65. Pfeifer GP, Denissenko MF, Olivier M, Tretyakova N, Hecht SS, Hainaut P (2002) TS carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene 21:7435–7451. CrossRefGoogle Scholar
  66. Prasad S, Cucullo L (2015) Impact of tobacco smoking and type-2 diabetes mellitus on public health: a cerebrovascular perspective. J Pharmacovigil (Suppl 2) pii: e003.
  67. Pryor WA, Stone K, Zang LY, Bermudez E (1998) Fractionation of aqueous cigarette tar extracts: fractions that contain the tar radical cause DNA damage. Chem Res Toxicol 11:441–448. CrossRefGoogle Scholar
  68. Pun PB, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res 43:348–364. CrossRefGoogle Scholar
  69. Rahimian P, He JJ (2017) HIV/neuroAIDS biomarkers. Prog Neurobiol 157:117–132. CrossRefGoogle Scholar
  70. Rahmanian S, Wewers ME, Koletar S, Reynolds N, Ferketich A, Diaz P (2011) Cigarette smoking in the HIV-infected population. Proc Am Thorac Soc 8:313–319. CrossRefGoogle Scholar
  71. Raij L, DeMaster EG, Jaimes EA (2001) Cigarette smoke-induced endothelium dysfunction: role of superoxide anion. J Hypertens 19:891–897CrossRefGoogle Scholar
  72. Reynolds NR (2009) Cigarette smoking and HIV: more evidence for action. AIDS Educ Prev 21(3 Suppl):106–121. CrossRefGoogle Scholar
  73. Robbins CS, Bauer CM, Vujicic N, Gaschler GJ, Lichty BD, Brown EG, Stampfli MR (2006) Cigarette smoke impacts immune inflammatory responses to influenza in mice. Am J Respir Crit Care Med 174:1342–1351. CrossRefGoogle Scholar
  74. Rock RB, Gekker G, Aravalli RN, Hu S, Sheng WS, Peterson PK (2008) Potentiation of HIV-1 expression in microglial cells by nicotine: involvement of transforming growth factor-β1. J NeuroImmune Pharmacol 3:143–149. CrossRefGoogle Scholar
  75. Shammas MA (2011) Telomeres, lifestyle, cancer, and aging. Curr Opin Clin Nutr Metab Care 14:28–34. CrossRefGoogle Scholar
  76. Shapshak P et al. (2011) Editorial NeuroAIDS review. AIDS 25(2):123–141. CrossRefGoogle Scholar
  77. Sharp PM, Hahn BH (2011) Origins of HIV and the AIDS pandemic. Cold Spring Harb Perspect Med 1(1):a006841.
  78. Shirley DK, Kaner RJ, Glesby MJ (2013) Effects of smoking on non-AIDS-related morbidity in HIV-infected patients. Clin Infect Dis 57:275–282. CrossRefGoogle Scholar
  79. Stampfli MR, Anderson GP (2009) How cigarette smoke skews immune responses to promote infection, lung disease and cancer. Nat Rev Immunol 9:377–384. CrossRefGoogle Scholar
  80. Strazza M, Pirrone V, Wigdahl B, Nonnemacher MR (2011) Breaking down the barrier: the effects of HIV-1 on the blood–brain barrier. Brain Res 1399:96–115. CrossRefGoogle Scholar
  81. Swan GE, Lessov-Schlaggar CN (2007) The effects of tobacco smoke and nicotine on cognition and the brain. Neuropsychol Rev 17(3):259–273. CrossRefGoogle Scholar
  82. Taylor RG, Woodman G, Clarke SW (1986) Plasma nicotine concentration and the white blood cell count in smokers. Thorax 41:407–408CrossRefGoogle Scholar
  83. Thomas JB, Brier MR, Snyder AZ, Vaida FF, Ances BM, Snyder AZ, Ances BM (2013) Pathways to neurodegeneration: effects of HIV and aging on resting-state functional connectivity. Neurology 80:1186–1193. CrossRefGoogle Scholar
  84. Togna AR, Latina V, Orlando R, Togna GI (2008) Cigarette smoke inhibits adenine nucleotide hydrolysis by human platelets. Platelets 19:537–542. CrossRefGoogle Scholar
  85. UNAIDS (2017) Fact sheet — Latest global and regional statistics on the status of the AIDS epidemic.Google Scholar
  86. U.S. Department of Veterans Affairs (2018) AIDS-defining illnessesGoogle Scholar
  87. Watkins CC, Treisman GJ (2015) Cognitive impairment in patients with Aids — prevalence and severity. HIV AIDS (Auckl) 7:35–47. Google Scholar
  88. Winstanley EL, Gust SW, Strathdee SA (2006) Drug abuse and HIV/AIDS: international research lessons and imperatives. Drug Alcohol Depend 82:1–5. CrossRefGoogle Scholar
  89. Yin W, Ghebrehiwet B, Weksler B, Peerschke EI (2008) Regulated complement deposition on the surface of human endothelial cells: effect of TS and shear stress. Thromb Res 122:221–228. CrossRefGoogle Scholar
  90. Zanet DL et al (2014) Association between short leukocyte telomere length and HIV infection in a cohort study: no evidence of a relationship with antiretroviral therapy. Clin Infect Dis 58:1322–1332. CrossRefGoogle Scholar
  91. Zeinolabediny Y et al (2017) HIV-1 matrix protein p17 misfolding forms toxic amyloidogenic assemblies that induce neurocognitive disorders. Sci Rep 7.
  92. Zhang YL, Ouyang YB, Liu LG, Chen DX (2015) Blood–brain barrier and neuro-AIDS. Eur Rev Med Pharmacol Sci 19:4927–4939Google Scholar
  93. Zhao L, Li F, Zhang Y, Elbourkadi N, Wang Z, Yu C, Taylor EW (2010) Mechanisms and genes involved in enhancement of HIV infectivity by TS. Toxicology 278:242–248. CrossRefGoogle Scholar
  94. Zlokovic BV (2008) The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesTexas Tech University Health Sciences CenterAmarilloUSA
  2. 2.Center for Blood–Brain Barrier ResearchTexas Tech University Health Sciences CenterAmarilloUSA
  3. 3.Pharmaceutical Sciences, Texas Tech University Health Sciences CenterSchool of PharmacyAmarilloUSA

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