Independent and Combined Effects of Nicotine or Chronic Tobacco Smoking and HIV on the Brain: A Review of Preclinical and Clinical Studies

Tobacco smoking is highly prevalent among HIV-infected individuals. Chronic smokers with HIV showed greater cognitive deficits and impulsivity, and had more psychopathological symptoms and greater neuroinflammation than HIV non-smokers or smokers without HIV infection. However, preclinical studies that evaluated the combined effects of HIV-infection and tobacco smoking are scare. The preclinical models typically used cell cultures or animal models that involved specific HIV viral proteins or the administration of nicotine to rodents. These preclinical models consistently demonstrated that nicotine had neuroprotective and anti-inflammatory effects, leading to cognitive enhancement. Although the major addictive ingredient in tobacco smoking is nicotine, chronic smoking does not lead to improved cognitive function in humans. Therefore, preclinical studies designed to unravel the interactive effects of chronic tobacco smoking and HIV infection are needed. In this review, we summarized the preclinical studies that demonstrated the neuroprotective effects of nicotine, the neurotoxic effects of the HIV viral proteins, and the scant literature on nicotine or tobacco smoke in HIV transgenic rat models. We also reviewed the clinical studies that evaluated the neurotoxic effects of tobacco smoking, HIV infection and their combined effects on the brain, including studies that evaluated the cognitive and behavioral assessments, as well as neuroimaging measures. Lastly, we compared the different approaches between preclinical and clinical studies, identified some gaps and proposed some future directions. Graphical abstract Independent and combined effects of HIV and tobacco/nicotine. Left top and bottom panels: Both clinical studies of HIV infected persons and preclinical studies using viral proteins in vitro or in vivo in animal models showed that HIV infection could lead to neurotoxicity and neuroinflammation. Right top and bottom panels: While clinical studies of tobacco smoking consistently showed deleterious effects of smoking, clinical and preclinical studies that used nicotine show mild cognitive enhancement, neuroprotective and possibly anti-inflammatory effects. In the developing brain, however, nicotine is neurotoxic. Middle overlapping panels: Clinical studies of persons with HIV who were smokers typically showed additive deleterious effects of HIV and tobacco smoking. However, in the preclinical studies, when nicotine was administered to the HIV-1 Tg rats, the neurotoxic effects of HIV were attenuated, but tobacco smoke worsened the inflammatory cascade.