Once a lethal pandemic, HIV has now taken the form of a chronic condition. As of 2018, at least 37.9 million people were living with HIV, with more than a million new cases each year [1]. The majority of these people living with HIV/AIDS (PLWHA) have a life expectancy comparable to healthy adults, which is attributed to remarkable advances in medicine, especially the introduction of combination anti-retroviral therapy (cART) [2,3,4,5]. However, a huge portion of PLWHA have a poor quality of life and suffer from high morbidity and mortality associated with drugs of abuse, including tobacco. More than 40% of PLWHA in the USA are cigarette smokers, which severely affect their life expectancy, reducing the average life span by over 6 years [6,7,8]. Mortality due to non-AIDS related malignancies is almost two-fold higher in HIV-positive smokers, irrespective of the use of cART [9]. Non-adherence to cART and/or attenuated treatment efficacy in HIV-positive smokers could possibly increase the risk of morbidity and mortality [10,11]. Smoking cessation can improve life expectancy, although studies have shown that smoking cessation is hard to achieve [12]. While the exact mechanistic pathway for smoking-mediated exacerbation of HIV pathogenesis is not fully understood, our studies have shown that tobacco smoke aggravates HIV pathogenesis, in part via the induction of cytochrome P450 (CYP)-mediated metabolism and activation of cigarette smoke constituents, resulting in oxidative stress [13,14,15,16,17,18]. In particular, we have demonstrated that benzo(a)pyrene (B(a)p), a potent component of cigarette smoke, exacerbates HIV replication via CYP-induced oxidative stress followed by the NF-κβ pathway [13].

Approximately 50% of PLWHA demonstrate a pattern of cognitive, motor, and behavioral dysfunction, cumulatively termed HIV-associated neurocognitive disorders (HAND) [19,20,21]. In the presence of cigarette smoke, the risk of peripheral neuropathy and HAND in PLWHA increases significantly [7,22,23,24,25]. Some reports demonstrate a conflicting impact of cigarette smoke on PLWHA in terms of neurocognitive disorders [26,27,28], which further strengthens the necessity to study whether cigarette smoking is a causative factor for HAND in PLWHA.

One possible mechanistic pathway of tobacco smoking-induced HIV pathogenesis and HAND could be the transportation of oxidative stress-related agents and inflammatory modulators via extracellular vesicles (EVs), commonly referred to as exosomes prior to 2018. EVs are biological nanoparticles and are released by almost all cells [29,30]. They are considered as both inter and intra-cellular messengers, able to modify their cargo according to the condition or stimulus affecting the parent cells [31,32], which upon internalization by recipient cells, can modulate the pathophysiological state in those cells [33,34]. EVs play an important role in HIV pathogenesis - either in improving or deteriorating the existing condition; however, the exact role of EVs in HIV pathogenesis is poorly understood [35,36]. Currently, only a handful of studies have investigated the role of EVs in smoking-mediated toxicity in the setting of HIV [37,38,39].

The complete eradication of HIV is not currently feasible, with a few exceptions [40,41], due to viral latency in cellular reservoirs, e.g. CD4 T cells, cells of the myeloid lineage (monocytes and macrophages) and dendritic cells [42,43,44,45]. Monocytes and macrophages are considered one of the most suitable cells for studying viral latency due to their long lifespan, as well as their ubiquitous presence throughout the body, including the brain [43,45,46]. EVs derived from monocytes and macrophages potentially have a profound effect on recipient cells [47,48]. For example, we have previously reported that EVs derived from uninfected monocytes protect recipient cells due to the specific packaging of protective elements [39], manuscript under revision). Conversely, HIV-infected macrophage-derived EVs lose this defense capacity, as evidenced by a higher viral load and increased cellular toxicity [39]. Proteomic and cytokine analyses of plasma EVs obtained from HIV-positive and negative smokers demonstrated a differential packaging of proteins in the EVs [37,49]. In addition, macrophage-derived EVs can readily cross the blood brain barrier, suggesting the potential role of EVs in either disseminating or alleviating HIV and HAND pathogenesis [30].

Evidently, there is a strong correlation between cigarette smoking and HIV and/or HAND pathogenesis as demonstrated via EVs. Nevertheless, there are unresolved questions to be answered. For example, what is the true nature/role of EVs in smoking-mediated HIV and HAND pathogenesis? Can we inhibit the viral transfection and oxidative stress through EVs? Is there any therapeutic application of EVs in this context? Can the components of EVs be used as biomarkers for HIV-tobacco smoking interactions that lead to HAND? Very recently, especially in the last five years, more and more studies are being conducted to answer these questions. This niche field has drawn researchers to connect the dots between HIV, cigarette smoking, HAND and EVs, and whether oxidative stress acts as a driving force to exacerbate the conditions.