Human immunodeficiency virus (HIV) is able to penetrate the central nervous system (CNS) through the blood-brain barrier, positioning itself in macrophages and microglia cells. This process can lead to neuroinflammation, neuronal injury, and neurological complications [1].

In the past, HIV-associated dementia was a severe diagnosis in acquired immune deficiency syndrome (AIDS) patients. However, the age-related neurodegenerative disorders observed in people living with HIV (PLWHIV) are now as common as in the rest of the population, representing a big health issue in developed and developing countries [2,3]. People living with HIV are at an increased risk of Alzheimer's dementia compared with age matched HIV-negative controls [4]. Based on previous observations on clinical and pathological similarities with Alzheimer's dementia and other neurodegenerative dementias, it has been proposed that HIV could facilitate the pathological processes of senescence and frailty, reducing the autonomy and increasing the need for care [4], [5], [6], [7]. However, the mechanisms of HIV-related neurocognitive disorders have not yet been completely clarified.

Several biomarkers are known to be correlated with neurological decline in the general population. The protein tau and its phosphorylated form (p-tau) are abundant in the neurons and maintain the stability of microtubules in axons [8], [9], [10]. β-amyloid-42 (Aβ42) seems to be involved in the activation of kinase enzymes, and protection against oxidative stress or antimicrobial activity [11,12]. Neopterin is involved in the type 1 T-helper cell-associated cellular immune response, which is now considered to be a systemic (serum) and local (cerebrospinal fluid, CSF) marker of disease activity in a wide range of infectious and inflammatory diseases [13].

Data on the potential role of these biomarkers in predicting the development of neurological complications in PLWHIV are inconsistent, with conflicting findings. Some studies have found that neopterin levels are higher in PLWHIV with blood-brain barrier damage, whereas other investigations have found no association of this biomarker with impaired blood-brain barrier [14,15]. In addition, few studies have focused on differentiating Alzheimer's dementia from HIV-related neurological disorders. In 2022, Trunfio et al. reported significant differences in CSF Alzheimer's dementia-associated biomarker levels (amyloid and tau proteins), comparing PLWHIV with neurological HIV-associated complications with Alzheimer's dementia affected patients without HIV [16].

The blood-brain barrier is an anatomical structure formed by brain capillary endothelial cells fused through tight junctions. It is known that it protects the CNS from toxic molecules and some drugs. Any condition that compromises the blood-brain barrier integrity could increase the penetration of xenobiotics, including antiretrovirals (ARVs), into the CNS [17,18]. This could be important in the pathogenesis of HIV-associated neurocognitive disorders (HAND). It could be hypothesised that HAND is a neurological complication of ARVs or that poor ARVs CNS penetration through the blood-brain barrier could be involved in the development of HAND [19]. In both cases, drug transporters, which are present in the blood-brain barrier regulating the movement of substances into or out of cells, could play a key role in the pathogenesis of HAND. Transporters are classified in adenosine triphosphate binding cassette (ABC) and solute carrier (SLC) transporters as efflux and influx transporters, respectively. Previous studies have shown that the penetration of some ARVs—such as efavirenz, raltegravir, and darunavir—into the CNS is significantly affected by the gene expression of some drug transporters [20], [21], [22]. Moreover, genetics could have an important impact on neurocognitive impairment; some polymorphisms of genes involved in different biological pathways could particularly affect HAND pathogenesis, as shown by Levine et al. [23].

It is believed that no studies have previously described potential associations between polymorphisms of genes encoding for proteins involved in drug absorption, metabolism, and elimination, and neurological biomarkers in PLWHIV. Consequently, this study evaluated whether variants of genes encoding transporters and their transcription factors could affect neopterin, tau, phospho-tau, and β-1,42 levels, in order to understand whether they could play a role in HIV-neurocognitive disorder development.