Exploring new frontiers in the treatment of HIV–associated neurocognitive disorder

The recent published paper by Jimenez-Torres et al (2025) reported the pharmacological profiles of a group of novel pyrimidine structure-based compounds that act as allosteric modulators of the dopamine (DA) transporter (DAT) and attenuate human immunodeficiency virus type-1 (HIV-1) Tat protein–induced inhibition of DA transport through DAT (Fig. 1). Prior research from this group revealed that SRI-32743, a novel allosteric modulator of DAT, normalizes HIV-1 Tat protein–induced inhibition of DA transport via DAT in vitro and in vivo and ameliorates Tat-potentiated cognitive deficits and cocaine reward in inducible Tat transgenic mice (Zhu et al, 2022). Using the backbone of SRI-32743, 170 new analogs of SRI-32743 were synthesized, and initial screening led to the identification of 21 atypical inhibitors of DAT. To further improve the activity and pharmacokinetic profile, structure-activity relationship studies recognized 4 promising compounds that were selected and assessed in vitro and ex vivo using CHO-K1 cells expressing wild-type human DAT and C57BL/6J mouse striatal synaptosomes. Consistent with in silico predictions, SRI-46564, SRI-46286, and SRI-47867 displayed atypical inhibition of DAT (E_max ≤ 60%) in the micromolar range, whereas SRI-47056 displayed inhibition in the nanomolar range. Moreover, the 4 compounds attenuated Tat-induced inhibition of DA uptake without affecting basal DA release in an allosteric modulatory manner and showed improved metabolic stability and solubility. The authors concluded that the current findings provide new insights into the potential development of novel therapeutic agents to attenuate DAT-Tat interactions and normalize DA neurotransmission in neuroHIV.

Fig. 1.

Graphical representation of proposed mechanism of Tat, cocaine, and SRI compounds on DAT. (A) Shows dynamic translocation processing (top panel) of DAT in healthy individuals with DA binding at the DA uptake site located on the extracellular site of DAT. The binding of cocaine (near DA binding site) and Tat (allosteric site) slows down the dynamic translocation processing of DAT (bottom panel), which increases DA levels in the synapse, leading to HAND in PLWH with concurrent cocaine use. (B) SRI-32743 was used as the lead compound, and numerous screening and structure-activity relationship (SAR) studies led to the development of 4 compounds with improved potency and pharmacokinetic profiles. (C) The novel SRI compounds are proposed to bind allosterically near the Tat binding site, which directly and indirectly disrupts the binding of Tat and cocaine, respectively, eventually restoring the dynamic translocation processing of DAT. ADME, absorption, distribution, metabolism, and excretion. Figure created with BioRender.com.

HIV infection continues to increase globally, with 1.3 million new infections registered in 2023, and there are an estimated 39.9 million people living with HIV (PLWH). Converging lines of clinical evidence demonstrate that HIV–associated neurocognitive disorder (HAND), including asymptomatic and milder forms, affects 39.6% of PLWH despite the widespread use of combined antiretroviral therapy (cART) (Keng et al, 2023). Drug use, including cocaine use, has been shown to enhance the incidence of depression in PLWH and exacerbate its severity. This study addresses an important public health issue, as the current treatment options are ineffective for treating HAND, which is accompanied by impulsivity alterations and depression, specifically in PLWH with comorbid substance use disorder. Despite the advent of cART, prolonged exposure to HIV-1 viral proteins causes dysregulation of DA transmission, a pathophysiological change that is a key factor in promoting HAND. HIV-1 Tat, a critical viral protein that plays a major role in HAND pathogenesis, is secreted from HIV-infected microglia and astrocytes and taken up by neurons, leading to neuronal damage (Frankel and Pabo, 1988; Marino et al, 2020). HIV-1 Tat is the only detectable viral protein identified in the cerebrospinal fluid (CSF) of PLWH receiving cART (Mediouni et al, 2012) and has been associated with the presence of HAND (Henderson et al, 2019). Clinical observations revealed that in early disease stages, DA levels are increased in the CSF of PLWH (Scheller et al, 2010; Horn et al, 2013), whereas in advanced infection, decreased DA levels have been found in postmortem brains of PLWH (Kumar et al, 2009) and in the CSF of PLWH (Larsson et al, 1991), during both the pre-cART and post-cART eras (Berger et al, 1994; di Rocco et al, 2000). Cocaine use, via inhibition of DAT, exacerbates Tat-induced dysregulation of DA transmission. Of importance, HIV-induced upregulation of DA levels in the central nervous system (CNS) within DA-rich brain regions can stimulate viral replication in human macrophages (Gaskill et al, 2009), resulting in release of viral proteins, which has been implicated in HAND pathophysiology (Li et al, 2009).

A key finding from this group is that Tat-induced inhibition of DAT is mediated by direct binding to allosteric binding site(s) on DAT and not by competitively interacting with the DA uptake site (Zhu et al, 2009; Zhu et al, 2011; Midde et al, 2013). This novel finding raises a possibility of blocking Tat binding to DAT by an allosteric modulator without affecting basal physiological DA transport. Because the 4 SRI-32743 analogs do not affect basal physiological DA transport, they can be considered neutral allosteric modulators of DAT. Through computational modeling and pharmacological validation, a series of studies from this group has demonstrated several binding modes of Tat-DAT interactions (Midde et al, 2013; Quizon et al, 2021). Based on the Tat-DAT interaction, SRI-32743 has been identified to attenuate Tat-induced inhibition of DAT and DAT-mediated release. Thus, developing compounds directly targeting the specific binding sites on DAT for Tat or indirectly targeting structurally distinct binding sites could provide a viable approach for treatment of Tat-induced DA dysregulation.

Additionally, it is noteworthy to mention that the study also demonstrates that the 4 SRI analogs slow down the dissociation rate of cocaine binding to DAT. This is supported by the previous study of the original SRI-32742 compound that not only demonstrated inhibition of cocaine binding to DAT but also reported reversal of Tat-induced potentiation of cocaine-conditioned place preference (Zhu et al, 2022). Because the SRI compounds are designed for interactions with Tat-DAT, it is not clear whether the SRI compounds also disrupt cocaine binding with DAT. It is possible that the SRI compounds could target the modulatory allosteric site and decrease cocaine affinity through changes in DAT conformation, which should be addressed in future studies.

In summary, this paper evaluates and characterizes the pharmacological profiles of the optimized second-generation analogs of SRI-32743, which has previously been shown to attenuate Tat binding to DAT via allosteric modulation. The paper reports important clinically relevant findings and proposes that allosteric DAT modulators could be promising treatment options/interventions for HAND. One of the strengths of this study includes a novel finding that supports the pyrimidine structure-based compounds, which display an allosteric role in attenuation of Tat-inhibited DAT-mediated DA transport without affecting physiological DA uptake. Overall, this is a very interesting and important study with high impact that can take the neuroHIV field into a new direction.

While there is currently no promising treatment for HAND, this work aims to assess the effects of novel allosteric modulators of DAT on Tat-DAT interaction as a potential therapeutic intervention for the dysregulation of DA observed in PLWH, which is of high clinical significance. Determining the effects of allosteric DAT modulators on DA uptake via DAT in the presence of other HIV-1 viral proteins is important for future directions. Considering the monoamine hypothesis of HAND, future studies need to determine whether the SRI compounds disrupt not only Tat-DAT interaction but also Tat and cocaine interaction with norepinephrine and serotonin transporters. Of note, unlike cocaine, amphetamine acts as a substrate to inhibit not only DAT but also vesicular monoamine transporter type-2 in presynaptic terminals, ultimately inducing DA release by reversing DAT. Thus, another interesting direction for future study is to verify whether these SRI compounds inhibit vesicular monoamine transporter type-2 with the potential capability to attenuate the effects of amphetamine- or methamphetamine-mediated dysregulation of DA homeostasis.

HAND is associated with viral proteins accumulating in the CNS despite cART, which is specifically true for the HIV-1 Tat protein because it is the first protein expressed upon cell infection and is present in the brains of PLWH receiving cART. Considering the elevated DA levels in the CSF of PLWH in the early stage of infection, the effectiveness of an early intervention for HAND may depend on a therapeutic strategy that combines allosteric DAT modulators with cART, with minimal side effects on normal physiological function of DAT.

Conflict of interest

The authors declare no conflicts of interest.