Table 1.
A summary of recent studies showing that HIV-1 infection and methamphetamine (METH) use synergistically impair the neurovascular unit (NVU).
| Study and Year | Experimental Model | Viral Inoculum Dose/Route | METH Dosing Regimen | Synergistic Effects on NVU |
|---|---|---|---|---|
| Combined In Vivo and In Vitro Studies | ||||
| Huang et al., 2021 [34] | Tree shrews; HCMEC/D3 cell line (human) | Tat (100 ng) by tail i.v. injection; 25 to 200 nM of Tat | 8 mg/kg i.p. for 10 consecutive days; 0.05 to 2.0 mM for 24 h | Enhanced BBB permeability due to alterations in TRPM2 channels and TJ protein expression both in vivo and in vitro |
| Li et al., 2021 [35] | Tree shrews; HCMEC/D3 cell line (human) | Tat (100 ng) by tail i.v. injection; 100 nM of Tat | 8 mg/kg i.p. for 10 consecutive days; 500 μM for 24 h | Decreased expression of TJ proteins and increased BBB permeability both in vivo and in vitro; Downregulation of GLUT1 and GLUT3 protein expression both in vivo and in vitro |
| Zeng et al., 2018 [36] | Rats; SH-SY5Y neuroblastoma cell line (human) | Tat (50 ng/kg) by tail i.v. injection; 50 and 100 nM of Tat | 10 mg/kg i.p. for 7 consecutive days; 1 and 2 mM for 24 h | Exacerbation of oxidative stress both in vivo and in vitro |
| Park et al., 2021 [37] | C57BL/6 mice; human primary neural progenitor cells | EcoHIV (1 μg of p24) via left internal carotid artery injection; HIV-1 NL4-3 (60 ng/mL of p24) | Escalating dose regimen for 6 days: 1.0–4.0 mg/kg i.p.; 100 μM for 24 h | Enhanced neural progenitor cell proliferation both in vivo and in vitro |
| Yu et al., 2017 [38] | HIV-1 transgenic rats; primary human fetal astrocytes | N/A; HIV-1 BaL (10 ng or 20 ng of p24) | 10 mg/kg i.p. every 2 h for 4 days; 10, 30, 100, 300 and 1000 μM daily for 5 days | Induction of astrocyte senescence both in vivo and in vitro |
| In Vivo Studies | ||||
| Li et al., 2018 [39] | Sprague-Dawley rats | Tat (50 ng) i.c.v. | 10 mg/kg i.p. for 7 consecutive days | Decreased expression of TJ proteins and increased BBB permeability; Exacerbation of oxidative stress and neuronal damage |
| Hoefer et al., 2015 [40] | HIV-1 gp120 transgenic mice | N/A | Escalating dose multiple-binge regimen for 25 days: 0.1–6.0 mg/kg s.c. | Reduction in post-tetanic potentiation in hippocampal slices; Decreased dendritic spine density |
| de Guglielmo et al., 2015 [41] | HIV-1 transgenic rats | N/A | Escalating dose multiple-binge regimen for 15 consecutive sessions: 0.5 mg/kg/0.1 mL 6 h/day i.v. | Gene expression changes indicative of an increase in neuronal damage and impaired aerobic glucose metabolism in the medial prefrontal cortex |
| Ohene-Nyako et al., 2018 [42] | HIV-1 transgenic rats | N/A | 0.02–0.04 mg/kg/0.05 mL i.v. infusion 2 h/day for 21 days | Upregulation of DRD1 and deltaFosB expression in the nucleus accumbens |
| Baek et al., 2020 [43] | Doxycycline-inducible HIV-1 Tat transgenic mice | N/A | 2 mg/kg i.p. once a day for 7 days (acquisition phase); 1 mg/kg (challenge phase) | Reduction in DRD2 and DRD5 mRNA levels in the striatum |
| Najera et al., 2016 [44] | Rhesus macaques | SIVmac251 i.v. (infectious dose was not reported) | Escalating dose regimen for 23 weeks with a final dose of 2.5 mg/kg i.m. | Upregulation of genes encoding proteins involved in DNA damage and senescence in microglia |
| Niu et al., 2020 [45] | Rhesus macaques | SIVmac251 i.v. (infectious dose was not reported) | Escalating dose regimen over a month-long period: 0.1–2.5 mg/kg i.m. | Upregulation of genes encoding proteins involved in cell death pathways and deficiencies in the BDNF-signaling pathway in brain microglia/macrophages |
| Postmortem Human Brain Ex Vivo Studies | ||||
| Soontornniyomkij et al., 2016 [22] | Human postmortem brain samples | N/A | Lifetime METH dependence | Focal cerebral microgliosis |
| Doulias et al., 2021 [46] | Human postmortem brain samples | N/A | Duration of METH use was not reported | Increase in S-nitrosylation of tricarboxylic acid enzymes |
| In Vitro Studies | ||||
| Patel et al., 2017 [47] | HCMEC/D3 cell line (human) | Tat (100 nM) | 10 μM for 24 h | Reduced ZO-1 TJ protein expression (in line with in vivo studies [34,35,39]); Increased rhodamine 123 accumulation |
| Cao et al., 2016 [48] | Simian virus 40 (SV40)-transformed astrocyte cell line (human) | gp120 (400 pM) | 500 μM for 24 h | Autophagy initiation |
| Castellano et al., 2016 [49] | Human primary mixed cultures of neurons and astrocytes | HIV-1 ADA (infectious dose was not reported) | 1 and 10 μM for 7,14 and 21 days | Enhancement of apoptosis |
| Teodorof-Diedrich et al., 2020 [50] | Human primary neurons | gp120, Tat or gp120/Tat (100 ng/mL) | 300 μM for 24 h | DRP1-dependent mitochondrial fragmentation; Neurite length reduction (in line with in vivo study [50]) |
| Li et al., 2018 [51] | Tree shrew primary midbrain neuronal cells | Tat (50 nM and 100 nM) | 0.1–0.5 mM at varying time periods | Autophagy initiation |
| Liu et al., 2017 [52] | Cultured rat microglial cells | gp120 (0.1, 0.5 and 1.5 nM) | 2, 20, and 200 µM for 24 h | Induced KV1.3 potassium channel- mediated microglial neurotoxicity; Increased caspase-3/7 activity in microglia (in line with in vivo studies [52,53]) |
BBB: blood–brain barrier; BDNF: brain derived neurotrophic factor; DRD1: dopamine receptor D1; DRD2: dopamine receptor D2; DRD5: dopamine receptor D5; DRP1: dynamin-related protein 2; FOXO3: forkhead box O transcriptional factor; GLUT1: glucose transporter 1; GLUT3: glucose transporter 3; i.c.v.: intracerebroventricular; i.m.: intramuscular; i.p.: intraperitoneal; i.v.: intravenous; METH: methamphetamine; NVU: neurovascular unit; ROS: reactive oxygen species; s.c.: subcutaneous; TJ: tight junction; TRPM2: transient receptor potential melastatin 2; ZO-1: zona occludens-1.