Synergistic Impairment of the Neurovascular Unit by HIV-1 Infection and Methamphetamine Use: Implications for HIV-1-Associated Neurocognitive Disorders

The neurovascular units (NVU) are the minimal functional units of the blood–brain barrier (BBB), composed of endothelial cells, pericytes, astrocytes, microglia, neurons, and the basement membrane. The BBB serves as an important interface for immune communication between the brain and peripheral circulation. Disruption of the NVU by the human immunodeficiency virus-1 (HIV-1) induces dysfunction of the BBB and triggers inflammatory responses, which can lead to the development of neurocognitive impairments collectively known as HIV-1-associated neurocognitive disorders (HAND). Methamphetamine (METH) use disorder is a frequent comorbidity among individuals infected with HIV-1. METH use may be associated not only with rapid HIV-1 disease progression but also with accelerated onset and increased severity of HAND. However, the molecular mechanisms of METH-induced neuronal injury and cognitive impairment in the context of HIV-1 infection are poorly understood. In this review, we summarize recent progress in the signaling pathways mediating synergistic impairment of the BBB and neuronal injury induced by METH and HIV-1, potentially accelerating the onset or severity of HAND in HIV-1-positive METH abusers. We also discuss potential therapies to limit neuroinflammation and NVU damage in HIV-1-infected METH abusers.     

HIV-1, Methamphetamine and Astrocyte Glutamate Regulation: Combined Excitotoxic Implications for Neuro-AIDS

Glutamate, the most abundant excitatory transmitter in the brain can lead to neurotoxicity when not properly regulated. Excitotoxicity is a direct result of abnormal regulation of glutamate concentrations in the synapse, and is a common neurotoxic mediator associated with neurodegenerative disorders. It is well accepted that methamphetamine (METH), a potent central nervous stimulant with high abuse potential, and human immunodeficiency virus (HIV)-1 are implicated in the progression of neurocognitive malfunction. Both have been shown to induce common neurodegenerative effects such as astrogliosis, compromised blood brain barrier integrity, and excitotoxicity in the brain. Reduced glutamate uptake from neuronal synapses likely leads to the accumulation of glutamate in the extracellular spaces. Astrocytes express the glutamate transporters responsible for majority of the glutamate uptake from the synapse, as well as for vesicular glutamate release. However, the cellular and molecular mechanisms of astrocyte-mediated excitotoxicity in the context of METH and HIV-1 are undefined. Topics reviewed include dysregulation of the glutamate transporters, specifically excitatory amino acid transporter-2, metabotropic glutamate receptor(s) expression and the release of glutamate by vesicular exocytosis. We also discuss glutamate concentration dysregulation through astrocytic expression of enzymes for glutamate synthesis and metabolism. Lastly, we discuss recent evidence of various astrocyte and neuron crosstalk mechanisms implicated in glutamate regulation. Astrocytes play an essential role in the neuropathologies associated with METH/HIV-1-induced excitotoxicity. We hope to shed light on common cellular and molecular pathways astrocytes share in glutamate regulation during drug abuse and HIV-1 infection.     

Evidence for a cytopathogenicity determinant in HIV-1 Vpr

HIV-1 is cytopathic for CD4(+) T lymphocytes in vitro and this property of HIV-1 is generally considered to account for some of its in vivo cytopathogenicity. Thus, the extent of lymphocyte depletion correlates with the level of viremia whereas low levels of viral replication are typically associated with stable lymphocyte levels and asymptomatic infection such as is observed in non-progressors. Here, we describe a non-progressor who did not fit this general pattern in that CD4(+) T lymphocyte homeostasis was maintained in the face of high-level viral replication. Biological viral isolates from this patient replicated in primary lymphocytes without inducing cytopathicity. Because this phenotype is reminiscent of Vpr-deleted viruses, we examined the contribution of the Vpr gene to the viral phenotype. Vpr alleles derived from this patient contained both premature stop codons and an unusual Q3R polymorphism. Insertion of patient-derived Vpr alleles or a Q3R substitution into a cytopathic HIV-1 clone resulted in a marked impairment of cytopathicity without affecting viral replication efficiency. The effect of Vpr on cytopathicity was unrelated to reported activities of Vpr including virion association, interaction with uracil DNA glycosylase, G(2) arrest, or enhancement of macrophage infection but correlated with the ability of Vpr to induce host cell apoptosis. This study suggests the presence of a determinant of in vivo cytopathogenicity within HIV-1 Vpr and further indicates that viral replication can be uncoupled from cytopathicity in vitro and in vivo.     

Exposure of Rats to Ethanol from Postnatal Days 4 to 8: Alterations of Cholinergic Neurochemistry in the Hippocampus and Cerebellum at Day 20

Brief neonatal ethanol exposure (3.0 g/kg/dose, twice daily; postnatal day (PN) 4 to PN8) resulted in cholinergic neurochemical alterations in the cerebellum, but not the hippocampus of rats assayed on PN20. Analysis revealed that the binding affinity of cerebellar muscarinic receptors for [3H]quinuclidinyl benzilate was decreased by ethanol, but only in female pups. Other gender-specific but treatment-independent cerebellar differences were identified as well, including lower levels of choline acetyltransferase activity and S1-level (1,000 x g) crude protein in males and females, respectively. No evidence of ethanol-induced cholinergic change was noted in the hippocampus of the same pups on PN20. However, collapsed across treatment, male hippocampi were found to contain less S1-level protein than their female counterparts. Neither muscarinic receptor density nor acetyl cholinesterase activity were found to differ between treatments or genders, in either brain region. Consistent with the developmental timetables for regional cholinergic synaptogenesis in the rat, observations on PN20 confirm a hypothesis of cerebellar cholinergic vulnerability and hippocampal cholinergic resilience to neonatal ethanol insult.     

Intraneuronal β-Amyloid Accumulation: Aging HIV-1 Human and HIV-1 Transgenic Rat Brain

The prevalence of HIV-1 associated neurocognitive disorders (HAND) is significantly greater in older, relative to younger, HIV-1 seropositive individuals; the neural pathogenesis of HAND in older HIV-1 seropositive individuals, however, remains elusive. To address this knowledge gap, abnormal protein aggregates (i.e., β-amyloid) were investigated in the brains of aging (>12 months of age) HIV-1 transgenic (Tg) rats. In aging HIV-1 Tg rats, double immunohistochemistry staining revealed abnormal intraneuronal β-amyloid accumulation in the prefrontal cortex (PFC) and hippocampus, relative to F344/N control rats. Notably, in HIV-1 Tg animals, increased β-amyloid accumulation occurred in the absence of any genotypic changes in amyloid precursor protein (APP). Furthermore, no clear amyloid plaque deposition was observed in HIV-1 Tg animals. Critically, β-amyloid was co-localized with neurons in the cortex and hippocampus, supporting a potential mechanism underlying synaptic dysfunction in the HIV-1 Tg rat. Consistent with these neuropathological findings, HIV-1 Tg rats exhibited prominent alterations in the progression of temporal processing relative to control animals; temporal processing relies, at least in part, on the integrity of the PFC and hippocampus. In addition, in post-mortem HIV-1 seropositive individuals with HAND, intraneuronal β-amyloid accumulation was observed in the dorsolateral PFC and hippocampal dentate gyrus. Consistent with observations in the HIV-1 Tg rat, no amyloid plaques were found in these post-mortem HIV-1 seropositive individuals with HAND. Collectively, intraneuronal β-amyloid aggregation observed in the PFC and hippocampus of HIV-1 Tg rats supports a potential factor underlying HIV-1 associated synaptodendritic damage. Further, the HIV-1 Tg rat provides a biological system to model HAND in older HIV-1 seropositive individuals.     

The Actions of Dopamine on the Blood Pressure and Heart Rate of Conscious Hypertensive Rats: Evidence for Reduced Dopaminergic Activity in Rats of the Japanese Strains

The effects of intracerebroventricularly (icv) and intravenously (iv) administered dopamine (DA) on mean arterial pressure (MAP) and heart rate were investigated in conscious spontaneously hypertensive rat (SHR), stroke-prone SHR (spSHR) and normotensive Wistar-Kyoto (WKY) rat of Japanese strains, genetically hypertensive (GHR) and normotensive (NT-NZ) rat of New Zealand strains, Sprague-Dawley (SD) rat, and left renal artery stenosed hypertensive WKY (WKYLRAS) and SD (SDLRAS) rats. Icv DA (0.0125-0.4 mg/kg) caused a linear dose-related decrease in MAP, accompanied by bradycardia in all animals. By contrast, the same doses of DA given iv caused a linear dose-related increase in MAP, accompanied by reflex bradycardia in most groups (except the spSHR, SHR and WKYLRAS where tachycardia occurred to most of the doses employed), indicating that the decrease in MAP following icv DA is centrally-mediated. A “greater” relative hypotensive effect to icv DA was seen in the Japanese hypertensive strains SHR and spSHR compared to the WKY, but not between the New Zealand strains or the renal hypertensive animals. Our data also show that this marked hypotensive responsiveness is not related to the basal MAP, but appears to be strain-specific. It is thus possible that the alleged reduced central dopaminergic activity in the Japanese strains of hypertensive rats may be responsible for exaggerated hypotensive responses observed in these strains.     

Exposure of Rats to Ethanol from Postnatal Days 4 to 8: Alterations of Cholinergic Neurochemistry in the Cerebral Cortex and Corpus Striatum at Day 20

Male and female rat pups were administered ethanol (3 g/kg/dose) twice daily by intragastric intubation between postnatal Day (PN) 4 and 8. Pups were maternally reared throughout the exposure period and until sacrifice on PN20. The consequences of this growth spurt exposure to ethanol were measured by an impact upon body growth, as well as upon specific growth parameters and cholinergic neurochemical factors within the cerebral cortex and corpus striatum. Specific endpoints included muscarinic receptor binding dynamics, acetylcholinesterase (AChE) and choline acetyltransferase (CAT) activities, regional wet weights, and subcellular protein content. In male pups, ethanol resulted in a significant enhancement of body weight gain and an increase in striatal but not cortical mass. Additionally, ethanol exposure resulted in a significant increase in striatal muscarinic receptor affinity, regardless of gender. This was accompanied by evidence of a significantly greater density of striatal muscarinic receptors in males versus females, regardless of treatment. Overall, the ethanol-associated effects are suggestive of a drug-induced developmental delay. Gender-specific, treatment-independent differences were also detected in the developing brain regions. Thus, regardless of treatment, cerebral cortical S1-level protein content was found to be significantly greater in males than in females. Furthermore, there were gender-based, significant differences in AChE activity within the striatum of control pups (males greater than females). Ethanol exposure resulted in a loss of this gender-based difference. We conclude that the cholinergic neurochemical development occurring in the striatum of the female rat brain between PN4 and 8 is exquisitely sensitive to ethanol-induced developmental delays which are not remediable by 12 subsequent days of maternal rearing in the absence of ethanol exposure.     

Dynamics of HIV-1 Gag Processing as Revealed by Fluorescence Lifetime Imaging Microscopy and Single Virus Tracking

The viral polyprotein Gag plays a central role for HIV-1 assembly, release and maturation. Proteolytic processing of Gag by the viral protease is essential for the structural rearrangements that mark the transition from immature to mature, infectious viruses. The timing and kinetics of Gag processing are not fully understood. Here, fluorescence lifetime imaging microscopy and single virus tracking are used to follow Gag processing in nascent HIV-1 particles in situ. Using a Gag polyprotein labelled internally with eCFP, we show that proteolytic release of the fluorophore from Gag is accompanied by an increase in its fluorescence lifetime. By tracking nascent virus particles in situ and analyzing the intensity and fluorescence lifetime of individual traces, we detect proteolytic cleavage of eCFP from Gag in a subset (6.5%) of viral particles. This suggests that for the majority of VLPs, Gag processing occurs with a delay after particle assembly.     

Methamphetamine Induces the Release of Proadhesive Extracellular Vesicles and Promotes Syncytia Formation: A Potential Role in HIV-1 Neuropathogenesis

Despite the success of combinational antiretroviral therapy (cART), the high pervasiveness of human immunodeficiency virus-1 (HIV)-associated neurocognitive disorders (HAND) poses a significant challenge for society. Methamphetamine (meth) and related amphetamine compounds, which are potent psychostimulants, are among the most commonly used illicit drugs. Intriguingly, HIV-infected individuals who are meth users have a comparatively higher rate of neuropsychological impairment and exhibit a higher viral load in the brain than infected individuals who do not abuse meth. Effectively, all cell types secrete nano-sized lipid membrane vesicles, referred to as extracellular vesicles (EVs) that can function as intercellular communication to modulate the physiology and pathology of the cells. This study shows that meth treatments on chronically HIV-infected promonocytic U1 cells induce the release of EVs that promote cellular clustering and syncytia formation, a phenomenon that facilitates HIV pathogenesis. Our analysis also revealed that meth exposure increased intercellular adhesion molecule-1 (ICAM-1) and HIV-Nef protein expression in both large (10 K) and small (100 K) EVs. Further, when meth EVs are applied to uninfected naïve monocyte-derived macrophages (MDMs), we saw a significant increase in cell clustering and syncytia formation. Furthermore, treatment of MDMs with antibodies against ICAM-1 and its receptor, lymphocyte function-associated antigen 1 (LFA1), substantially blocked syncytia formation, and consequently reduced the number of multinucleated cells. In summary, our findings reveal that meth exacerbates HIV pathogenesis in the brain through release of proadhesive EVs, promoting syncytia formation and thereby aiding in the progression of HIV infection in uninfected cells.     

1H MR Spectroscopy of the Brain in HIV-1-Seropositive Subjects: Evidence for Diffuse Metabolic Abnormalities

PURPOSE: To analyze brain metabolite changes in HIV-1-seropositive subjects in order to define whether the neuronal impairment is a localized or more diffuse process.MATERIALS and METHODS: 15 patients and 18 volunteers underwent multivoxel proton magnetic resonance (MR) spectroscopy at 1.5T. Nine patients were classified as being neuropsychiatrically unimpaired and six as having HIV-1-associated dementia on the basis of a full neuropsychological examination. Spectra were analysed from multiple voxels located in the fronto-parietal cortex and white matter at the level of centrum semiovale.RESULTS: A significant reduction in mean peak area ratios of NAA/Cr (p<0.005 in the grey matter, p<0.01 in the white matter) and an elevation in mean Cho/Cr (p<0.005 in both grey matter and white matter) were observed in patients with HIV-1-associated dementia when compared to healthy volunteers. No significant metabolite abnormalities were detected in the neuropsychiatrically unimpaired group, although there was a similar trend in the metabolite ratios. The changes in metabolite ratios were of the same order of magnitude in the cortical grey matter and subcortical white matter as in the deeper white matter in all patients. There were also no significant regional variations in mean metabolite ratios between right and left hemispheres or anterior and posterior voxels at the level of the brain studied. There were no abnormalities in Glx/Cr in any spectra analysed from either patient group.CONCLUSION: The absence of significant regional variation in metabolite ratios at the level of the centrum semiovale provides some evidence that abnormalities of cerebral metabolites in HIV-infected patients may be part of a diffuse process.     

Evidence from Zaire that breast-feeding by HIV-1-seropositive mothers is not a major route for perinatal HIV-1 transmission but does decrease morbidity

Breast-feeding as a route of HIV-1 transmission during infancy but also as a protective measure against early childhood morbidity has been investigated prospectively in children born to HIV-1-seropositive mothers and control children born to age- and parity-matched HIV-1-seronegative women. The mothers of all study children had been enrolled antenatally at a maternity hospital in Kinshasa, Zaire, which served a relatively affluent group of women who sometimes chose not to breast-feed their infants. In 106 children born to HIV-1-seropositive women, the rate of HIV-1 transmission was 21% in 28 infants exclusively breast-fed, 19% in 68 infants both breast- and bottle-fed and 0% in 10 infants who were bottle-fed only (P = 0.35). In contrast, non-HIV-1-infected children of both HIV-1-seropositive and HIV-1-seronegative mothers who were exclusively breast-fed compared with uninfected children who were not exclusively breast-fed had significantly lower incidence rates of acute diarrhea, fever and lower respiratory tract infection. The lack of a dose-response effect between breast-feeding and perinatal HIV-1 transmission and the presence of a protective effect of breast-feeding against common causes of early childhood morbidity and mortality support the current World Health Organization recommendation that breast-feeding should continue to be promoted in all developing countries, including those with high HIV-1 prevalence rates in women of childbearing age.     

Sensitization, Duration, and Pharmacological Blockade of Anxiety-Like Behavior Following Repeated Ethanol Withdrawal in Adolescent and Adult Rats

Background: Repeated ethanol withdrawal sensitizes anxiety‐like behavior in adult rats and causes anxiety‐like behavior and decreased seizure thresholds in adolescent rats. Current experiments determined if adolescent rats exhibit sensitized anxiety‐like behavior, the duration of this effect, if drug pretreatments blocked these effects, and if these effects differed from those seen in adults. Methods: Male adolescent rats received three 5‐day cycles of 2.5% ethanol diet (ED) separated by two 2‐day withdrawal periods, continuous 15 days of 2.5%ED, or a single 5‐day cycle of 2.5%ED. Male adult rats received three 5‐day cycles of either 2.5% or 3.5%ED. These groups were tested 5 hours into the final withdrawal for social interaction (SI) deficits (an index of anxiety‐like behavior). Ethanol intake was monitored throughout and blood concentrations were obtained from separate groups of rats. Additionally, adolescent rats were tested for SI 1, 2, 7, 14, and 18 days and adults 1 and 2 days after the final withdrawal. Some adolescent rats were also pretreated with the CRF₁ antagonist CP‐154,526, the 5‐HT_1A agonist buspirone, or the benzodiazepine receptor antagonist flumazenil during the first 2 withdrawals. Results: SI was reduced in adolescent rats following repeated withdrawals of 2.5%ED while neither a continuous or single cycle ED exposure caused this effect. Adult rats also had reduced SI following repeated withdrawals from both 2.5% and 3.5%ED. This effect was present up to 1 week following the final withdrawal in adolescents but returned to baseline by 1 day in adults. CP‐154,526, buspirone, or flumazenil prevented this reduction in SI in adolescent rats. Conclusions: Adolescent rats exhibit sensitized anxiety‐like behavior following repeated withdrawals at ED concentrations similar to those used in adults. However, this effect is longer lasting in adolescent rats. Drugs modulating CRF, 5‐HT, or GABA systems during initial withdrawals prevent the development of anxiety‐like behavior otherwise manifest during a final withdrawal in adolescent rats.     

The Relationships between HIV-1 Infection,History of Methamphetamine Use Disorder,and Soluble Biomarkers in Blood and Cerebrospinal Fluid

Methamphetamine (METH) use disorder is highly prevalent among people with HIV (PWH) and is a significant public health problem. HIV and METH use are each associated with immune system dysfunction; however, the combined effects on the immune system are poorly understood. This cross-sectional project measured soluble immune biomarkers in plasma and cerebrospinal fluid (CSF) collected from a control group, people with a history of a METH use disorder (METH+), PWH with no history of METH use disorder (HIV+), and PWH with a history of METH use disorder (HIV+/METH+). HIV, METH, and immune dysfunction can also be associated with affective and cognitive deficits, so we characterized mood and cognition in our participants. Two factor analyses were performed for the plasma and CSF biomarkers. Plasma IL-8, Ccl2, VEGF, and 8-isoprostane loaded onto one factor that was highest in the HIV+/METH+ group (p < 0.047) reflecting worse inflammation, vascular injury, and oxidative stress. This plasma factor was also negatively correlated with delayed recall (R = −0.49, p = 0.010), which was worst in the HIV+/METH+ group (p = 0.030 compared to the control group). Overall, these data implicate that combined HIV-1 infection and METH use may exacerbate inflammation, leading to worse cognition.     

Women's barriers to HIV-1 testing and disclosure: challenges for HIV-1 voluntary counselling and testing

In view of the ever-increasing HIV/AIDS epidemic in sub-Saharan Africa, the expansion of HIV-1 voluntary counselling and testing (VCT) as an integral part of prevention strategies and medical research is both a reality and an urgent need. As the availability of HIV-1 VCT grows two limitations need to be addressed, namely: low rates of HIV-1 serostatus disclosure to sexual partners and negative outcomes of serostatus disclosure. Results from a study among men, women and couples at an HIV-1 VCT clinic in Dar es Salaam, Tanzania are presented. The individual, relational and environmental factors that influence the decision to test for HIV-1 and to share test results with partners are described. The most salient barriers to HIV-1 testing and serostatus disclosure described by women include fear of partners' reaction, decision-making and communication patterns between partners, and partners' attitudes towards HIV-1 testing. Perception of personal risk for HIV-1 is the major factor driving women to overcome barriers to HIV-1 testing. The implications of findings for the promotion of HIV-1 VCT programmes, the implementation of partner notification policies and the development of post-test support services are discussed.     

Noninfectious papilloma virus-like particles inhibit HIV-1 replication: implications for immune control of HIV-1 infection by IL-27

Human papilloma virus (HPV)-like particles (VLPs) have been used as a vaccine to prevent HPV infection. Recent studies demonstrate that VLPs bind to dendritic cells and induce the expression of antiviral cytokines such as interferon-alpha (IFN-alpha), interleukin-10 (IL-10) and IFN-gamma. In the present study, we evaluated the effect of VLPs on HIV-1 replication in peripheral blood mononuclear cells (PBMCs), CD4+ T cells, and macrophages. Here, we show that VLPs suppress the replication of both X4 and R5 HIV-1 without affecting the expression of CD4, CXCR4, and CCR5. Soluble factor(s) released by PBMCs and macrophages on VLPs treatment inhibited HIV-1 replication. To determine the inhibitory factors, DNA microarray analysis was performed using VLP-treated PBMCs and macrophages. VLPs induced the genes associated with IFN induction, immune responses, and antiviral responses, among with the recently described cytokine IL-27. Subsequently, IL-27 was found to be a potent inhibitor of HIV-1 replication in PBMCs, CD4+ T cells, and macrophages. Taken together, our studies identify a novel role of IL-27 in restricting HIV-1 replication and suggest that further examination of the inhibitory property of IL-27 may pave the way for a novel therapy for HIV-1 infection.     

Gossypol Activates Pancreatic Polyamine Catabolism in Normal Rats and Induces Acute Pancreatitis in Transgenic Rats Over-expressing Spermidine/Spermine N 1 -Acetyltransferase

Background: The male antifertility agent gossypol has been reported to induce spermidine/spermine N 1 -acetyltransferase (SSAT) in canine prostate cells. As SSAT is the rate-controlling enzyme in the catabolism of the polyamines and is involved in the development of acute pancreatitis in a recent transgenic rat model, we exposed normal and transgenic rats over-expressing SSAT to gossypol to evaluate its effect on pancreatic polyamine metabolism and organ integrity. Methods: Pancreatic SSAT activity, polyamine pools, pancreatic histology and plasma &#33 -amylase activity were determined after different doses of gossypol. Results: Gossypol increased pancreatic putrescine and decreased spermidine and spermine pools in normal rats accompanied by tissue oedema and significantly elevated plasma amylase activity. In transgenic rats, the drug strikingly induced SSAT, profoundly depleted the higher polyamines and caused distinct pancreatitis. The combination of gossypol at doses harmless to transgenic pancreas with an inhibitor of polyamine oxidase caused massive synergistic induction of SSAT, profound depletion of the polyamine pools and acute pancreatitis. Conclusions: The results indicate that gossypol induces pancreatitis through an activation of polyamine catabolism.     

Adolescent Inhalant Use among Male Patients in Treatment for Substance and Behavior Problems: Two-Year Outcome

Adolescent inhalant users are significantly more likely than other patients to have conduct disorder, to report abuse and neglect, and to have previously attempted suicide. Yet little has been published regarding treatment outcome for inhalant users. Methods: Eighty male adolescents admitted to a residential treatment program underwent baseline assessment during treatment, and follow-up assessment at two-years post admission. Subjects reporting any lifetime inhalant use at baseline (n = 34) were compared to the other patients (n = 46) on 4 outcome variables. Results: Adolescents reporting any lifetime inhalant use at baseline assessment reported twice as many past-year conduct disorder symptoms at two-year follow up (p = 0.03). The relationship between inhalant use and conduct disorder symptoms remained significant (p = 0.03) in analyses that controlled for age, time in jail or restricted environments in the 6-months preceding follow-up, as well as baseline-reported lifetime number of conduct disorder symptoms. Inhalant users were not significantly worse on these other outcome measures: crime in the last month (p = 0.60), days of nontobacco substance use in the last 6 months (p = 0.65), or, commission of selected crimes in the last 6 months (p = 0.06). Conclusions: Inhalant use among adolescent males in treatment for substance and behavior problems may predict more severe conduct disorder symptoms after treatment.     

Evidence of blood-brain barrier alteration and activation in HIV-1 gp120 transgenic mice

OBJECTIVE: To verify whether HIV envelope protein gp120 changes the blood-brain barrier in vivo, as a fundamental mechanism of early central nervous system damage by HIV-1. DESIGN: Analysis of the functional integrity and immune activation of the blood-brain barrier in brains of HIV-1 gp120 transgenic mice secreting circulating gp120 at levels similar to those detected in AIDS patients. METHODS: Number of vessels/mm2 section area with perivascular albumin and percentage of vessels expressing adhesion molecules (ICAM-1 and VCAM-1) were determined by immunohistochemistry in frozen brains from autopsied transgenic and non-transgenic mice. The percentage of vessels showing substance P immunoreactivity was also calculated, as this neuropeptide is known to mediate the increase in permeability of the rat brain endothelium in vitro caused by HIV-1 gp120. RESULTS: The number of vessels with albumin extravasation was significantly higher in transgenic than non-transgenic mice brains (P = 0.0003). A greater percentage of ICAM-1- and VCAM-1-positive brain vessels in transgenic than non-transgenic mice was shown (P = 0.0017 and P = 0.0008 respectively). Significant immunoreactivity for substance P was detected in brain vessels in transgenic mice and a significant correlation was found between the percentage of substance P-positive and ICAM-1-positive brain vessels (P < 0.0001) in transgenic mice. CONCLUSIONS: These findings demonstrate that HIV-1 gp120 is capable of changing and activating in vivo the vascular component of the blood-brain barrier.