Although highly active anti-retroviral therapy has resulted in remarkable decline in the morbidity and mortality in AIDS patients, inadequately low delivery of anti-retroviral drugs across the blood-brain barrier results in virus persistence. The capability of high-efficacy-targeted drug delivery and on-demand release remains a formidable task. Here we report an in vitro study to demonstrate the on-demand release of azidothymidine 5'-triphosphate, an anti-human immunodeficiency virus drug, from 30 nm CoFe2O4@BaTiO3 magneto-electric nanoparticles by applying a low alternating current magnetic field. Magneto-electric nanoparticles as field-controlled drug carriers offer a unique capability of field-triggered release after crossing the blood-brain barrier. Owing to the intrinsic magnetoelectricity, these nanoparticles can couple external magnetic fields with the electric forces in drug-carrier bonds to enable remotely controlled delivery without exploiting heat. Functional and structural integrity of the drug after the release was confirmed in in vitro experiments with human immunodeficiency virus-infected cells and through atomic force microscopy, spectrophotometry, Fourier transform infrared and mass spectrometry studies.

Two new tryptophan derivatives, N-sulfonyl-L-tryptophan (tryptorheedei A) (1) and 3-(N-sulfonylindolyl)-D-lactic acid (tryptorheedei B) (2) together with the known 5-O-β-D-glucopyranosyl-2-hydroxyphenylacetic acid (3), 1-O-methylglucopyranoside, entadamide A, homogentisic acid and 3-O-β-D-glucopyranosyl-β-sitosterol, were isolated from the seed kernels of Entada rheedei (Mimosaceae). Their structures were established using 1D and 2D NMR spectroscopy, mass spectrometry and by comparison with spectroscopic data reported in the literature. Compounds 1 and 2 showed no toxicity to TZM and Human PBMC cells. Both compounds 1 and 2 were found to promote early infection events in HIV, likely by inhibiting the enzyme indolamine 2,3-dioxygenase (IDO) and preventing tryptophan depletion. Inhibition of IDO acutely in HIV infection inhibits viral replication, but chronic activation of IDO leads to immune impairment in AIDS. IDO is also the gatekeeper enzyme for kynurenine metabolism, a pathway involved in serotonin and melatonin biosynthesis and the regulation of glutamate and dopamine levels in the brain. Therefore inhibition of IDO might explain both the reported medicinal and neuropsychiatric effects of E. rheedei.

Large unselected studies on representative samples of HIV-infected patients with a whole battery of neuropsychological tests and cerebral MRI scan are required to assess the frequency of neurocognitive impairment (NCI), the determinants of mild neurocognitive disorders (MNDs), or HIV-associated dementia (HAD) and the relationship between NCI and MRI scan findings.Investigation of 400 consecutively enrolled HIV-1-infected adults from the ANRS CO3 Aquitaine Cohort, using standardized neurocognitive tests chosen to achieve consistency with Frascati's criteria. Half of the patients had a cerebral MRI scan allowing gray and white matter volume measurement. Factors associated with NCI were studied by logistic regression models.Median age of participants was 47 years, 79% were male and 89% received combination antiretroviral treatment (cART), of whom 93% had plasma HIV RNA below 500 copies/ml. Median CD4 cell count was 515 cells/μl. Prevalence of NCI was 59%, including 21% of asymptomatic NCI, 31% of MND, and 7% of HAD. A low level of education, prior neurologic AIDS-defining disorders event, anxiety, depressive symptoms, and prior history of brain damage were independently associated with MND or HAD, but neither HIV nor cART-related variables. The presence of NCI was significantly associated with lower gray matter fraction.In this large unselected cohort, a high prevalence of symptomatic neurocognitive disorders was mainly related to its traditional determinants and associated with gray matter atrophy at early stages of the disease.

Alcoholism and acquired immune deficiency syndrome are associated with severe muscle wasting. This impairment in nitrogen balance arises from increased protein degradation and a decreased rate of protein synthesis. The regulation of protein synthesis is a complex process involving alterations in the phosphorylation state and protein-protein interaction of various components of the translation machinery and mammalian target of rapamycin (mTOR) complexes. This review describes mechanisms that regulate protein synthesis in cultured C2C12 myocytes following exposure to either alcohol or human immunodeficiency virus antiretroviral drugs. Particular attention is given to the upstream regulators of mTOR complexes and the downstream targets which play an important role in translation. Gaining a better understanding of these molecular mechanisms could have important implications for preventing changes in lean body mass in patients with catabolic conditions or illnesses.

Dural-based brain tumours, apart from meningiomas, are rare. Epstein-Barr virus (EBV)-associated smooth muscle tumor (SMT) is a documented but rare disease that occurs in immunocompromized patients. These tumours may be located at unusual sites including the brain. We present a 37-year-old patient, positive for the human immunodeficiency virus (HIV), who was admitted after generalized tonic-clonic seizures. MRI and CT scan revealed a dural-based brain tumour, intraoperatively thought to be a meningioma, but with an eventual histological diagnosis of EBV-SMT. Clinically the patient was well postoperatively with a Glasgow coma scale score of 15/15 and no focal neurologic deficit. This case confirms the association between EBV and SMT in patients with HIV/acquired immunodeficiency syndrome (AIDS). It also highlights the need to include EBV-SMT in the differential diagnosis of intracranial mass lesions in patients with HIV/AIDS.

Meningeal hemangiopericytoma is a rare, aggressive CNS tumor that tends to invade locally, metastasize, and has a high rate of recurrence. HIV classically increases the risk of 3 AIDS-defining malignancies: Kaposi's sarcoma, non-Hodgkin's lymphoma and invasive cervical cancer. More recently, considerable interest has been paid to the link between HIV and a wider range of non-AIDS-defining cancers. An HIV-positive patient with meningeal hemangiopericytoma is described.A 36-year-old HIV-positive male presented with worsening headache and ataxia. The patient had experienced similar neurologic symptoms 4 months prior and MRI at that time had showed an extra-axial left cerebellar mass most consistent with benign meningioma. Repeat MRI showed the tumor had increased in size by a factor of greater than 20 in this 4-month period, with 4 small additional foci of similar enhancement. Subtotal resection was performed on the mass and final pathological diagnosis was meningeal hemangiopericytoma.This represents the first reported case of meningeal hemangiopericytoma in an HIV-positive patient. This is also the shortest time to intracranial metastasis ever reported for a meningeal hemangiopericytoma. Although the increased risk in the HIV-positive population of non-AIDS-defining cancers that has been observed in recent years can largely be attributed to cancers with a known viral pathogenesis, it is speculated that HIV infection in this patient may have contributed to the occurrence or unique behavior of this rare tumor.

To compare cerebrospinal fluid (CSF) darunavir and ritonavir concentrations in patients receiving darunavir/ritonavir 800/100 mg once daily or 600/100 mg twice daily. To determine the influence of single-nucleotide polymorphisms in the genes encoding for blood-brain barrier transporters (ABCB1 3435 C>T, ABCB1 1236 C>T, ABCB1 2677 G>T, SLCO1A2 38 A>G, SLCO1A2 516 A>C, ABCC2 -24 G>A) on darunavir and ritonavir penetration into CSF.Comparative pharmacokinetics study in patients.Plasma and CSF darunavir and ritonavir concentrations (2-26 h after drug intake) were determined by a validated HPLC coupled with mass spectrometry method in adults on darunavir-based combination antiretroviral therapy undergoing a lumbar puncture.HIV-infected patients on once-daily darunavir/ritonavir had significantly lower CSF darunavir trough concentrations and CSF-to-plasma ratios than patients on darunavir/ritonavir twice-daily (10.7 versus 38.2 ng/ml and 0.32 versus 0.90%; P < 0.05). No significant effect of single-nucleotide polymorphisms in the genes encoding for blood-brain barrier transporters was noted apart from slightly higher CSF darunavir penetration in patients carrying OATP1A2 uncommon variants.This is the first study to compare darunavir CSF concentrations in patients taking the once-daily or the twice-daily dosage: our data show that darunavir and ritonavir dosing significantly affects not only CSF concentrations but also the extent of drug penetration into the CSF. Furthermore a minority of patients in the once-daily arm presented very low CSF concentration of potential concern for HIV control in the central nervous system. The relative importance of pharmacogenetics in influencing CSF darunavir pharmacokinetics deserves further clinical investigation.

A 43-year-old Caucasian homosexual man with AIDS presented with blurring of vision, change of personality, and memory loss in March 1999. He had first been admitted 2 months previously for treatment of Pneumocystis jiroveci pneumonia. A magnetic resonance imaging scan on admission showed multiple white matter lesions involving both subcortical cerebral hemispheres and cerebellar regions, with no mass effect or surrounding edema. JC virus was detected by nested polymerase chain reaction in the cerebrospinal fluid. These findings were diagnostic of progressive multifocal leukoencephalopathy (PML). His CD4 count was 34 cells/mL, and his HIV ribonucleic acid level was 800,789 copies/mL. He was treated with a combination antiretroviral therapy. He was last reviewed in October 2011. He was fully independent socially and mentally, but he still had some residual neurologic signs with right-sided homonymous hemianopia and visual agnosia. His HIV ribonucleic acid level was undetectable, and his CD4 count was 574 cells/mm(3). Although the median survival of patients with PML was poor before the antiretroviral therapy era, our patient, who is now aged 55 years, is still alive 12 years after the diagnosis. The diagnosis of PML and differential diagnosis of focal neurologic signs in HIV-positive patients are discussed in this case report.

BACKGROUND:

Up to 50% of patients with severe immune deficiency experience an excessive inflammatory response called immune reconstitution inflammatory syndrome (IRIS) after the initiation of antiretroviral therapy (ART). IRIS has been observed after various opportunistic infections with pathogens such as mycobacteria, including Bacille Calmette-Guérin, cryptococci, human herpesvirus-8, non-Hodgkin's lymphoma, and progressive multifocal leukoencephalopathy. Non-acquired immune deficiency-defining illnesses can also deteriorate after commencement of ART. Renal IRIS has been reported in a few patients with mycobacterial infections, but to the best of our knowledge no cases of nephrotic syndrome and IRIS have been described. CASE-DIAGNOSIS/TREATMENT: We report the case of an infant with human immunodeficiency virus-1 (HIV-1) infection, Pneumocystis pneumonia, and encephalopathy. During immune reconstitution the patient developed nephrotic syndrome. Treatment of nephrotic syndrome was initiated with prednisone, an angiotensin-converting enzyme inhibitor (lisinopril), and low-molecular-weight heparin. ART was continued, but only a low level of lopinavir/ritonavir could be achieved. There was no relapse of nephrotic syndrome during 10 months of follow-up.

CONCLUSIONS:

Nephrotic syndrome may occur in infants during immune reconstitution and should not be overlooked.