Development and characterization of positively selected brain-adapted SIV

HIV is found in the brains of most infected individuals but only 30% develop neurological disease. Both viral and host factors are thought to contribute to the motor and cognitive disorders resulting from HIV infection. Here, using the SIV/rhesus monkey system, we characterize the salient characteristics of the virus from the brain of animals with neuropathological disorders. Nine unique molecular clones of SIV were derived from virus released by microglia cultured from the brains of two macaques with SIV encephalitis. Sequence analysis revealed a remarkably high level of similarity between their env and nef genes as well as their 3' LTR. As this genotype was found in the brains of two separate animals, and it encoded a set of distinct amino acid changes from the infecting virus, it demonstrates the convergent evolution of the virus to a unique brain-adapted genotype. This genotype was distinct from other macrophage-tropic and neurovirulent strains of SIV. Functional characterization of virus derived from representative clones showed a robust in vitro infection of 174xCEM cells, primary macrophages and primary microglia. The infectious phenotype of this virus is distinct from that shown by other strains of SIV, potentially reflecting the method by which the virus successfully infiltrates and infects the CNS. Positive in vivo selection of a brain-adapted strain of SIV resulted in a near-homogeneous strain of virus with distinct properties that may give clues to the viral basis of neuroAIDS

Gene expression and chromatin conformation of microglia in virally suppressed people with HIV

The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful

Methamphetamine Increases LPS-Mediated Expression of IL-8, TNF-α and IL-1β in Human Macrophages through Common Signaling Pathways

The use of methamphetamine (MA) has increased in recent years, and is a major health concern throughout the world. The use of MA has been associated with an increased risk of acquiring HIV-1, along with an increased probability of the acquisition of various sexually transmitted infections. In order to determine the potential effects of MA exposure in the context of an infectious agent, U937 macrophages were exposed to various combinations of MA and bacterial lipopolysaccharide (LPS). Treatment with MA alone caused significant increases in the levels of TNF-α, while treatment with both MA and LPS resulted in significant increases in TNF-α, IL-1β and the chemokine IL-8. The increases in cytokine or chemokine levels seen when cells were treated with both LPS and MA were generally greater than those increases observed when cells were treated with only LPS. Treatment with chemical inhibitors demonstrated that the signal transduction pathways including NF-kB, MAPK, and PI3-Akt were involved in mediating the increased inflammatory response. As discussed in the paper, these pathways appear to be utilized by both MA and LPS, in the induction of these inflammatory mediators. Since these pathways are involved in the induction of inflammation in response to other pathogens, this suggests that MA-exacerbated inflammation may be a common feature of infectious disease in MA abusers

Dopamine Receptor Activation Increases HIV Entry into Primary Human Macrophages

Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers

Arthroscopic management of glenohumeral arthrosis: humeral osteoplasty, capsular release, and arthroscopic axillary nerve release as a joint-preserving approach

Abstract: Glenohumeral arthrosis frequently results in substantial discomfort and activity limitations. Shoulder arthroplasty has been shown to provide reliable pain relief under these circumstances in older, less active populations. Younger patients, however, who desire to continue participation in high-demand activities, may not be optimal candidates for glenohumeral arthroplasty. Arthroscopic debridement has been reported to provide incomplete symptomatic relief in this cohort of patients. It is evident from cadaveric studies that the axillary nerve runs in close proximity to the inferior glenohumeral capsule. An inferior humeral osteophyte of sufficient size may compress the axillary nerve and potentially contribute to posterior shoulder pain in a manner similar to quadrilateral space syndrome. Therefore we present a technique for and early results of the arthroscopic management of glenohumeral arthrosis in young, high-demand patients. This technique combines traditional glenohumeral debridement and capsular release with inferior humeral osteoplasty and arthroscopic transcapsular axillary nerve decompression. In the appropriate patient, these additions may provide symptomatic relief that is greater than that with simple debridement alone

Glenohumeral Joint Preservation: A Review of Management Options for Young, Active Patients with Osteoarthritis

The management of osteoarthritis of the shoulder in young, active patients is a challenge, and the optimal treatment has yet to be completely established. Many of these patients wish to maintain a high level of activity, and arthroplasty may not be a practical treatment option. It is these patients who may be excellent candidates for joint-preservation procedures in an effort to avoid or delay joint replacement. Several palliative and restorative techniques are currently optional. Joint debridement has shown good results and a combination of arthroscopic debridement with a capsular release, humeral osteoplasty, and transcapsular axillary nerve decompression seems promising when humeral osteophytes are present. Currently, microfracture seems the most studied reparative treatment modality available. Other techniques, such as autologous chondrocyte implantation and osteochondral transfers, have reportedly shown potential but are currently mainly still investigational procedures. This paper gives an overview of the currently available joint preserving surgical techniques for glenohumeral osteoarthritis