Methamphetamine Increases the Proportion of SIV-Infected Microglia/Macrophages,Alters Metabolic Pathways,and Elevates Cell Death Pathways: A Single-Cell Analysis

Both substance use disorder and HIV infection continue to affect many individuals. Both have untoward effects on the brain, and the two conditions often co-exist. In the brain, macrophages and microglia are infectable by HIV, and these cells are also targets for the effects of drugs of abuse, such as the psychostimulant methamphetamine. To determine the interaction of HIV and methamphetamine, we isolated microglia and brain macrophages from SIV-infected rhesus monkeys that were treated with or without methamphetamine. Cells were subjected to single-cell RNA sequencing and results were analyzed by statistical and bioinformatic analysis. In the animals treated with methamphetamine, a significantly increased proportion of the microglia and/or macrophages were infected by SIV. In addition, gene encoding functions in cell death pathways were increased, and the brain-derived neurotropic factor pathway was inhibited. The gene expression patterns in infected cells did not cluster separately from uninfected cells, but clusters comprised of microglia and/or macrophages from methamphetamine-treated animals differed in neuroinflammatory and metabolic pathways from those comprised of cells from untreated animals. Methamphetamine increases CNS infection by SIV and has adverse effects on both infected and uninfected microglia and brain macrophages, highlighting the dual and interacting harms of HIV infection and drug abuse on the brain.     

Adrenocortical function in patients with systemic mycoses

The systemic mycoses like paracoccidioidomycosis and histoplasmosis, are the main cause of adrenal insufficiency in the countries where they arc endemic. In Venezuela an elevated frequency of these mycoses has been registered. The objective of this study was to evaluate the glucocorticoid adrenal function in patients with paracoccidioidomycosis and histoplasmosis hospitalized in the University Hospital "Ruiz y Pácz" of Ciudad Bolivar (Bolivar state) and in the Hospital "Luis Felipe Rojas Guevara", of El Tigre (Anzoátegui state), Venezuela, between January 2003 and January 2004. The test of fast stimulation with synthetic adrenocorticotrophin hormone (ACTH) was applied to a total of 12 patients with diagnosis of some of these mycoses and data of epidemiologic interest were taken. The proportion men:women was of 5:1, the average age was 35.1 +/- 0.37 years, similar to the control group. Basal plasmatic cortisol levels were within the normal rank in all the patients. After the injection of synthetic ACTH, an increase of plasmatic cortisol values in the same rank for patients with a normal adrenal function was observed, but it was significantly lower than the observed for the control group. These results suggest that there is an adrenal gland functional reserve diminution in patients with either Paracoccidioidomycosis or Histoplasmosis. In patients with systemic mycoses, it is important to evaluate the response to the test of fast stimulation with ACTH due to the frequency of impairment of the glucocorticoid adrenal function in our location.     

Epidemiological survey of histoplasmine and paracoccidioidine skin reactivity in an agricultural area in Bolívar state, Venezuela

Paracoccidiodomycosis and histoplasmosis are endemic diseases in the south of Venezuela, representing a public health problem. Prevalence of Paracoccidiodes brasiliensis and Histoplasma capsulatum infections were estimated in Monte Ralo, a rural community area of Bolivar state using paracoccidiodine and histoplasmine skin tests. Paracoccidiodine was intradermically injected to 173 persons and readings were made at 24 and 48 h afterwards to 167 persons (97.85%). Reaction was positive in 8.5% (n = 14) at 24 h post-injection and 13.2% (n = 20) at 48 h. Farmers showed the higher percentage of positivity at 24 and 48 h. One hundred-seventy five persons were intradermically injected with histoplasmine but 167 and 157 of them attended for reading of the dermal reaction at 24 and 48 h post-injection respectively. Tests were positive in 25.7% (n = 43) at 24 h and 42.7% (n = 67) at 48 h. Further studies are needed in surrounding places to delimit the endemic area of these mycosis in the Bolivar state. However, epidemiological vigilance of PCM and H should be considered by local health authorities.     

CCR2 on Peripheral Blood CD14+CD16+ Monocytes Correlates with Neuronal Damage,HIV-Associated Neurocognitive Disorders,and Peripheral HIV DNA: reseeding of CNS reservoirs?

HIV-associated neurocognitive disorders (HAND) occur in ~50% of HIV infected individuals despite combined antiretroviral therapy. Transmigration into the CNS of CD14⁺CD16⁺ monocytes, particularly those that are HIV infected and express increased surface chemokine receptor CCR2, contributes to neuroinflammation and HAND. To examine whether in HIV infected individuals CCR2 on CD14⁺CD16⁺ monocytes serves as a potential peripheral blood biomarker of HAND, we examined a cohort of 45 HIV infected people. We correlated CCR2 on CD14⁺CD16⁺ monocytes with cognitive status, proton magnetic resonance spectroscopy (¹H-MRS) measured neurometabolite levels, and peripheral blood mononuclear cell (PBMC) HIV DNA copies. We determined that CCR2 was increased specifically on CD14⁺CD16⁺ monocytes from people with HAND (median [interquartile range (IQR)]) (63.3 [51.6, 79.0]), compared to those who were not cognitively impaired (38.8 [26.7, 56.4]) or those with neuropsychological impairment due to causes other than HIV (39.8 [30.2, 46.5]). CCR2 was associated with neuronal damage, based on the inverse correlation of CCR2 on CD14⁺CD16⁺ monocytes with total N-Acetyl Aspartate (tNAA)/total Creatine (tCr) (r² = 0.348, p = 0.01) and Glutamine-Glutamate (Glx)/tCr (r² = 0.356, p = 0.01) in the right and left caudate nucleus, respectively. CCR2 on CD14⁺CD16⁺ monocytes also correlated with PBMC HIV DNA copies (ρ = 0.618, p = 0.02) that has previously been associated with HAND. These findings suggest that CCR2 on CD14⁺CD16⁺ monocytes may be a peripheral blood biomarker of HAND, indicative of increased HIV infected CD14⁺CD16⁺ monocyte entry into the CNS that possibly increases the macrophage viral reservoir and contributes to HAND.