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HIV infects astrocytes in a restricted manner but leads to abundant expression of Nef, a major viral factor for HIV replication and disease progression. However, the roles of Nef in HIV gene expression and replication in astrocytes and viral transfer from astrocytes to CD4+ T cells remain largely unclear. In this study, we attempted to address these issues by transfecting human primary astrocytes with HIV molecular clones with intact Nef and without Nef (a nonsense Nef mutant) and comparing gene expression and replication in astrocytes and viral transfer from astrocytes to CD4+ T cells MT4. First, we found that lack of Nef expression led to increased extracellular virus production from astrocytes and intracellular viral protein and RNA expression in astrocytes. Using a HIV LTR-driven luciferase reporter gene assay, we showed that ectopic Nef expression alone inhibited the HIV LTR promoter activity in astrocytes. Consistent with the previously established function of Nef, we showed that the infectivity of HIV derived from astrocytes with Nef expression was significantly higher than that with no Nef expression. Next, we performed the co-culture assay to determine HIV transfer from astrocytes transfected to MT4. We showed that lack of Nef expression led to significant increase in HIV transfer from astrocytes to MT4 using two HIV clones. We also used Nef-null HIV complemented with Nef in trans in the co-culture assay and demonstrated that Nef expression led to significantly decreased HIV transfer from astrocytes to MT4. Taken together, these findings support a negative role of Nef in HIV replication and pathogenesis in astrocytes. [ABSTRACT FROM AUTHOR]

This special issue contains 10 invited review papers that highlighted and extended the presentations at the NIDA-sponsored workshop "Unraveling NeuroAIDS in the Presence of Substance Use Disorders" at the 25th Society on NeuroImmune Pharmacology conference in 2019. The topics covered by these papers focused on the interactive, additive or synergistic effects of substance use disorders (SUD) with HIV infection on the immune system and on neuropathogenesis. These papers reviewed four categories of substances of abuse (opioids, tobacco, stimulants, and cannabis) and how comorbid HIV infection (including models with HIV proteins, HIV transgenic rodent models and SIV) might further impact the dysregulated dopaminergic and immune systems, and the subsequent neuropathogenesis and behavioral disorders known as HIV-associated neurological disorders (HAND). These reviews provided detailed background knowledge regarding how each of these addictive substances and HIV individually or collectively affected the immune system at the cellular, molecular and system levels, and the subsequent clinical and behavioral outcomes. The authors also identified gaps, confounds or constraints in the current disease models and approaches, and proposed future research directions. [ABSTRACT FROM AUTHOR]

Tobacco smoking is highly prevalent among HIV-infected individuals. Chronic smokers with HIV showed greater cognitive deficits and impulsivity, and had more psychopathological symptoms and greater neuroinflammation than HIV non-smokers or smokers without HIV infection. However, preclinical studies that evaluated the combined effects of HIV-infection and tobacco smoking are scare. The preclinical models typically used cell cultures or animal models that involved specific HIV viral proteins or the administration of nicotine to rodents. These preclinical models consistently demonstrated that nicotine had neuroprotective and anti-inflammatory effects, leading to cognitive enhancement. Although the major addictive ingredient in tobacco smoking is nicotine, chronic smoking does not lead to improved cognitive function in humans. Therefore, preclinical studies designed to unravel the interactive effects of chronic tobacco smoking and HIV infection are needed. In this review, we summarized the preclinical studies that demonstrated the neuroprotective effects of nicotine, the neurotoxic effects of the HIV viral proteins, and the scant literature on nicotine or tobacco smoke in HIV transgenic rat models. We also reviewed the clinical studies that evaluated the neurotoxic effects of tobacco smoking, HIV infection and their combined effects on the brain, including studies that evaluated the cognitive and behavioral assessments, as well as neuroimaging measures. Lastly, we compared the different approaches between preclinical and clinical studies, identified some gaps and proposed some future directions. [ABSTRACT FROM AUTHOR]

Astrocytes are susceptible to HIV infection and potential latent HIV reservoirs. Tat is one of three abundantly expressed HIV early genes in HIV-infected astrocytes and has been shown to be a major pathogenic factor for HIV/neuroAIDS. In this study, we sought to determine if and how Tat expression would affect HIV infection and latency in astrocytes. Using the glycoprotein from vesicular stomatitis virus-pseudotyped red-green HIV (RGH) reporter viruses, we showed that HIV infection was capable of establishing HIV latency in astrocytes. We also found that Tat expression decreased the generation of latent HIV-infected cells. Activation of latent HIV-infected astrocytes showed that treatment of GSK126, a selective inhibitor of methyltransferase enhancer of zeste homolog 2 (Ezh2) that is specifically responsible for tri-methylation of histone 3 lysine 27 (H3K27me3), led to activation of significantly more latent HIV-infected Tat-expressing astrocytes. Molecular analysis showed that H3K27me3, Ezh2, MeCP2, and Tat all exhibited a similar bimodal expression kinetics in the course of HIV infection and latency in astrocytes, although H3K27me3, Ezh2, and MeCP2 were expressed higher in Tat-expressing astrocytes and their expression were peaked immediately preceding Tat expression. Subsequent studies showed that Tat expression alone was sufficient to induce H3K27me3 expression, likely through its regulation of Ezh2 and MeCP2 expression. Taken together, these results showed for the first time that Tat expression induced H3K27me3 expression and contributed to HIV latency in astrocytes and suggest a new role and novel mechanism for Tat in HIV latency. [ABSTRACT FROM AUTHOR]

This correction notice is for an article titled "Tat expression led to increased histone 3 tri-methylation at lysine 27 and contributed to HIV latency in astrocytes through regulation of MeCP2 and Ezh2 expression" published in the Journal of NeuroVirology. The correction addresses incorrect images in Figure 3A and provides the corrected version in Figure 3B. The errors in the images do not affect the scientific conclusions of the article. The correction notice also includes a graph showing the expression of Ezh2, H3K27me3, MeCP2, and Tat in relation to HIV infection and latency in astrocytes. The publisher, Springer Nature, remains neutral regarding jurisdictional claims and institutional affiliations. [Extracted from the article]

HIV-1 Tat is known to be neurotoxic and important for HIV/neuroAIDS pathogenesis. However, the overwhelming majority of the studies involved use of recombinant Tat protein. To understand the contributions of Tat protein to HIV/neuroAIDS and the underlying molecular mechanisms of HIV-1 Tat neurotoxicity in the context of a whole organism and independently of HIV-1 infection, a doxycycline-inducible astrocyte-specific HIV-1 Tat transgenic mouse (iTat) was created. Tat expression in the brains of iTat mice was determined to be in the range of 1-5 ng/ml and led to astrocytosis, loss of neuronal dendrites, and neuroinflammation. iTat mice have allowed us to define the direct effects of Tat on astrocytes and the molecular mechanisms of Tat-induced GFAP expression/astrocytosis, astrocyte-mediated Tat neurotoxicity, Tat-impaired neurogenesis, Tat-induced loss of neuronal integrity, and exosome-associated Tat release and uptake. In this review, we will provide an overview about the creation and characterization of this model and its utilities for our understanding of Tat neurotoxicity and the underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]

In the original article the name of author Chris Sanborn was misspelled. It is correct here. Also, in the Acknowledgments section there was an error in the NIH/NINDS grant numbers. [ABSTRACT FROM AUTHOR]