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Human immunodeficiency virus type-1 (HIV-1) is responsible for significant mortality and morbidity worldwide. Despite complete control of viral replication with antiretrovirals, cells with integrated HIV-1 provirus can produce viral transcripts. In a cross-sectional study of 84 HIV+ individuals of whom 43 were followed longitudinally, we found that HIV-1 RNAs are present in extracellular vesicles (EVs) derived from cerebrospinal fluid and serum of all individuals. We used seven digital droplet polymerase chain reaction assays to evaluate the transcriptional status of the latent reservoir. EV-associated viral RNA was more abundant in the CSF and correlated with neurocognitive dysfunction in both, the cross-sectional and longitudinal studies. Sequencing studies suggested compartmentalization of defective viral transcripts in the serum and CSF. These findings suggest previous studies have underestimated the viral burden and there is a significant relationship between latent viral transcription and CNS complications of long-term disease despite the adequate use of antiretrovirals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To investigate the relationship between neurocognitive deficits and structural changes on brain magnetic resonance imaging in people living with HIV (PLWH) with good virological control on combination antiretroviral therapy, compared with socioeconomically matched control participants recruited from the same communities., Methods: Brain magnetic resonance imaging scans, and clinical and neuropsychological data were obtained from virologically controlled PLWH (viral load of <50 c/mL and at least 1 year of combination antiretroviral therapy) and socioeconomically matched control participants. Magnetic resonance imaging was carried out on 3 T scanner with 8-channel head coils and segmented using Classification using Derivative-based Features. Multiple regression analysis was performed to examine the association between brain volume and various clinical and neuropsychiatric parameters adjusting for age, race, and sex. To evaluate longitudinal changes in brain volumes, a random coefficient model was used to evaluate the changes over time (age) adjusting for sex and race., Results: The cross-sectional study included 164 PLWH and 51 controls, and the longitudinal study included 68 PLWH and 20 controls with 2 or more visits (mean 2.2 years, range 0.8-5.1 years). Gray matter (GM) atrophy rate was significantly higher in PLWH compared with control participants, and importantly, the GM and global atrophy was associated with the various neuropsychological domain scores. Higher volume of white matter hyperintensities were associated with increased atherosclerotic cardiovascular disease risk score, and decreased executive functioning and memory domain scores in PLWH., Interpretation: These findings suggest ongoing neurological damage even in virologically controlled participants, with significant implications for clinical management of PLWH. ANN NEUROL 2024;95:941-950., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The study of the role of retroviruses in amyotrophic lateral sclerosis (ALS) dates back to the 1960s shortly after transposable elements themselves were first discovered. It was quickly realized that in wild mice both horizontal and vertical transmissions of retroviral elements were key to the development of an ALS-like syndrome leading to the postulate that endogenous retroviruses (ERVs) contribute significantly to the pathogenicity of this disease. Subsequent studies identified retroviral reverse transcriptase activity in brains of individuals with ALS from Guam. However, except for a single study from the former Soviet Union, ALS could not be transmitted to rhesus macaques. The discovery of an ALS-like syndrome in human immunodeficiency virus (HIV) and human T cell leukemia virus infected individuals led to renewed interest in the field and reverse transcriptase activity was found in the blood and cerebrospinal fluid of individuals with sporadic ALS. However, exogenous retroviruses could not be found in individuals with ALS which further reinforced the possibility of involvement of a human ERV (HERV). The first demonstration of the involvement of a HERV was the discovery of the activation of human endogenous retrovirus-K subtype HML-2 in the brains of individuals with ALS. The envelope protein of HML-2 is neurotoxic and transgenic animals expressing the envelope protein develop an ALS-like syndrome. Activation of HML-2 occurs in the context of generalized transposable element activation and is not specific for ALS. Individuals with HIV-associated ALS show a remarkable response to antiretroviral therapy; however, antiretroviral trials in ALS down-regulate HML-2 without ameliorating the disease. This highlights the need for specific drugs to be developed against HML-2 as a novel therapeutic target for ALS. Other approaches might include antisense oligonucleotides, shRNA targeted against the envelope gene or antibodies that can target the extracellular envelope protein. Future clinical trials in ALS should consider combination therapies to control these ERVs., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)