Lateral amyotrophic sclerosis-like onset after combined antiretroviral treatment initiation

Quevedo-Ramirez, Andres; Montenegro-Idrogo, Juan José; Resurrección-Delgado, Cristhian; Salazar-Mesones, Blanca; Gallardo-Cartagena, Jorge A; Cornejo-Venegas, Gonzalo; Méndez-Guerra, Carolina; Vargas-Matos, Iván; Chiappe-Gonzalez, Alfredo

doi:10.1016/j.idcr.2020.e00994

Cited by 5 publications

(2 citation statements)

References 11 publications

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“…Previous studies of HIV patients have shed further light on the relevance of the systemic immune system in ALS. These studies have reported a higher prevalence of ALS-like syndrome in HIV patients, which improves following anti-HIV treatment ( 79 – 83 ), correlating impaired immune system with ALS symptoms. Relative to the studies of motor neurons and glial cells in ALS, much less work has been done on the systemic aspect of ALS.…”

Section: Resultsmentioning

confidence: 99%

Causal ALS genes impact the MHC class II antigen presentation pathway

Chi,

Öztürk,

Paraggio

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in RNA/DNA-binding proteins cause amyotrophic lateral sclerosis (ALS), but the underlying disease mechanisms remain unclear. Here, we report that a set of ALS-associated proteins, namely FUS, EWSR1, TAF15, and MATR3, impact the expression of genes encoding the major histocompatibility complex II (MHC II) antigen presentation pathway. Both subunits of the MHC II heterodimer, HLA-DR, are down-regulated in ALS gene knockouts/knockdown in HeLa and human microglial cells, due to loss of the MHC II transcription factor CIITA. Importantly, hematopoietic progenitor cells (HPCs) derived from human embryonic stem cells bearing the FUS R495X mutation and HPCs derived from C9ORF72 ALS patient induced pluripotent stem cells also exhibit disrupted MHC II expression. Given that HPCs give rise to numerous immune cells, our data raise the possibility that loss of the MHC II pathway results in global failure of the immune system to protect motor neurons from damage that leads to ALS.

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Section: Resultsmentioning

confidence: 99%

Causal ALS genes impact the MHC class II antigen presentation pathway

Chi,

Öztürk,

Paraggio

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Previous studies of HIV patients shed further light on the importance of the systemic immune system in ALS. These studies reported that HIV patients are more likely to exhibit an ALS-like syndrome, and this condition improves after anti-HIV treatment (Satin and Bayat 2021; Bowen et al 2016; MacGowan et al 2001; Quevedo-Ramirez et al 2020; Verma and Berger 2006). Relative to the studies of motor neurons and glial cells in ALS, much less work has been done on the systemic aspect of ALS.…”

Section: Resultsmentioning

confidence: 99%

Three ALS genes regulate expression of the MHC class II antigen presentation pathway

Chi

Öztürk

Paraggio

et al. 2022

Preprint

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Here we report that the major histocompatibility complex II (MHC II) antigen presentation pathway is regulated by the ALS-causative genes, FUS, TAF15, or MATR3. Of >6000 proteins detected by quantitative mass spectrometry, the subunits of the MHC II heterodimer, HLA-DR, were the top 2 downregulated proteins in HeLa knock outs (KO) of these ALS genes, but not the related gene, EWSR1. Moreover, CD74, which is the 3rd essential component of HLA-DR, was downregulated in the 3 KOs. We show that the downregulations are due to loss of CIITA, a transcription factor dedicated to expression of MHC II genes. Thus, our results reveal the 1st shared cellular pathway regulated by multiple ALS genes, and this pathway is ALS genes -> CIITA -> MHC II genes. We obtained the same results in HMC3 cells, a microglia cell line, showing that loss of the MHC II pathway extends to an ALS-relevant cell type in the central nervous system (CNS). Furthermore, the MHC II pathway is downregulated in hematopoietic progenitor cells (HPCs) bearing the ALS FUSR495X mutation. This observation may be highly significant to ALS pathogenesis as HPCs give rise to a multitude of CNS-specific and systemic immune cells, both of which have known or suspected roles in ALS. Together, our data raise the possibility that loss of the MHC II pathway in a large range of immune cells results in global failure of the immune system to protect motor neurons from damage that leads to the disease. Consequently, CIITA and the other genes in the MHC II pathway may be important new therapeutic targets for the disease.

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Association between motor neuron disease and HIV infection: A systematic review of case reports

Fernandes,

Garcia,

Gouhie

et al. 2024

Int J STD AIDS

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Background Motor neuron disease (MND) is a well-known group of neurodegenerative diseases, with amyotrophic lateral sclerosis (ALS) being the most common form. Since 1985, a possible association between MND/ALS and HIV infection has been described. Methods We performed a systematic review of case reports and case series involving people living with HIV with MND/ALS through PubMed, Bireme, Embase, and Lilacs databases. The risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tool for Case Reports. Results We analyzed 36 articles presenting 88 cases. The mean age was 41.6 years. Antiretroviral therapy (ART) was used by 89.8% and riluzole by 16.9%. First signs and symptoms were similarly present on cervical/upper (25%) and lumbosacral/lower limbs (23.9%), mostly with fasciculations (69.8%) and hyperreflexia (58.8%). MND had a progressive course in 32.9% patients and a clinical improve in 54.6% following ART. The mean survival of the 32 patients who died was 12.3 months and the mean survival of the living patients was 62 months. Respiratory failure was the main cause of death (35.7%). Conclusions MND/ALS may present differently in the people living with HIV as a rapidly progressive disease in younger people but with the potential to improve weakness and survival through antiretroviral therapy.

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Lateral amyotrophic sclerosis-like onset after combined antiretroviral treatment initiation

Cited by 5 publications

References 11 publications

Causal ALS genes impact the MHC class II antigen presentation pathway

Causal ALS genes impact the MHC class II antigen presentation pathway

Three ALS genes regulate expression of the MHC class II antigen presentation pathway

Association between motor neuron disease and HIV infection: A systematic review of case reports

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