HIV-1 Tat and cocaine impact astrocytic energy reservoirs and epigenetic regulation by influencing the LINC01133-hsa-miR-4726-5p-NDUFA9 axis

People living HIV may develop a spectrum of cognitive, motor, and/or mood problems collectively known as HIV-Associated Neurocognitive Disorder (HAND). Extensive research efforts  to explore the molecular mechanisms underlying HAND have been reported. However, the understanding of the pathophysiological process of HAND is still limited. Although antiretroviral therapy (ART) has significantly decreased the HIV-1 associated mortality and morbidity, however, conventional ARV regimens are insufficient to improve HAND. This is partly because many ARTs can not across the blood brain barrier which results in low tissue bioavailability and subtherapeutic ARTs concentrations in the brain.

Cocaine is one of the most popular psychostimulant drugs abused by HIV patients and has been found to hasten the development of AIDS and worsen neurodegeneration. The progression of neurological disease in HANDs is strongly correlated with the mechanisms of astrocyte cell death, which can impair a number of cellular activities by altering the epigenetic expression of messenger RNAs (mRNAs) and microRNAs (miRNAs).

Long non-coding RNAs (lncRNAs) by definition are RNA transcripts more than 200 nucleotides in length that do not encode proteins.  Emerging evidence suggests that they play key roles in various biological and physiological processes including chromatin remodeling, epigenetic regulation, RNA splicing, and protein transport and directly relate to neurodegenerative disorders. Another factor suggested to contribute to the development of HAND is altered expression of microRNAs. These also small noncoding RNAs can regulate both host and viral gene expression and profiling miRNAs in different pathological conditions has yielded important insights into underlying disease mechanisms. However, the roles of lncRNAs and microRNAs in the process of HAND are still unknown.

To better understand the roles of lncRNAs and miRNAs play in regulating messenger RNA (mRNA) targets affected by concurrent cocaine use and HIV infection. Texas A&M University researchers: Dr. Mayur Doke,  Dr. James Cai, Dr. Mansoor Khan and Professor Thangavel Samikkannu used small-RNA and whole-RNA sequencing (RNA-seq) techniques to study the impact of HIV-1 Tat and cocaine exposure on the expression profiles of miRNA and lncRNA in human primary astrocytes which play key roles in the regulation of brain energy metabolism. The new study is now published in the peer-review journal Molecular Therapy: Nucleic Acids. Professor Jay McLaughlin from the University of Florida, Professor Gurudutt Pendyala from the University of Nebraska Medical Centre, Dr. Fatah Kashanchi at George Mason University were also co-authors in the study.

The research team looked at the molecular mechanisms by which cocaine and HIV-1 Tat affect astrocyte energy metabolism in order to affect the lncRNA-miRNA-mRNA regulatory network, which may further cause neurodegeneration. The authors conducted an integrative bioinformatics approach, and showed that the coexposure of human primary astrocytes to cocaine and HIV-1 Tat dramatically changed 10 miRNAs and 10 lncRNAs. They reported 198 gene targets, and the KEGG database was used to examine how these genes were involved in various biological processes. The authors’ findings identified an increased NDUFA9, LIPG, KYNU, and HKDC1 protein and mRNA expression levels. Afterward they looked in more details at two miRNAs, hsa-miR-2355 and hsa-miR-4726-5p, using a methodical bioinformatics approach. Molecular expression using PCR showed four lncRNAs, including LINC01133, HHIP, H19, and NOPA-14 are elevated in response to HIV-1 Tat- and cocaine-coexposure in human primary astrocytes.

In a nutshell, utilizing functional annotation using the KEGG database, the authors discovered four gene targets of two DE miRNAs and four lncRNAs engaged in numerous biological processes. The outcomes of this sophisticated and integrative bioinformatics research is providing unique insights into the regulation of crucial lncRNA-miRNA-mRNA signature markers during HIV-1 infection with cocaine exposure through modification of targeted metabolic pathways and neurodegenerative pathways.