Mitochondrial DNA, neurologic and systemic inflammation, and immune dysregulation.

Type: Poster
Title: Mitochondrial DNA, neurologic and systemic inflammation, and immune dysregulation.
Authors: Pérez-Santiago J, De Oliveira MF, Murrell B, Var S, Day T, Woods S, Ellis R, Gianella S, Mehta S
Year: 2015
Publication: Conference on Retroviruses and Opportunistic Infections.

Background: We recently demonstrated that higher levels of cell-free mitochondrial (mtDNA) in cerebrospinal fluid (CSF) were associated with more neurologic and systemic inflammation in a clinically heterogeneous cohort of HIV-infected individuals. Here we investigated how CSF mtDNA levels relate to inflammation and immune status in a cohort of virologically suppressed individuals, and in five individuals following structured treatment interruption (STI).

Methodology: Using droplet digital PCR, we quantified cell-free mtDNA levels from the CSF supernatant in 41 HIV-infected individuals with completely suppressed HIV RNA levels in CSF and blood plasma (<50 copies/mL), and in five HIV infected individuals who underwent STI. For each CSF and plasma sample, we also measured markers of inflammation and cellular trafficking (IP-10, MCP-1, IL-6, IL-8, TNF-α, MIP-1α and sCD14). Statistical analyses were performed in R statistical software.

Results: Levels of mtDNA in CSF were significantly higher in individuals with a previous diagnosis of AIDS when compared to participants without AIDS (median: 6.34 vs. 3.81 log10 copies/mL, p=0.0003). Using fixed-effects regression analyses, higher levels of mtDNA in CSF were associated with lower CD4+ T-cell nadir (r=-0.43, p=0.004), more inflammation in CSF as measured by MCP-1 (r=0.56, p=0.0002) and TNF-α (r=0.73, p=0.01), and in blood plasma as measured by IL-8 (r=0.44, p=0.004) and TNF-α (r=0.43, p=0.005). Levels of mtDNA remained positively associated with levels of MCP-1 (p=0.03) and TNF-a (p=0.01) in CSF when adjusted for AIDS status. In subjects undergoing STI, mtDNA levels in CSF rebounded prior to CSF and blood plasma HIV RNA and prior to pleocytosis in all individuals. Furthermore, pleocytosis was associated with both levels of mtDNA (p=0.03) and HIV RNA in CSF (p=0.01) when evaluated in a multivariate mixed-effects model.

Conclusions: In virologically suppressed individuals, higher levels of mtDNA in CSF were strongly associated with more neurologic and systemic inflammation, and with a lower CD4+ nadir and AIDS status. Also after STI, mtDNA levels rose prior to HIV rebound and pleocytosis in CSF. These results suggest that increased levels of cell-free mtDNA in CSF play a role in neuro-inflammation especially in individuals with more advanced HIV disease. Our data provide important insights to the pathophysiology of immune dysregulation in the central nervous system during AIDS.