Large Mitochondrial DNA Deletions in HIV Sensory Neuropathy

Abstract

Objective: The primary objective of this study was to evaluate the correlation of large mitochondrial DNA (mtDNA) deletions in skin samples of people with HIV (PWH) with measures of neuropathy and prior exposure to therapy. We hypothesized that deletions would be associated with neuropathy. As secondary objectives, we determined the correlation of deletion burden with demographic data and neuropathy measures.

Methods: In this retrospective cohort study, we measured the accumulation of large mtDNA deletions in skin biopsies from PWH recruited as part of the AIDS Clinical Trials Group (ACTG). Our cohort includes individuals with and without sensory neuropathy, as well as individuals with normal or abnormal skin biopsies. Skin biopsies, sural and peroneal nerve conduction studies, total neuropathy score, and deletion burden scores were measured, along with baseline demographic data such as age, CD4+ cell count, viral counts, and prior nucleoside reverse transcriptase inhibitor exposures.

Results: Sixty-seven PWH were enrolled in the study. The mean age of the cohort (n = 67) was 44 years (SD 6.8, range 32-65 years), and 9 participants were female. The mean CD4+ T-cell count was 168 cells/mm3 (SD 97 cells/mm3, range 1-416 cells/mm3) and mean viral load was 51,129 copies/mL (SD 114,586 copies/mL, range 147-657,775 copies/mL). We determined that there was a correlation between the total mtDNA deletion and intraepidermal nerve fiber density (IENFD) (r = -0.344, p = 0.04) and sural nerve amplitude (r = -0.359, p = 0.004).

Conclusions: Both IENFD and sural nerve amplitude statistically correlate with mitochondrial mutation burden in PWH, specifically in those with HIV-associated sensory neuropathy as assessed by skin biopsy.

Trial registration: ClinicalTrials.gov NCT00017771.

© 2021 American Academy of Neurology.

Figures

Figure 1. Mitochondrial DNA Map Showing Locations of Markers Used During This Study

Figure 2. Neuropathy Measurements and Demographics

(A) Heat map showing Pearson correlation scores and statistical significance between sural nerve amplitudes and intraepidermal nerve fiber density (IENFD) for the cohort and the neuropathy and no neuropathy subgroups. (B) Deletion scores for each region were measured, and the total deletion score (TDS) for the sample was calculated. (C) There was no correlation between any of the demographic data and TDS. There was an expected strong negative correlation between CD4 count and viral load. AU = arbitrary units.

Figure 3. Correlation Between TDS and Objective Measures of Neuropathy

(A) The total neuropathy score (TNS) and peroneal nerve amplitude did not correlate with total deletion score (TDS) for the whole cohort. Intraepidermal nerve fiber density (IENFD) and sural nerve amplitude did. Linear regression analysis of the (B) sural amplitude and (C) IENFD demonstrated that a small fraction of the data were explained by the association. Gray area represents 95% confidence interval.

Figure 4. Subregion Analysis of Deletions

(A) For the total cohort, region 3 is responsible for most of the correlation with neuropathy measures. When those (B) without neuropathy and (C) with neuropathy are separated, regions 2 and 3, respectively, are correlated. Gray area represents 95% confidence interval. IENFD = intraepidermal nerve fiber density.