Impaired reinnervation in HIV infection following experimental denervation

Abstract

Objective: To determine whether abnormalities in peripheral nerve regeneration are present in HIV-infected individuals.

Design: We studied human epidermal nerve fiber reinnervation by collateral and regenerative sprouting using validated cutaneous nerve injury models in healthy control subjects and those infected with HIV. Characteristics associated with the degree of reinnervation were identified.

Methods: Seventy-one healthy volunteers and 22 HIV+ individuals underwent topical capsaicin treatment at the distal lateral thigh resulting in complete epidermal denervation. Regenerative sprouting was quantified in skin biopsies at intervals up to 100 days. Five healthy subjects and 5 HIV+ individuals underwent a 3-mm distal thigh punch skin biopsy to create an intracutaneous axotomy, followed 2 months later by a 4-mm overlapping biopsy. The collateral sprouting distance was measured.

Results: The mean rate of regenerative sprouting was highest for healthy control subjects (0.17 +/- 0.073 fibers/mm/day), followed by HIV+ subjects without neuropathy (0.13 +/- 0.06) and then HIV+ subjects with neuropathy (0.097 +/- 0.07) (p = 0.002). Regenerative sprouting was significantly associated with the baseline intraepidermal nerve fiber density (p < 0.001) but not with HIV viral load, HIV duration, CD4 cell count, or ApoE epsilon4 status. HIV+ individuals were also found to have a reduced collateral sprouting rate compared to controls (5.31 mum +/- 0.73 vs 9.78 mum +/- 1.5/day, p = 0.03).

Conclusions: Abnormalities in both regenerative and collateral sprouting are present in people infected with HIV, and are detectable in subjects with and without evidence of peripheral nerve dysfunction. Our results indicate that abnormalities in nerve regeneration occur early in HIV infection and provide a rationale to include neuropathy-free HIV subjects in regenerative peripheral nerve trials.