Distal sensory polyneuropathy (DSP) is the most common neurological complication of HIV infection; however measures to detect and monitor DSP are suboptimal. The main goal of this revised R21 proposal is to assess the potential of in-vivo reflectance confocal microscopy (RCM) of Meissner's Corpuscles (MCs) to serve as a novel, painless, rapid and non-invasive measure of HIV-associated DSP. MCs are sensory receptors composed of both myelinated and unmyelinated fibers found in non-hairy skin of the hands and feet that mediate touch-pressure sensation. The investigators, in early preliminary data, have identified MCs using a portable in-vivo RCM device and found reduced MC densities in the skin of subjects with HIV DSP compared to HIV negative controls. This proof of concept proposal will test the hypothesis that in-vivo RCM of MCs can serve as a non-invasive measure of peripheral nerve injury associated with HIV infection, and detect reductions in MC density (relative to normal controls) in HIV subjects with clinically-defined DSP, as well as subclinical sensory neuropathy in HIV-infected subjects without clinical evidence of DSP. In order to test this hypothesis the PI will 1) Compare in a cross-sectional study MC density by in-vivo RCM at the sole of the foot and hand between HIV infected subjects with clinically-defined DSP and healthy control subjects; 2) Compare in a cross-sectional study MC density by in-vivo RCM at the sole of the foot and hand between HIV infected subjects without clinical evidence of DSP and healthy control subjects; 3) Determine in the HIV infected cohort, relationships among MC density at the hand and foot and standard measures of peripheral sensory function and structure (quantitative sensory testing, nerve conduction studies and epidermal nerve fiber density). Development of in-vivo RCM assessment of MC density may prove to have wide application for early identification and monitoring of HIV DSP during the course of disease and therapy, and as a novel outcome measure for therapeutic trials in HIV DSP and other sensory neuropathies. The main goal of this revised R21 proposal is to assess the potential of in-vivo reflectance confocal microscopy (RCM) of Meissner's Corpuscle (MC) nerve endings in the skin, to serve as a new, painless, rapid and non-invasive approach to detect and monitor HIV-associated distal sensory neuropathy, the commonest neurological complication of HIV infection. In-vivo RCM of MCs may prove to have wide application for early identification of sensory peripheral neuropathies, and to assess effectiveness of therapy. [unreadable] [unreadable] [unreadable]