Background:The prevalence, predictors, and consequences of peripheral neuropathy in the elderly have not been well defined.Methods: Seven hundred ninety-five noninstitutionalized patients 65 years of age and older, recruited from the practices of family physicians, completed questionnaires and underwent peripheral neurologic examinations and tests of gait and balance. Variables included sociodemographic information, medical conditions, symptoms (numbness, pain, trouble with balance or walking, and restless legs), quality of life measures, ankle reflexes, position sense, vibratory sense, fine touch sensation, Tinnetti balance examination, and a 50-foot timed walk.Results: The prevalence of at least one bilateral sensory deficit rose from 26% for 65-to 74-yearolds to 54% for those 85 and older. The most common deficit was loss of ankle reflex followed by loss of fine touch. Only 40% of those with bilateral deficits reported having a disease known to cause peripheral neuropathy. Predictors of bilateral deficits included increasing age, income less than $15,000, a history of military service, increasing body mass index, self-reported history of diabetes mellitus, Vitamin B 12 deficiency or rheumatoid arthritis, and absence of a history of hypertension. Deficits were associated with numbness, pain, restless legs, trouble walking, trouble with balance, and reduced quality of life.Conclusions

We have genetically engineered CD4+ and CD8+ T cells with human immunodeficiency virus (HIV) specificity by inserting a gene, CD4ζ, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (ζ) chain of the T-cell receptor (which mediates T-cell activation). Twenty-four HIV-positive subjects received a single infusion of 2 to 3 × 1010 autologous CD4ζ-modified CD4+and CD8+ T cells administered with (n = 11) or without (n = 13) interleukin-2 (IL-2). Subjects had CD4 counts greater than 50/μL and viral loads of at least 1000 copies/mL at entry. T cells were costimulated ex vivo through CD3 and CD28 and expanded for approximately 2 weeks. CD4ζ was detected in 1% to 3% of blood mononuclear cells at 8 weeks and 0.1% at 1 year after infusion, and survival was not enhanced by IL-2. Trafficking of gene-modified T cells to bulk rectal tissue and/or isolated lamina propria lymphocytes was documented in a subset of 5 of 5 patients at 14 days and 2 of 3 at 1 year. A greater than 0.5 log mean decrease in rectal tissue–associated HIV RNA was observed for at least 14 days, suggesting compartmental antiviral activity of CD4ζ T cells. CD4+ counts increased by 73/μL at 8 weeks in the group receiving IL-2. There was no significant mean change in plasma HIV RNA or blood proviral DNA in either treatment arm. This sustained, high-level persistence of gene-modified T cells demonstrates the feasibility of ex vivo T-cell gene therapy in HIV-infected adults and suggests the importance of providing HIV-specific T-helper function.

Increasing evidence suggests that HIV-1-specific cytotoxic T lymphocytes (CTLs) are a key host immune response to HIV-1 infection. Generation of CTL responses for prevention or therapy of HIV-1 infection has several intrinsic technical barriers such as antigen expression and presentation, the varying HLA restrictions between different individuals, and the potential for viral escape by sequence variation or surface molecule alteration on infected cells. A strategy to circumvent these limitations is the construction of a chimeric T cell receptor containing human CD4 or HIV-1-specific Ig sequences linked to the signaling domain of the T cell receptor chain (universal T cell receptor). CD8؉ CTLs transduced with this universal receptor can then bind and lyse infected cells that express surface HIV-1 gp120. We evaluated the ability of universal-receptorbearing CD8؉ cells from a seronegative donor to lyse acutely infected cells and inhibit HIV-1 replication in vitro. The kinetics of lysis and efficiency of inhibition were comparable to that of naturally occurring HIV-1-specific CTL clones isolated from infected individuals. Further study will be required to determine the utility of these cells as a therapeutic strategy in vivo.