Peripheral Neuropathy in Primary HIV Infection Associates With Systemic and Central Nervous System Immune Activation

Abstract

Background Peripheral neuropathy (PN) is a frequent complication of chronic HIV infection. We prospectively studied individuals with primary HIV infection (PHI, <1 year after transmission) to assess the presence of and laboratory associations with PN in this early stage. Methods Standardized examination and analysis of blood and cerebrospinal fluid (CSF) was performed in participants with laboratory-confirmed PHI. PN was defined as ≥1 of the following unilateral or bilateral signs: decreased distal limb position, vibration, or temperature sense, or hyporeflexia; symptomatic PN (SPN) as presence of these signs with symptoms. Analysis employed nonparametric statistics. Results 20/58 (35%) antiretroviral-naïve male subjects without diabetes evaluated at a median 107 days post HIV transmission (dpt) met criteria for PN. 13/20 (65%) of PN subjects met criteria for SPN; 6/20 (30%) had bilateral findings. PN subjects and no PN subjects (NPN) did not differ in median age, dpt, blood CD4 or CD8 counts, CSF or plasma HIV RNA levels, CSF white blood cell counts, or CSF:blood albumin ratio. PN and SPN subjects had elevated CSF neopterin (p=0.003 and p=0.0005), CSF MCP-1 (p=0.006 and p=0.01) and blood neopterin (p=0.006 and p=0.009) compared to NPN. PN subjects had a higher percentage of activated phenotype CSF CD8+ T lymphocytes than NPN subjects (p=0.009). Conclusions Signs of PN were detected by detailed neurologic exam in 35% of men enrolled in a neurological study at a median 3.5 months after HIV transmission. PN during this early period may be mediated by systemic and nervous system immune responses to HIV.

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

“…Distal sensory polyneuropathy has been found to occur at the early stage of primary HIV infection due to high rate of activated macrophage, cytokines, and chemokines infiltration in the CNS resulting from systemic and nervous system immune responses [25]. Studies in the SIV-infected primate models have shown that primary HIV-infection induces sensory neuropathy by damaging dorsal root ganglia nerve fibers and intra-epidermal nerve fiber density [26, 27].…”

Correlation of (1→3)-β-D-glucan with other inflammation markers in chronically HIV infected persons on suppressive antiretroviral therapy

“…Such microbial translocation most likely leads to local and systemic immune activation, characterized by increased levels of pro-inflammatory cytokines such as tumour-necrosis-factor α (TNF-α), neopterin, cluster of differentiation 14 (CD14), interleukin-8 (IL-8), and interleukin-6 (IL-6) [6], [7], [8], [9]. In particular, plasma neopterin is an established marker of monocyte activation and was repeatedly associated with HIV disease progression, greater peripheral monocyte HIV DNA reservoirs and negative neurocognitive and cardiovascular outcomes [10], [11], [12]. …”

Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy

“…HIV infiltrates the CNS during PHI [6][7][8], as indicated by the presence of HIV RNA in the cerebrospinal fluid (CSF) compartment, even in the absence of neurological symptoms [1,[8][9][10][11]. CNS immune activation accompanies this viral invasion, as reflected by elevations in the CSF white blood cell count and the soluble CSF biomarkers neopterin (reflecting macrophage activation) and CXCL-10/IP-10 (a lymphocyte chemokine) and by T-lymphocyte activation in CSF [1,[12][13][14][15]. Furthermore, markers of immune activation may reflect the degree of viral load and neurocognitive impairment [16].…”