Signs of Peripheral Neuropathy Associate with Elevated Inflammatory Biomarkers in Blood and Cerebrospinal Fluid in Primary HIV Infection
Reported by Jules Levin CROI 2012
From Jules: Study reports 35% of ART-naïve patients during early/primary HIV-infection have neuropathy & 65% of these have symptomatic neuropathy, that this study finds appears to be caused by nervous system immune activation that begins during early/primary HIV infection. Since CSF viral load levels were similar in patients with & without neuropathy the investigators feel the neuropathy appears to be due to the immune activation that starts shortly after HIV infection.
Samantha XY Wang1, Marie Grill2, Evelyn Lee2, Julia Peterson2, Emily Ho3, Emilie Jalbert4, Elizabeth Sinclair2, Dietmar Fuchs5, Richard W. Price2, Serena Spudich1
1Yale University, New Haven CT; 2University of California, San Francisco (UCSF), San Francisco, CA; 3University of Washington, Seattle, WA; 4John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii;
5Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria
· Signs and symptoms of peripheral neuropathy are present at a median of 3.5 months after HIV transmission.
· Pro-inflammatory cytokines MCP-1 and IP-10, and the macrophage activation marker neopterin are elevated in the CSF of PHI subjects with peripheral neuropathy, while HIV RNA levels are not.
· Percent CD8+ T lymphocyte activation in CSF is elevated in PHI subjects with signs of peripheral neuropathy.
· [therefore] Host-derived immune activation in the nervous system during PHI may contribute to development of peripheral neuropathy and neurological dysfunction.
· Peripheral neuropathy (PN) is a frequent complication of chronic HIV infection.
· Systemic and nervous system immune activation begins during primary HIV infection(PHI).
· Immune activation markers associate with the presence of neurological disorders in chronic infection.
· We investigated whether PN presents during PHI and if correlations exist between infectious and inflammatory markers and signs of PN during this stage of infection.
Signs of Peripheral Neuropathy Associate with Elevated Inflammatory Biomarkers in Blood and Cerebrospinal Fluid in Primary HIV-1 Infection
Samantha Wang*1, M Grill2, E Lee2, J Peterson2, E Ho3, E Jalbert2, E Sinclair2, R Price2, and S Spudich1
1Yale Univ Sch of Med, New Haven, CT, US; 2Univ of California, San Francisco, US; and 3Univ of Washington Sch of Med, Seattle, US
Background: Peripheral neuropathy (PN) is a frequent complication of chronic HIV infection, potentially mediated by pathologic effects of systemic and nervous system inflammation. Given that immune activation in the nervous system begins during primary HIV infection (PHI), we hypothesized that PN may be present during PHI, and that correlations may exist between levels of infectious and inflammatory biomarkers and signs of peripheral neuropathy in this setting.
Methods: Subjects within the first 12 months after transmission as confirmed by laboratory testing underwent clinical exams and analysis of blood and cerebrospinal fluid (CSF) including quantification of infectious and inflammatory biomarkers at the baseline visit of a longitudinal study. Subjects were categorized as PN if they had one or more of the following on a standardized clinical (NeuroMacro) exam by a neurologist: decreased position, vibration, pinprick or temperature sense at great toes, distal pain or paresthesia, absent or decreased ankle jerks, or hyporeflexia. Two subjects with diabetes were excluded from the study. Statistical analysis employed the nonparametric Mann-Whitney U test.
Results: Fifty-eight ART-naïve subjects (100% male) were evaluated at a median107 days post estimated HIV transmission; 20 (35%) met criteria for PN, 38 were considered no-PN (NPN). PN tended to be older than NPN subjects (median 39.5 vs 34.0 years, p = 0.054), but the groups did not significantly differ in terms of days post-HIV transmission at evaluation or blood CD4 and CD8 counts. Elevated CSF neopterin (p = 0.003) and MCP-1 (p = 0.006) and blood neopterin (p = 0.006) characterized PN as compared to NPN. There was a trend for CSF IP-10 levels to be elevated in PN (p = 0.09). Evaluation between presence of PN and of cell surface markers of activation in CD8+ T lymphocytes and monocytes in a subset of subjects revealed a higher percentage of activated CSF CD8+ T lymphocytes in PN (p = 0.0035). There were no differences between the 2 groups in levels of CSF and blood HIV RNA, CSF white blood cells, CSF protein, or ratios of CSF:serum albumin.
Conclusions: Signs of PN are present in one third of HIV-infected individuals at a median 3.5 months after viral transmission. Significant correlations between signs of PN and CSF measures of neopterin, MCP-1, and CD8 T cell activation as well blood levels of neopterin support the hypothesis that a component of PN during this early period is mediated by host immune responses to HIV infection