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Peripheral Neuropathy in Primary HIV Infection Associates With Systemic and Central Nervous System Immune Activation
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JAIDS 2014
Wang, Samantha X.Y. BA*; Ho, Emily L. MD, PhD; Grill, Marie MD; Lee, Evelyn BA; Peterson, Julia BS; Robertson, Kevin PhD; Fuchs, Dietmar PhD‖; Sinclair, Elizabeth PhD; Price, Richard W. MD; Spudich, Serena MD*
"in HIV-DSP, macrophage secretion of proinflammatory molecules within the nerve may lead to CNS immune activation"
"Our findings suggest that increased migration to or accumulation of "activated" phenotype CD8+T lymphocytes within the CSF pathologically associates with PN. This is the first study to examine T-lymphocyte activation in the CNS compartment in relation to clinical neurological disease in HIV. Whether these findings indicate that PN is associated with processes accelerating disease progression within the nervous system or another mechanism of injury warrants further study"
This is the first study to examine the prevalence of PN among ART-naive individuals within the first months after HIV acquisition.
We found a high rate of PN among PHI subjects that correlated with an increased levels of systemic and intrathecal proinflammatory markers. Recognition of PHI as an essential period of immune activation associated with PN and neurological disorders may provide rationale for more aggressive screening for recent HIV infection, and early institution of ART and possibly immunomodulatory therapy during this early period.
"PN is a frequent neurological disorder reported in HIV, classically in the setting of chronic untreated HIV infection or after exposure to certain antiretroviral medications. However, we found that signs (35%), or signs and symptoms (22%), of PN were evident in a cohort of ART-naive subjects recruited to a neurological study at a median of 3.5 months after initial HIV transmission. We further examined mechanisms for peripheral nerve dysfunction identified during this stage, revealing that markers of systemic and CNS immune activation are elevated in subjects with signs of neuropathy (PN) compared with those with no signs of neuropathy (NPN)."
Amplified immune activation characterized our subjects with signs of PN. CSF markers have been previously implicated in advanced stages of HIV neurological disease progression: CSF neopterin increases along with CNS HIV disease severity and decreases following ART31; levels of IP-10 positively correlate with the presence of HIV-associated dementia (HAD)32; elevated MCP-1 is detected in the brain and CSF of subjects with HIV encephalitis and HAD.33,34 Our results support the premise that immune activation is crucial to peripheral neurological dysfunction in HIV. The chemoattractants MCP-1 and IP-10 likely escalate disease through augmentation of viral replication in already-infected cells and enhance local inflammation by lymphocyte and monocyte recruitment.35,36 With increased monocyte activation and macrophage presence, HIV cellular transmission perpetuates, and infection leads to macrophage priming and induction of proinflammatory cytokines and TNF-α, leading to neuronal dysfunction. Furthermore, in rat models, endothelial cells that supply DRGs are highly fenestrated, suggesting that this area of the PNS may be particularly vulnerable to toxic effects of circulating activated monocytes and proinflammatory cytokines.37
Our findings of increased CNS inflammation in the presence of PN may be explained through alternative models: HIV concurrently infects both the CNS and PNS, and our detected associations are coincidental, or alternatively, PN induces secondary changes within the CNS. In support of the former, studies of simian immunodeficiency virus-infected macaques at 12 weeks post inoculation have detected increased monocyte infiltration of DRGs and decreased DRG neuronal density and conduction velocity in the absence of neuritis or damage to myelinated peripheral nerves.38 Thus, although there may be an association between central and peripheral immune activation, the presence of CNS and PNS lesions may not correlate. Alternatively, in HIV-DSP, macrophage secretion of proinflammatory molecules within the nerve may lead to CNS immune activation. In support of this, perineural application of the HIV envelope glycoprotein gp120 to rat sciatic nerves leads to TNF-α expression in the DRG and glial cells in the spinal cord.39 Proinflammatory cytokines may promote a paracellular route for HIV-1 across the BBB, facilitating HIV infection of the CNS.40 MCP-1 contributes to blood–spinal cord barrier permeability after peripheral nerve injury, and individuals with mutant MCP-1 genotypes have an increased risk of HAD and accelerated disease progression.41,42 Therefore, a cycle of immune activation and subsequent overproduction of proinflammatory cytokines and chemokines may allow for further cell trafficking from the periphery into the CNS to create further inflammation and neuronal damage.
In our participants, flow cytometry analysis of T-lymphocyte activation demonstrated elevated percentages of CD38+/HLA-DR+ CD8+ T lymphocytes in the CSF of PN subjects. HLA-DR and CD38 expression on CD8+ T lymphocytes correlates with clinical stages of HIV disease, with simultaneous expression of both increasing in symptomatic disease.43 MHC class II molecule HLA-DR expression increases in CD8+ T lymphocytes upon HIV seroconversion and remains stable, whereas the expression of CD38 levels on CD8+ lymphocytes increases throughout disease and is thought to be a predictor of AIDS progression and death.44,45 The percentage of CD38+ and HLA-DR+ CD8+ T lymphocytes increases progressively with advancing HIV disease in pre-ART subjects,46 although ART decreases the level of blood CD38+/HLA-DR+ coexpression on CD8+ T lymphocytes, even in subjects only partially responsive to treatment.47 Our findings suggest that increased migration to or accumulation of "activated" phenotype CD8+T lymphocytes within the CSF pathologically associates with PN. This is the first study to examine T-lymphocyte activation in the CNS compartment in relation to clinical neurological disease in HIV. Whether these findings indicate that PN is associated with processes accelerating disease progression within the nervous system or another mechanism of injury warrants further study.
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