Background
Host genetic factors are important determinants for risk of HIV-1 infection and disease progression. This study examined associations of host genetic variants and neurocognitive impairment in Chinese subjects infected through contaminated blood products.
Methods
201 HIV-infected subjects from Anhui, China had neuropsychological (NP) tests at baseline and 12 months. DNA was genotyped for APOE ε2, ε3 and ε4 alleles, MBL2-A/O,CCR5-wt/Δ32, CCR5-59029-G/A, CCR2-180-G/A, SDF-1-G/A, IL4-589-C/T, MCP-1-2518-A/G, CX3CR1-745-G/A, -849-C/T polymorphisms and CCL3L1 copy number variants (CNVs) using real-time PCR. Univariate and multivariate analyses were performed.
Results
The cohort was 61% males, mean education: 5.5 years, AIDS diagnosis: 113(55%), on antiretrovirals: 114(56%), mean baseline CD4+ count: 349/mm3 and mean log10 RNA 4.09. At baseline, 37% had global NP impairment increasing to 44% after 12 months. Of 43 subjects with the APOE ε4 allele, 58% were cognitively impaired versus 31% without the ε4 allele (P=0.001, OR: 3.09; 95% CI: 1.54, 6.18). The mean GDS for ε4 positive participants on antiretrovirals for 12 months was 0.88 (0.55) versus 0.63 (.54) for ε4 negatives (P = 0.053, 95%CI: -0.004, 0.51). For MBL2, 52% of subjects with the O/O genotype declined in cognitive function over 12 months versus 23% with A/A (OR = 3.62. 95% CI: 1.46, 9.03; P=0.004). No associations were observed for the other genetic variants.
Conclusions
The APOE ε4 allele was associated with increased risk for cognitive deficits, while the MBL2 O/O genotype was associated with increased risk for progressive cognitive decline in Chinese subjects infected with HIV through contaminated blood products.
Aberrant microglial activation and neuroinflammation is a pathological hallmark of amyotrophic lateral sclerosis (ALS). Fractalkine (CX3CL1) is mostly expressed on neuronal cells. The fractalkine receptor (CX3CR1) is predominantly expressed on microglia. Many progressive neuroinflammatory disorders show disruption of the CX3CL1/CX3CR1 communication system. But the exact role of the CX3CL1/CX3CR1 in ALS pathology remains unknown. F1 nontransgenic/CX3CR1+/− females were bred with SOD1G93A/CX3CR1+/− males to produce F2 SOD1G93A/CX3CR1−/−, SOD1G93A/CX3CR1+/+. We analyzed end-stage (ES) SOD1G93A/CX3CR1−/− mice and progression-matched SOD1G93A/CX3CR1+/+ mice. Our study showed that the male SOD1G93A/CX3CR1−/− mice died sooner than male SOD1G93A/CX3CR1+/+ mice. In SOD1G93A/CX3CR1−/− mice demonstrated more neuronal cell loss, more microglial activation and exacerbated SOD1 aggregation at the end-stage of ALS. The NF-κB pathway was activated; the autophagy-lysosome degradation pathway and the autophagosome maturation were impaired. Our results indicated that the absence of CX3CR1/CX3CL1 signaling in the central nervous system (CNS) may worsen neurodegeneration. The CX3CL1/CX3CR1 communication system has anti-inflammatory and neuroprotective effects and plays an important role in maintaining autophagy activity. This effort may lead to new therapeutic strategies for neuroprotection and provide a therapeutic target for ALS patients.
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