Journal of NeuroVirology

The efficacy and safety of interferon-free therapies for hepatitis C virus (HCV) infection have been reported. Considering the accumulating evidence for a direct central nervous system infection by HCV, we aim to evaluate the effect of direct acting antivirals (DAA) therapy on cognitive function in HCV patients. We conducted a longitudinal analysis of the cognitive performance of 22 patients (8 HCV+, 14 HCV+/HIV+) who completed neuropsychological testing at baseline and at week 12 after DAA therapy. In 20 patients, we analyzed specific attention parameters derived from an experimental testing based on the Theory of Visual Attention (TVA). Depression, fatigue, and mental health were assessed as patient reported outcomes. At baseline, 54.5% of the patients met the criteria for cognitive impairment and 40% showed impairment in TVA parameters. Follow-up analysis revealed significant improvements in the domains of visual memory/learning, executive functions, verbal fluency, processing speed, and motor skills but not in verbal learning and attention/working memory. We did not observe significant improvement in visual attention measured by TVA. Fatigue and mental health significantly improved at follow-up. Our findings indicate that successful DAA treatment leads to cognitive improvements in several domains measured by standard neuropsychological testing. The absence of improvement in TVA parameters and of significant improvement in the domain of attention/working memory might reflect the persistence of specific cognitive deficits after HCV eradication. In summary, DAA treatment seems to have a positive effect on some cognitive domains and leads to an improvement in mental health and fatigue in HCV-infected patients.

Prior findings led us to hypothesize that West Nile virus (WNV) preferentially transports along motor axons instead of sensory axons. WNV is known to undergo axonal transport in cell culture and in infected hamsters to infect motor neurons in the spinal cord. To investigate this hypothesis, WNV was injected directly into the left sciatic nerve of hamsters. WNV envelope-staining in these hamsters was only observed in motor neurons of the ipsilateral ventral horn of the spinal cord, but not in the dorsal root ganglion (DRG). To evaluate the consequence of motor neuron infection by WNV, the authors inoculated wheat germ agglutinin—horseradish peroxidase (WGA-HRP) 9 days after WNV sciatic nerve injection, and stained the spinal cord and the DRG for HRP activity 3 days later. The degree of HRP-staining in DRG was the same in WNV- and sham-infected animals, but the HRP-staining in the motor neuron in the ventral horn was considerably less for WNV-infected hamsters. To investigate the mechanism of WNV transport, hamsters were treated with colchicine, an inhibitor of membranous microtubule-mediated transport. The intensity of the WNV-stained area in the spinal cord of colchicine-treated hamsters at 6 days after WNV infection were significantly reduced (P≤.05) compared to the placebo-treated hamsters. These data suggest that WNV is preferentially transported through the motor axons, but not the sensory axons, to subsequently infect motor neurons and cause motor weakness and paralysis.

Since the initial description of progressive multifocal leukoencephalopathy (PML) in 1958, clinical and basic science investigators have demonstrated a growing interest in the area of neurovirology, with a recent focus on polyomaviruses. In this review, the authors present an overview of the biological properties of the human polyomavirus, JC virus (JCV), and its association with PML as the etiologic agent. Additionally, the authors provide a discussion of the current understanding of JCV molecular pathogenesis and therapeutic strategies.

The human immunodeficiency virus type 1 (HIV-1) enters the central nervous system (CNS) during the acute phase of infection and causes AIDS-related encephalitis and dementia in 30% of individuals. Previous studies show that HIV-1 sequences derived from the CNS of infected patients, including the sequence encoding reverse transcriptase (RT), are genetically distinct from sequences in other tissues. The hypothesis of the current study is that the RT sequence of HIV-1 is under positive selection within the CNS. Multiple alignments of non-CNS-derived and CNS-derived HIV-1 RT sequences were constructed using the ClustalW 1.8 program. The multiple alignments were analyzed with the Synonymous/Nonsynonymous Analysis Program. Codon positions 122–125, 135–149, and 166–212 of the CNS-derived RT sequences underwent a greater accumulation of nonsynonymous than synonymous substitutions, which was markedly different from the analysis results of the non-CNS-derived RT sequences. These residues are located in the finger and palm subdomains of the RT protein structure, which encodes the polymerase active site. The analysis of CNS-derived partial-length RT sequences that encompass these regions yielded similar results. A comparison of CNS-derived RT sequences to a non-CNS-derived RT consensus sequence revealed that a majority of the nonsynonymous substitutions resulted in a specific amino acid replacement. These results indicate that reverse transcriptase is under positive selection within the CNS. The amino acid replacements were visualized on a three-dimensional structure of HIV-1 RT using the Sybyl software suite. The protein structure analysis revealed that the amino acid replacements observed among the CNS-derived sequences occurred in areas of known structural and functional significance.

Over 50 % of HIV-infected (HIV+) persons are expected to be over age 50 by 2015. The pathogenic effects of HIV, particularly in cases of long-term infection, may intersect with those of age-related illnesses and prolonged exposure to combined antiretroviral therapy (cART). One potential outcome is an increased prevalence of neurocognitive impairment in older HIV+ individuals, as well as an altered presentation of HIV-associated neurocognitive disorders (HANDs). In this study, we employed stepwise regression to examine 24 features sometimes associated with HAND in 40 older (55–73 years of age) and 30 younger (32–50 years of age) HIV+, cART-treated participants without significant central nervous system confounds. The features most effective in generating a true assessment of the likelihood of HAND diagnosis differed between older and younger cohorts, with the younger cohort containing features associated with drug abuse that were correlated to HAND and the older cohort containing features that were associated with lipid disorders mildly associated with HAND. As the HIV-infected population grows and the demographics of the epidemic change, it is increasingly important to re-evaluate features associated with neurocognitive impairment. Here, we have identified features, routinely collected in primary care settings, that provide more accurate diagnostic value than a neurocognitive screening measure among younger and older HIV individuals.

Conventional brain and spinal cord magnetic resonance images were performed in 21 patients with human T-cell lymphotropic virus (HTLV)-1 associated myelopathy/tropical spastic paraparesis, to assess the role of conventional magnetic resonance imaging (MRI) in the disease diagnosis. These patients had no other central nervous system conditions or related risk factors at the time of tropical spastic paraparesis diagnosis. Eleven (52.4%) patients showed nonspecific brain abnormalities on T2-weighted images. The majority (77.2%) of brain abnormalities were located in the deep white matter. A transient contrast-enhancing lesion was identified in the brain of only one patient. In the brain of another patient, 9.0% of the T2-hyperintense lesion load was hypointense on the correspondent T1-weighted images. No differences in terms of demographic, biological, or clinical variables were present between patients with abnormal brain images and those with normal brain magnetic resonance images. Spinal cord T2-weighted images were abnormal in three (14.3%) patients. In one of these three patients, a diffuse but transient edema was found along the entire tract of the spinal cord. White matter lesions were present in the central nervous system of 60% of the cases in this study. However, no correlations between magnetic resonance imaging and clinical findings, and no specificity of lesions were observed. Hence, conventional magnetic resonance imaging is a sensitive but not highly specific tool for diagnosis of tropical spastic paraparesis.

Here the authors discuss evidence in human and animal models supporting two opposing views regarding the pathogenesis of human immunodeficiency virus (HIV) in the central nervous system (CNS): (1) HIV infection in the CNS is a compartmentalized infection, with the virus-infected macrophages entering the CNS early, infecting resident microglia and astrocytes, and achieving a state of latency with evolution toward a fulminant CNS infection late in the course of disease; or alternatively, (2) events in the periphery lead to altered monocyte/macrophage (MΦ) homeostasis, with increased CNS invasion of infected and/or uninfected MΦs. Here the authors have reevaluated evidence presented in the favor of the latter model, with a discussion of phenotypic characteristics distinguishing normal resident microglia with those accumulating in HIV encephalitis (HIVE). CD163 is normally expressed by perivascular MΦs but not resident microglia in normal CNS of humans and rhesus macaques. In agreement with other studies, the authors demonstrate expression of CD163 by brain MΦs in HIVE and simian immunodeficiency virus encephalitis (SIVE). CNS tissues from HIV-sero positive individuals with HIVE or HIV-associated progressive multifocal leukoencephalopathy (PML) were also examined. In HIVE, the authors further demonstrate colocalization of CD163 and CD16 (FcγIII recptor) gene expression, the latter marker associated with HIV infection of monocyte in vivo and permissivity of infection. Indeed, CD163+ MΦs and microglia are often productively infected in HIVE CNS. In SIV infected rhesus macaques, CD163+ cells accumulate perivascularly, within nodular lesions and the parenchyma in animals with encephalitis. Likewise, parenchymal microglia and perivascular MΦs are CD163+ in HIVE. In contrast to HIVE, CD163+ perivascular and parenchymal MΦs in HIV-associated PML were only associated with areas of demyelinating lesions. Interestingly, SIV-infected rhesus macaques whose viral burden was predominantly at 1 × 106 copies/ml or greater developed encephalitis. To further investigate the relationship between CD163+/CD16+ MΦs/microglia in the CNS and altered homeostasis in the periphery, the authors performed flow-cytometric analyses of peripheral blood mononuclear cells (PBMCs) from SIV-infected rhesus macaques. The results demonstrate an increase in the percent frequency of CD163+/CD16+ monocytes in animals with detectable virus that correlated significantly with increased viral burden and CD4+ T-cell decline. These results suggest the importance of this monocyte subset in HIV/SIV CNS disease, and also in the immune pathogenesis of lentiviral infection. The authors further discuss the potential role of CD163+/CD16+ monocyte/MΦ subset expansion, altered myeloid homeostasis, and potential consequences for immune polarization and suppression. The results and discussion here suggest new avenues for the development of acquired immunodeficiency syndrome (AIDS) therapeutics and vaccine design.

HIV-associated sensory neuropathy remains an important complication of combination antiretroviral therapy and HIV infection. Mitochondrial DNA haplogroups and single nucleotide polymorphisms (SNPs) have previously been associated with symptomatic neuropathy in clinical trial participants. We examined associations between mitochondrial DNA variation and HIV-associated sensory neuropathy in CNS HIV Antiretroviral Therapy Effects Research (CHARTER). CHARTER is a USA-based longitudinal observational study of HIV-infected adults who underwent a structured interview and standardized examination. HIV-associated sensory neuropathy was determined by trained examiners as ≥1 sign (diminished vibratory and sharp–dull discrimination or ankle reflexes) bilaterally. Mitochondrial DNA sequencing was performed and haplogroups were assigned by published algorithms. Multivariable logistic regression of associations between mitochondrial DNA SNPs, haplogroups, and HIV-associated sensory neuropathy were performed. In analyses of associations of each mitochondrial DNA SNP with HIV-associated sensory neuropathy, the two most significant SNPs were at positions A12810G [odds ratio (95 % confidence interval) = 0.27 (0.11–0.65); p = 0.004] and T489C [odds ratio (95 % confidence interval) = 0.41 (0.21–0.80); p = 0.009]. These synonymous changes are known to define African haplogroup L1c and European haplogroup J, respectively. Both haplogroups were associated with decreased prevalence of HIV-associated sensory neuropathy compared with all other haplogroups [odds ratio (95 % confidence interval) = 0.29 (0.12–0.71); p = 0.007 and odds ratio (95 % confidence interval) = 0.42 (0.18–1.0); p = 0.05, respectively]. In conclusion, in this cohort of mostly combination antiretroviral therapy-treated subjects, two common mitochondrial DNA SNPs and their corresponding haplogroups were associated with a markedly decreased prevalence of HIV-associated sensory neuropathy.