No evidence of neuronal damage as measured by neurofilament light chain in a HIV cure study utilising a kick-and-kill approach,Journal of Virus Eradication

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No evidence of neuronal damage as measured by neurofilament light chain in a HIV cure study utilising a kick-and-kill approach
Journal of Virus Eradication ( IF 3.5 ) Pub Date : 2021-09-14 , DOI: 10.1016/j.jve.2021.100056
Jasmini Alagaratnam _{1,

2} , Wolfgang Stöhr ₃ , Jamie Toombs ₄ , Amanda Heslegrave ₄ , Henrik Zetterberg _{4,

5,

6,

7} , Magnus Gisslén _{8,

9} , Sarah Pett _{3,

10,

11} , Mark Nelson ₁₂ , Amanda Clarke ₁₃ , Nneka Nwokolo ₁₂ , Margaret A Johnson ₁₄ , Maryam Khan ₁ , Tomas Hanke _{15,

16} , Jakub Kopycinski ₁₇ , Lucy Dorrell ₁₇ , Julie Fox ₁₈ , Sabine Kinloch ₁₄ , Jonathan Underwood _{1,

19} , Matthew Pace ₂₀ , John Frater _{20,

21} , Alan Winston _{1,

2} , Sarah Fidler _{1,

2} ,

Affiliation

Department of Infectious Disease, St Mary's Hospital Campus, Imperial College London, London, W2 1NY, United Kingdom.
Genitourinary Medicine and HIV Department, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, W2 1NY, United Kingdom.
Medical Research Council Clinical Trials Unit at UCL, 90 High Holborn, Holborn, London, WC1V 6LJ, United Kingdom.
UK Dementia Research Institute at University College London, UCL Cruciform Building, Gower Street, Bloomsbury, London, WC1E 6BT, UK.
Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, United Kingdom.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Wallingsgatan 6, 431 41, Mölndal, Sweden.
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Blå Stråket 5, 413 45, Göteborg, Sweden.
Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Blå Stråket 5, 413 45, Göteborg, Sweden.
Institute for Global Health, University College London, Gower St, Bloomsbury, London, WC1E 6BT, UK.
Mortimer Market Centre, Central and North West London NHS Foundation Trust, Capper St, Bloomsbury, London, WC1E 6JB, UK.
Department of Genitourinary Medicine and HIV, Chelsea & Westminster NHS Foundation Trust, 369 Fulham Rd, Chelsea, London, SW10 9NH, UK.
Department of Genitourinary Medicine and HIV, Brighton & Sussex University Hospitals NHS Trust, Kemptown, Brighton, BN2 1ES, UK.
Department of Infection and Immunity, Royal Free Hospital, Pond Street, London, NW3 2QG, United Kingdom.
The Jenner Institute, University of Oxford, Old Road Campus Research Build, Roosevelt Dr, Headington, Oxford, OX3 7DQ, UK.
The Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan.
Nuffield Department of Medicine, University of Oxford, Oxford, OX1 2JD, UK.
Department of Genitourinary Medicine and HIV, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UK.
Division of Infection and Immunity, School of Medicine, Cardiff University, School of Medicine, UHW Main Building, Heath Park, Cardiff, CF14 4XN, UK.
Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, South Parks Road, Oxford, OX1 3SY, UK.
Oxford University National Institute of Health Research Biomedical Research Centre, Oxford, OX1 2JD, UK.

Objective

HIV-remission strategies including kick-and-kill could induce viral transcription and immune-activation in the central nervous system, potentially causing neuronal injury. We investigated the impact of kick-and-kill on plasma neurofilament light (NfL), a marker of neuro-axonal injury, in RIVER trial participants commencing antiretroviral treatment (ART) during primary infection and randomly allocated to ART-alone or kick-and-kill (ART + vaccination + vorinostat (ART + V + V)).

Design

Sub-study measuring serial plasma NfL concentrations.

Methods

Plasma NfL (using Simoa digital immunoassay), plasma HIV-1 RNA (using single-copy assay) and total HIV-1 DNA (using quantitative polymerase chain reaction in peripheral CD4⁺ T-cells) were measured at randomisation (following ≥22 weeks ART), week 12 (on final intervention day in ART + V + V) and week 18 post-randomisation. HIV-specific T-cells were quantified by intracellular cytokine staining at randomisation and week 12. Differences in plasma NfL longitudinally and by study arm were analysed using mixed models and Student's t-test. Associations with plasma NfL were assessed using linear regression and rank statistics.

Results

At randomisation, 58 male participants had median age 32 years and CD4⁺ count 696 cells/μL. No significant difference in plasma NfL was seen longitudinally and by study arm, with median plasma NfL (pg/mL) in ART-only vs ART + V + V: 7.4 vs 6.4, p = 0.16 (randomisation), 8.0 vs 6.9, p = 0.22 (week 12) and 7.1 vs 6.8, p = 0.74 (week 18). Plasma NfL did not significantly correlate with plasma HIV-1 RNA and total HIV-1 DNA concentration in peripheral CD4⁺ T-cells at any timepoint. While higher HIV-specific T-cell responses were seen at week 12 in ART + V + V, there were no significant correlations with plasma NfL. In multivariate analysis, higher plasma NfL was associated with older age, higher CD8⁺ count and lower body mass index.

Conclusions

Despite evidence of vaccine-induced HIV-specific T-cell responses, we observed no evidence of increased neuro-axonal injury using plasma NfL as a biomarker up to 18 weeks following kick-and-kill, compared with ART-only.

中文翻译：

在使用踢杀方法的艾滋病毒治疗研究中，通过神经丝轻链测量，没有神经元损伤的证据

客观的

包括“踢杀”在内的艾滋病毒缓解策略可能会诱导中枢神经系统中的病毒转录和免疫激活，从而可能导致神经元损伤。我们研究了踢杀对血浆神经丝光（NfL）（神经轴突损伤标志物）的影响，研究对象是在原发感染期间开始抗逆转录病毒治疗（ART）的 RIVER 试验参与者，并随机分配至单独 ART 组或踢杀组-杀死（ART + 疫苗接种 + 伏立诺他 (ART + V + V)）。

设计

测量连续血浆 NfL 浓度的子研究。

方法

随机测量血浆 NfL（使用 Simoa 数字免疫测定）、血浆 HIV-1 RNA（使用单拷贝测定）和总 HIV-1 DNA（使用外周 CD4 ⁺ T 细胞的定量聚合酶链反应）（≥22 周后） ART）、第 12 周（ART + V + V 的最后干预日）和随机化后第 18 周。在随机分组和第 12 周，通过细胞内细胞因子染色对 HIV 特异性 T 细胞进行定量。使用混合模型和学生 t 检验分析纵向和研究组的血浆 NfL 差异。使用线性回归和排名统计评估与血浆 NfL 的关联。

结果

随机分组时，58 名男性参与者的中位年龄为 32 岁，CD4 ⁺计数为 696 个细胞/μL。纵向和各研究组的血浆 NfL 没有显着差异，仅 ART 与 ART + V + V 的中位血浆 NfL (pg/mL)：7.4 vs 6.4，p = 0.16（随机化）、8.0 vs 6.9，p = 0.22（第 12 周）和 7.1 vs 6.8，p = 0.74（第 18 周）。^{在任何时间点，血浆 NfL 与外周 CD4 +} T 细胞中血浆 HIV-1 RNA 和总 HIV-1 DNA 浓度均不显着相关。虽然 ART + V + V 在第 12 周观察到较高的 HIV 特异性 T 细胞反应，但与血浆 NfL 没有显着相关性。^{在多变量分析中，较高的血浆 NfL 与年龄较大、较高的 CD8 +}计数和较低的体重指数相关。