Human immunodeficiency virus dynamics in secondary lymphoid tissues and the evolution of cytotoxic T lymphocyte escape mutants.

In secondary lymphoid tissues, human immunodeficiency virus (HIV) can replicate in both the follicular and extrafollicular compartments. Yet, virus is concentrated in the follicular compartment in the absence of antiretroviral therapy, in part due to the lack of cytotoxic T lymphocyte (CTL)-mediated activity there. CTLs home to the extrafollicular compartment, where they can suppress virus load to relatively low levels. We use mathematical models to show that this compartmentalization can explain seemingly counter-intuitive observations. First, it can explain the observed constancy of the viral decline slope during antiviral therapy in the peripheral blood, irrespective of the presence of CTL in Simian Immunodeficiency Virus (SIV)-infected macaques, under the assumption that CTL-mediated lysis significantly contributes to virus suppression. Second, it can account for the relatively long times it takes for CTL escape mutants to emerge during chronic infection even if CTL-mediated lysis is responsible for virus suppression. The reason is the heterogeneity in CTL activity and the consequent heterogeneity in selection pressure between the follicular and extrafollicular compartments. Hence, to understand HIV dynamics more thoroughly, this analysis highlights the importance of measuring virus populations separately in the extrafollicular and follicular compartments rather than using virus load in peripheral blood as an observable; this hides the heterogeneity between compartments that might be responsible for the particular patterns seen in the dynamics and evolution of the HIV in vivo

Control of the Germinal Center by Follicular Regulatory T Cells During Infection

Follicular regulatory T cells (Tfr) are a unique subset of CD4 T cells that control and impact adaptive immune responses in the lymphoid follicles and germinal centers (GC). Since their relatively recent discovery, several studies have revealed that Tfr interact with other cells within this niche and shape ensuing responses. Recent advances defining the functional and developmental characteristics of Tfr have revealed key characteristics of Tfr differentiation, GC recruitment and retention, and regulatory properties. Further, Tfr shape the GC response and balance tolerance through interactions with Tfh, by modifying Tfh number, diversity and function, as well as with B cells. Mechanisms by which Tfr regulate the GC include cell-to-cell interactions with Tfh and B cells, as well as altering their environment through cytokine production and sequestration. Tfr have been shown to have a diverse T cell receptor (TCR) repertoire and can be specific for immunizing agents, demonstrating a potential role in vaccine development. Due to these important characteristics and functions, Tfr play a major role in immune tolerance, response to infection, and vaccine efficacy

HIV-1 infection and CD4 T cell depletion in the humanized Rag2(-/-)γc(-/- )(RAG-hu) mouse model

BACKGROUND: The currently well-established humanized mouse models, namely the hu-PBL-SCID and SCID-hu systems played an important role in HIV pathogenesis studies. However, despite many notable successes, several limitations still exist. They lack multi-lineage human hematopoiesis and a functional human immune system. These models primarily reflect an acute HIV infection with rapid CD4 T cell loss thus limiting pathogenesis studies to a short-term period. The new humanized Rag2(-/-)γc(-/- )mouse model (RAG-hu) created by intrahepatic injection of CD34 hematopoietic stem cells sustains long-term multi-lineage human hematopoiesis and is capable of mounting immune responses. Thus, this model shows considerable promise to study long-term in vivo HIV infection and pathogenesis. RESULTS: Here we demonstrate that RAG-hu mice produce human cell types permissive to HIV-1 infection and that they can be productively infected by HIV-1 ex vivo. To assess the capacity of these mice to sustain long-term infection in vivo, they were infected by either X4-tropic or R5-tropic HIV-1. Viral infection was assessed by PCR, co-culture, and in situ hybridization. Our results show that both X4 and R5 viruses are capable of infecting RAG-hu mice and that viremia lasts for at least 30 weeks. Moreover, HIV-1 infection leads to CD4 T cell depletion in peripheral blood and thymus, thus mimicking key aspects of HIV-1 pathogenesis. Additionally, a chimeric HIV-1 NL4-3 virus expressing a GFP reporter, although capable of causing viremia, failed to show CD4 T cell depletion possibly due to attenuation. CONCLUSION: The humanized RAG-hu mouse model, characterized by its capacity for sustained multi-lineage human hematopoiesis and immune response, can support productive HIV-1 infection. Both T cell and macrophage tropic HIV-1 strains can cause persistent infection of RAG-hu mice resulting in CD4 T cell loss. Prolonged viremia in the context of CD4 T cell depletion seen in this model mirrors the main features of HIV infection in the human. Thus, the RAG-hu mouse model of HIV-1 infection shows great promise for future in vivo pathogenesis studies, evaluation of new drug treatments, vaccines and novel gene therapy strategies

Patterns of brain atrophy in recently-diagnosed relapsing-remitting multiple sclerosis

Recurrent neuroinflammation in relapsing-remitting MS (RRMS) is thought to lead to neurodegeneration, resulting in progressive disability. Repeated magnetic resonance imaging (MRI) of the brain provides non-invasive measures of atrophy over time, a key marker of neurodegeneration. This study investigates regional neurodegeneration of the brain in recently-diagnosed RRMS using volumetry and voxel-based morphometry (VBM). RRMS patients (N = 354) underwent 3T structural MRI <6 months after diagnosis and 1-year follow-up, as part of the Scottish multicentre 'FutureMS' study. MRI data were processed using FreeSurfer to derive volumetrics, and FSL for VBM (grey matter (GM) only), to establish regional patterns of change in GM and normal-appearing white matter (NAWM) over time throughout the brain. Volumetric analyses showed a decrease over time (q<0.05) in bilateral cortical GM and NAWM, cerebellar GM, brainstem, amygdala, basal ganglia, hippocampus, accumbens, thalamus and ventral diencephalon. Additionally, NAWM and GM volume decreased respectively in the following cortical regions, frontal: 14 out of 26 regions and 16/26; temporal: 18/18 and 15/18; parietal: 14/14 and 11/14; occipital: 7/8 and 8/8. Left GM and NAWM asymmetry was observed in the frontal lobe. GM VBM analysis showed three major clusters of decrease over time: 1) temporal and subcortical areas, 2) cerebellum, 3) anterior cingulum and supplementary motor cortex; and four smaller clusters within the occipital lobe. Widespread GM and NAWM atrophy was observed in this large recently-diagnosed RRMS cohort, particularly in the brainstem, cerebellar GM, and subcortical and occipital-temporal regions; indicative of neurodegeneration across tissue types, and in accord with limited previous studies in early disease. Volumetric and VBM results emphasise different features of longitudinal lobar and loco-regional change, however identify consistent atrophy patterns across individuals. Atrophy measures targeted to specific brain regions may provide improved markers of neurodegeneration, and potential future imaging stratifiers and endpoints for clinical decision making and therapeutic trials

Fatigue in early multiple sclerosis; MRI metrics of neuroinflammation, relapse and neurodegeneration

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease affecting the brain and spinal cord. Fatigue is a common disabling symptom from MS onset, however the mechanisms by which underlying disease processes cause fatigue remain unclear. Improved pathophysiological understanding offers potential for improved treatments for MS-related fatigue. MRI provides insights into in vivo neuroinflammatory activity and neurodegeneration, although existing evidence for imaging correlates of MS fatigue is mixed. We explore associations between fatigue and MRI measures in the brain and spinal cord to identify neuroinflammatory and regional neurodegenerative substrates of fatigue in early relapsing-remitting MS (RRMS). Recently diagnosed (&lt;6 months), treatment-naive people with RRMS (n = 440) were recruited to a longitudinal multi-centre nationally representative cohort study. Participants underwent 3-Tesla brain MRI at baseline and one year. We calculated global and regional white and grey matter volumes, white matter lesion (WML) load and upper cervical spinal cord cross-sectional area levels C2-3, and assessed new/enlarging WMLs visually. Participants were classed as fatigued or non-fatigued at baseline according to the Fatigue Severity Scale (&gt;/≤36). Disability and depression were assessed with the expanded-disability status scale and Patient Health Questionnaire, respectively. MRI measures were compared between fatigue groups, both cross-sectionally and longitudinally, using regression analyses. Higher disability and depression scores were observed for participants with fatigue, with a higher number of fatigued participants receiving disease-modifying treatments at follow-up. Structural MRI data for brain were available for n = 313 (45% fatigued) and for spinal cord for n = 324 (46% fatigued). Cervical spinal cord cross-sectional area 2-3, white and grey matter volumes decreased, and WML volume increased, over time for both groups (q &lt; 0.05). However, no significant between-group differences in these measures were found either cross-sectionally or longitudinally (q &gt; 0.05). The presence of new/enlarging WMLs (49% in fatigued; 51% in non-fatigued) at follow-up also did not differ between groups (q &gt; 0.05). Our results suggest that fatigue is not driven by neuroinflammation or neurodegeneration measurable by current structural MRI in early RRMS. This novel negative finding in a large multi-centre cohort of people with recently diagnosed RRMS helps to resolve uncertainty in existing literature. Notably, we showed that fatigue is prevalent in patients without brain radiological relapse, who may be considered to have inactive disease. This suggests that symptom detection and treatment should remain a clinical priority regardless of neuroinflammatory disease activity. More sensitive objective biomarkers are needed to elucidate fatigue mechanisms in RRMS, and ultimately facilitate development of effective targeted treatments for this important 'hidden disability'.</p

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p &amp;lt; 0.001). Lesion volume (Spearman’s rho rs= 0.38, p &amp;lt; 0.001) and g-ratio (rs= 0.24 p &amp;lt; 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p &amp;lt; 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament

Fish Oil and Fenofibrate for the Treatment of Hypertriglyceridemia in HIV-Infected Subjects on Antiretroviral Therapy: Results of ACTG A5186

Fish oil has been shown to reduce serum triglyceride (TG) concentrations. In HIV-infected patients on antiretroviral therapy, high TG concentrations likely contribute to increased risk of cardiovascular disease. AIDS Clinical Trials Group A5186 examined the safety and efficacy of fish oil plus fenofibrate in subjects not achieving serum TG levels ≤200 mg/dL with either agent alone

The Setpoint Study (ACTG A5217): Effect of Immediate Versus Deferred Antiretroviral Therapy on Virologic Set Point in Recently HIV-1–Infected Individuals

(See the editorial commentary by Tossonian and Conway, on pages 10–12.