HIV-1 Vpr is necessary for maximal HIV infection and spread in macrophages. Evolutionary conservation of Vpr suggests an important yet poorly understood role for macrophages in HIV pathogenesis. Vpr counteracts a previously unknown macrophage-specific restriction factor that targets and reduces the expression of HIV Env. Here, we report that the macrophage mannose receptor (MR), is a restriction factor targeting Env in primary human monocyte-derived macrophages. Vpr acts synergistically with HIV Nef to target distinct stages of the MR biosynthetic pathway and dramatically reduce MR expression. Silencing MR or deleting mannose residues on Env rescues Env expression in HIV-1-infected macrophages lacking Vpr. However, we also show that disrupting interactions between Env and MR reduces initial infection of macrophages by cell-free virus. Together these results reveal a Vpr-Nef-Env axis that hijacks a host mannose-MR response system to facilitate infection while evading MR’s normal role, which is to trap and destroy mannose-expressing pathogens.

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There is an urgent need in multiple sclerosis (MS) patients to develop biomarkers and laboratory tests to improve early diagnosis, predict clinical relapses, and optimize treatment responses. In healthy individuals, the transport of proteins across the blood–brain barrier (BBB) is tightly regulated, whereas, in MS, central nervous system (CNS) inflammation results in damage to neuronal tissues, disruption of BBB integrity, and potential release of neuroinflammatory disease-induced CNS proteins (NDICPs) into CSF and serum. Therefore, changes in serum NDICP abundance could serve as biomarkers of MS. Here, we sought to determine if changes in serum NDICPs are detectable prior to clinical onset of experimental autoimmune encephalomyelitis (EAE) and, therefore, enable prediction of disease onset. Importantly, we show in longitudinal serum specimens from individual mice with EAE that pre-onset expression waves of synapsin-2, glutamine synthetase, enolase-2, and synaptotagmin-1 enable the prediction of clinical disease with high sensitivity and specificity. Moreover, we observed differences in serum NDICPs between active and passive immunization in EAE, suggesting hitherto not appreciated differences for disease induction mechanisms. Our studies provide the first evidence for enabling the prediction of clinical disease using serum NDICPs. The results provide proof-of-concept for the development of high-confidence serum NDICP expression waves and protein biomarker candidates for MS.

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Multiple sclerosis (MS) is an inflammatory autoimmune disorder affecting the central nervous system (CNS) which affects over 400,000 Americans and over 2.5 million people worldwide. Although most patients are initially diagnosed with relapsing-remitting MS, the majority of these patients later develop a chronic-progressive form of MS, for which there is no well-established mouse model. The most common genetic factor associated with MS susceptibility is the Human Leukocyte Antigen (HLA)-DR2b haplotype. Additionally, studies in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, showed that lack of TNF signaling through its receptor TNFR2 leads to disease exacerbation and severe demyelination. Here, we developed a mouse model which expresses HLA-DR2b and lacks TNFR2, designated DR2bΔR2. Strikingly, DR2bΔR2 mice develop progressive EAE with pathology and clinical features observed in progressive MS patients. Adoptive transfer studies revealed that the clinical phenotype of EAE in DR2bΔR2 mice are largely dependent on TNFR2 expression in the CNS. Subsequently, we showed that DR2bΔR2 mice have a significant increase of lesions in the cerebellum, associated with reduced of oligodendrocyte progenitor cells (OPC) recruitment or function. Moreover, we showed that DR2bΔR2 mice are presented with chronic astrogliosis in demyelinating lesions. Our studies provide key insights into CNS repair and regulatory mechanisms controlled by TNFR2 during neuroinflammation and provide novel therapeutic strategies for treating progressive MS.

Gold nanoparticles have shown great potential applications in biomedical diagnosis and therapeutic treatments due to their shape and size‐dependent optical properties. However, densely packed CTAB double layer (surfactant used to prevent nanoparticle aggregation) on the nanorod surfaces present challenges for effective biofunctionalization to setup a nanoparticle‐based platform with high detection sensitivity. In this study, we systematically studied the functionalization of gold nanorods (GNRs) with various bioconjugate linkers in pursuit of developing nanorod‐based immunosensors with maximal sensitivity and specificity. First, GNR chips were fabricated by chemically binding nanorods onto silanized glass substrate; then the GNRs were functionalized with carboxylic acid or amine group via thiol linkers for antibody conjugation. The effects of thiol linkers with different lengths such as 11‐mercaptoundecanic acid (MUDA), 4‐aminothiophenol (4‐ATP), 2‐mercaptopropionic acid (MPA), cysteamine hydrochloride (CAE) and 6‐mercaptohexanoic acid (MHA) were investigated. GNR nano‐biochip exhibited high detection sensitivity (0.3017/ IgGnM), low detection limit (1.3 nM) and high specificity, with the features of label free and simple detection mechanism. The optimized functionalization of GNR chip was applied to develop a nano‐biosensor to detect human serum IgG as a model system. Since the localized surface plasmon resonance is highly sensitive to the biological binding on the nanorod surface, this mechanism provides a label‐free biodetection, eliminating signaling labels such as fluorophore and radioactive agents. The miniaturized nano‐biochip is attractive for rapid medical diagnostics in clinics, due to its user‐friendly and cost‐effective features.

Tumor necrosis factor-alpha (TNF) is a pleiotropic inflammatory cytokine that has been associated with the pathogenesis of several autoimmune diseases, including multiple sclerosis (MS). Consequently, TNF-blocking drugs have been widely used to treat many inflammatory conditions and have proven highly effective. However, treatment of MS patients with anti-TNF drugs leads to disease exacerbation and severe demyelination. This effect has been specifically associated with lack of TNF signaling through its receptor, TNFR2. However, the underlying mechanisms are not fully understood. Experimental autoimmune encephalomyelitis (EAE) is the most common animal model used to study MS. Our lab has recently generated TNFR2−/− DR2b+/+ mice to study the role of TNFR2 signaling in EAE in the context of the HLA-DR2b (DRB1*1501), a haplotype strongly associated with MS. We found that these mice developed progressive EAE characterized by increased demyelinating lesions. Strikingly, this phenotype was not due to lack of TNFR2 expression in T cells, but rather was associated with a decreased numbers of oligodendrocyte progenitor cells (OPCs) in the CNS. Moreover, we demonstrated that TNFR2 signaling is critical for expression of chemokines in the CNS, suggesting its involvement in OPC function and recruitment. Our studies provide key insights into CNS repair and regulatory mechanisms controlled by TNF during inflammation, and this information may help develop novel therapeutic strategies.