Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity.

Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from ß-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.

ß-Barrels and Amyloids: Structural Transitions, Biological Functions, and Pathogenesis.

Insoluble protein aggregates with fibrillar morphology called amyloids and ß-barrel proteins both share a ß-sheet-rich structure. Correctly folded ß-barrel proteins can not only function in monomeric (dimeric) form, but also tend to interact with one another-followed, in several cases, by formation of higher order oligomers or even aggregates. In recent years, findings proving that ß-barrel proteins can adopt cross-ß amyloid folds have emerged. Different ß-barrel proteins were shown to form amyloid fibrils in vitro. The formation of functional amyloids in vivo by ß-barrel proteins for which the amyloid state is native was also discovered. In particular, several prokaryotic and eukaryotic proteins with ß-barrel domains were demonstrated to form amyloids in vivo, where they participate in interspecies interactions and nutrient storage, respectively. According to recent observations, despite the variety of primary structures of amyloid-forming proteins, most of them can adopt a conformational state with the ß-barrel topology. This state can be intermediate on the pathway of fibrillogenesis ("on-pathway state"), or can be formed as a result of an alternative assembly of partially unfolded monomers ("off-pathway state"). The ß-barrel oligomers formed by amyloid proteins possess toxicity, and are likely to be involved in the development of amyloidoses, thus representing promising targets for potential therapy of these incurable diseases. Considering rapidly growing discoveries of the amyloid-forming ß-barrels, we may suggest that their real number and diversity of functions are significantly higher than identified to date, and represent only "the tip of the iceberg". Here, we summarize the data on the amyloid-forming ß-barrel proteins, their physicochemical properties, and their biological functions, and discuss probable means and consequences of the amyloidogenesis of these proteins, along with structural relationships between these two widespread types of ß-folds.

The Amyloid Fibril-Forming ß-Sheet Regions of Amyloid ß and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ.

14-3-3 proteins are abundant, intramolecular proteins that play a pivotal role in cellular signal transduction by interacting with phosphorylated ligands. In addition, they are molecular chaperones that prevent protein unfolding and aggregation under cellular stress conditions in a similar manner to the unrelated small heat-shock proteins. In vivo, amyloid ß (Aß) and α-synuclein (α-syn) form amyloid fibrils in Alzheimer's and Parkinson's diseases, respectively, a process that is intimately linked to the diseases' progression. The 14-3-3ζ isoform potently inhibited in vitro fibril formation of the 40-amino acid form of Aß (Aß40) but had little effect on α-syn aggregation. Solution-phase NMR spectroscopy of 15N-labeled Aß40 and A53T α-syn determined that unlabeled 14-3-3ζ interacted preferentially with hydrophobic regions of Aß40 (L11-H21 and G29-V40) and α-syn (V3-K10 and V40-K60). In both proteins, these regions adopt ß-strands within the core of the amyloid fibrils prepared in vitro as well as those isolated from the inclusions of diseased individuals. The interaction with 14-3-3ζ is transient and occurs at the early stages of the fibrillar aggregation pathway to maintain the native, monomeric, and unfolded structure of Aß40 and α-syn. The N-terminal regions of α-syn interacting with 14-3-3ζ correspond with those that interact with other molecular chaperones as monitored by in-cell NMR spectroscopy.

Functionalization of amyloid fibrils via the Bri2 BRICHOS domain.

Amyloid fibrils are mechanically robust and partly resistant to proteolytic degradation, making them potential candidates for scaffold materials in cell culture, tissue engineering, drug delivery and other applications. Such applications of amyloids would benefit from the possibility to functionalize the fibrils, for example by adding growth factors or cell attachment sites. The BRICHOS domain is found in a family of human proteins that harbor particularly amyloid-prone regions and can reduce aggregation as well as toxicity of several different amyloidogenic peptides. Recombinant human (rh) BRICHOS domains have been shown to bind to the surface of amyloid-ß (Aß) fibrils by immune electron microscopy. Here we produce fusion proteins between mCherry and rh Bri2 BRICHOS and show that they can bind to different amyloid fibrils with retained fluorescence of mCherry in vitro as well as in cultured cells. This suggests a "generic" ability of the BRICHOS domain to bind fibrillar surfaces that can be used to synthesize amyloid decorated with different protein functionalities.

Liquid-liquid phase separation of type II diabetes-associated IAPP initiates hydrogelation and aggregation.

Amyloidoses (misfolded polypeptide accumulation) are among the most debilitating diseases our aging societies face. Amyloidogenesis can be catalyzed by hydrophobic-hydrophilic interfaces (e.g., air-water interface in vitro [AWI]). We recently demonstrated hydrogelation of the amyloidogenic type II diabetes-associated islet amyloid polypeptide (IAPP), a hydrophobic-hydrophilic interface-dependent process with complex kinetics. We demonstrate that human IAPP undergoes AWI-catalyzed liquid-liquid phase separation (LLPS), which initiates hydrogelation and aggregation. Insulin modulates these processes but does not prevent them. Using nonamyloidogenic rat IAPP, we show that, whereas LLPS does not require the amyloidogenic sequence, hydrogelation and aggregation do. Interestingly, both insulin and rat sequence delayed IAPP LLPS, which may reflect physiology. By developing an experimental setup and analysis tools, we show that, within the whole system (beyond the droplet stage), macroscopic interconnected aggregate clusters form, grow, fuse, and evolve via internal rearrangement, leading to overall hydrogelation. As the AWI-adsorbed gelled layer matures, its microviscosity increases. LLPS-driven aggregation may be a common amyloid feature and integral to pathology.

Correlation between amyloid deposits affecting renal compartments and glomerular filtration rate during renal biopsy in a renal amyloidosis case series.

Amyloidosis comprises a group of disorders that accumulate modified autologous proteins in organs, mainly the kidneys. Few studies have addressed the amyloid compartmental distribution and associated clinical outcomes. The aim of this study was to present a case series of renal amyloidosis correlating histopathological data with glomerular filtration rate (GFR) during kidney biopsy. We studied 53 cases reviewed by nephropathologists from 2000 to 2018 in a single kidney biopsy center in Brazil. GFR was estimated using the CKD-EPI formula. Cases were divided into Group A ≥60 and Group B <60 mL·min-1·(1.73 m2)-1 using the estimated GFR during kidney biopsy. Semiquantitative histopathological study was performed, including extension and distribution of amyloid deposits by compartments (glomeruli, tubulointerstitial tissue, and vessels). Statistical analyses were made to understand associations with lower GFR. No difference was seen for age, gender, proteinuria, hematuria, subtype of amyloid protein, arteriosclerosis, interstitial fibrosis/infiltrate, or glomerular and interstitial amyloid deposits. After a previous P value <0.1 in the descriptive analysis, the following variables were selected: globally sclerotic glomeruli, high blood pressure, and the extension of vascular amyloid deposition. A binary logistic regression model with GFR as the dependent variable showed history of hypertension and vascular amyloid to be robust and independent predictors of Group B <60 mL·min-1·(1.73 m2)-1. Beyond the histopathologic diagnosis of amyloidosis, a semiquantitative approach on renal biopsy could provide new insights. Vascular amyloid is an independent predictor of renal dysfunction in cases of renal amyloidosis.

The hydrophobic effect characterises the thermodynamic signature of amyloid fibril growth.

Many proteins have the potential to aggregate into amyloid fibrils, protein polymers associated with a wide range of human disorders such as Alzheimer's and Parkinson's disease. The thermodynamic stability of amyloid fibrils, in contrast to that of folded proteins, is not well understood: the balance between entropic and enthalpic terms, including the chain entropy and the hydrophobic effect, are poorly characterised. Using a combination of theory, in vitro experiments, simulations of a coarse-grained protein model and meta-data analysis, we delineate the enthalpic and entropic contributions that dominate amyloid fibril elongation. Our prediction of a characteristic temperature-dependent enthalpic signature is confirmed by the performed calorimetric experiments and a meta-analysis over published data. From these results we are able to define the necessary conditions to observe cold denaturation of amyloid fibrils. Overall, we show that amyloid fibril elongation is associated with a negative heat capacity, the magnitude of which correlates closely with the hydrophobic surface area that is buried upon fibril formation, highlighting the importance of hydrophobicity for fibril stability.

Functional amyloids of eukaryotes: criteria, classification, and biological significance.

Amyloids cause incurable diseases in humans and animals and regulate vital processes in bacteria and eukaryotes. Amyloid fibrils have unique properties, such as amazing resistance to a variety of agents, mechanical strength, and elasticity, and it is not surprising that in the course of evolution eukaryotes have learned to employ amyloid structures to regulate various vital processes. Proteins exhibiting amyloid properties have been detected in lower eukaryotes and in diverse cell lines of arthropods and vertebrates. A growing number of studies of eukaryotic proteins that demonstrate certain amyloid-like properties require clear criteria to systematize modern knowledge about the functional amyloids. In this review, we propose to separate eukaryotic proteins, whose amyloid properties are clearly proven, and proteins, which show some amyloid characteristics in vivo or in vitro. In order to assert that a protein is a functional amyloid, it is necessary to prove that it has a cross-ß structure in vivo. Here, we consider the advantages and disadvantages of various methods for the analysis of the amyloid properties of a protein. Analysis of the current data shows that amyloids play an important role in the regulation of vital processes in eukaryotes, and new functional amyloids should be searched primarily among structural, protective, and storage proteins. A systematic search for functional amyloids in eukaryotes is only beginning, and the use of novel proteomic methods opens up great prospects for identification of amyloids in any organs and tissues of various organisms.

Mechanism of rutin mediated inhibition of insulin amyloid formation and protection of Neuro-2a cells from fibril-induced apoptosis.

Many metabolic and neurodegenerative diseases are associated with protein misfolding and aggregation. Insulin a key hormone, under certain conditions aggregates and forms pathological amyloid fibrils. Several polyphenols have been studied extensively to elucidate their inhibitory effect on amyloid formation. In the present study, we used insulin as an amyloid model to test the mechanism and efficacy of rutin as an anti-amyloidogenic molecule. By using electron microscopy, dynamic light scattering and circular dichroism spectroscopy, we show that rutin inhibits the insulin aggregate and fibril formation. Further, rutin interacts with insulin directly and inhibits fibril formation in a dose-dependent manner as demonstrated by micro scale thermophoresis experiments. The molecular docking study predicted the potential binding pocket of rutin at the interface of chain A and chain B of insulin thereby preventing it from forming the aggregates. Since, rutin is a natural anti-oxidant, we studied its role in diminishing amyloid fibril induced cytotoxicity and apoptosis. Rutin, decreases the insulin amyloid fibrils-induced Neuro-2a cytotoxicity by reducing reactive oxygen species (ROS) levels which in turn downregulates Bax and upregulates Bcl-2 and pBad proteins. These findings suggest the potential action of rutin in preventing protein misfolding, cell death, and serves as a lead structure to design novel anti-amyloidosis compounds.

CPAD 2.0: a repository of curated experimental data on aggregating proteins and peptides.

The Curated Protein Aggregation Database (CPAD) is a manually curated and open-access database dedicated to providing comprehensive information related to mechanistic, kinetic and structural aspects of protein and peptide aggregation. The database has been updated to CPAD 2.0 by significantly expanding datasets and improving the user-interface. Key features of CPAD 2.0 are (i) 83,098 data points on aggregation kinetics experiments, (ii) 565 structures related to aggregation, which are classified into proteins, fibrils, and protein-ligand complexes, (iii) 2031 aggregating/non-aggregating peptides with pre-calculated aggregation properties, and (iv) 912 aggregation-prone regions in amyloidogenic proteins. This database will help the scientific community (a) by facilitating research leading to improved understanding of protein aggregation, (b) by helping develop, validate and benchmark mechanistic and kinetic models of protein aggregation, and (c) by assisting experimentalists with design of their investigations and dissemination of data generated by their studies. CPAD 2.0 can be accessed at https://web.iitm.ac.in/bioinfo2/cpad2/index.html.

The role of isoaspartate in fibrillation and its prevention by Protein-L-isoaspartyl methyltransferase.

BACKGROUND: Isomerization of aspartate to isoaspartate (isoAsp) on aging causes protein damage and malfunction. Protein-L-isoaspartyl methyltransferase (PIMT) performs a neuroprotective role by repairing such residues. A hexapeptide, Val-Tyr-Pro-(isoAsp)-His-Ala (VA6), a substrate of PIMT, is shown to form fibrils, while the normal Asp-containing peptide does not. Considering the role of PIMT against epileptic seizure, the combined effect of PIMT and two antiepileptic drugs (AEDs) (valproic acid and stiripentol) was investigated for anti-fibrillation activity. METHODS: Structural/functional modulations due to the binding of AEDs to PIMT were investigated using biophysical techniques. Thioflavin T (ThT) fluorescence assay and microscopic methods were employed to study fibril formation by VA6. In vitro experiments with PC12 cells were carried out with PIMT/AEDs. RESULTS: ThT assay indicated reduction of fibrillation of VA6 by PIMT. AEDs stabilize PIMT, bind close to the cofactor binding site, possibly exerting allosteric effect, increase the enzymatic activity, and anti-fibrillation efficacy. Furthermore, Aß42, implicated in Alzheimer's disease, undergoes ß-sheet to α-helix transition in presence of PIMT. Studies with PC12 derived neurons showed that PIMT and PIMT/AEDs exerted neuroprotective effect against anti-NGF induced neurotoxicity. This was further validated against neurotoxicity induced by Aß42 in primary rat cortical neurons. CONCLUSIONS: The study provides a new perspective to the role isoAsp in protein fibrillation, PIMT in its prevention and AEDs in enhancing the activity of the enzyme. GENERAL SIGNIFICANCE: IsoAsp, with an additional C atom in the main-chain of polypeptide chain, may make it more susceptible to fibrillation. PIMT alone, or in association with AEDs prevents this.

Correlation between amyloid deposits affecting renal compartments and glomerular filtration rate during renal biopsy in a renal amyloidosis case series

Amyloidosis comprises a group of disorders that accumulate modified autologous proteins in organs, mainly the kidneys. Few studies have addressed the amyloid compartmental distribution and associated clinical outcomes. The aim of this study was to present a case series of renal amyloidosis correlating histopathological data with glomerular filtration rate (GFR) during kidney biopsy. We studied 53 cases reviewed by nephropathologists from 2000 to 2018 in a single kidney biopsy center in Brazil. GFR was estimated using the CKD-EPI formula. Cases were divided into Group A ≥60 and Group B <60 mL·min−1·(1.73 m2)−1 using the estimated GFR during kidney biopsy. Semiquantitative histopathological study was performed, including extension and distribution of amyloid deposits by compartments (glomeruli, tubulointerstitial tissue, and vessels). Statistical analyses were made to understand associations with lower GFR. No difference was seen for age, gender, proteinuria, hematuria, subtype of amyloid protein, arteriosclerosis, interstitial fibrosis/infiltrate, or glomerular and interstitial amyloid deposits. After a previous P value <0.1 in the descriptive analysis, the following variables were selected: globally sclerotic glomeruli, high blood pressure, and the extension of vascular amyloid deposition. A binary logistic regression model with GFR as the dependent variable showed history of hypertension and vascular amyloid to be robust and independent predictors of Group B <60 mL·min−1·(1.73 m2)−1. Beyond the histopathologic diagnosis of amyloidosis, a semiquantitative approach on renal biopsy could provide new insights. Vascular amyloid is an independent predictor of renal dysfunction in cases of renal amyloidosis.

Macrophage-Mediated Phagocytosis and Dissolution of Amyloid-Like Fibrils in Mice, Monitored by Optical Imaging.

Light chain-associated amyloidosis is characterized by the extracellular deposition of amyloid fibrils in abdominothoracic organs, skin, soft tissue, and peripheral nerves. Phagocytic cells of the innate immune system appear to be ineffective at clearing the material; however, human light chain amyloid extract, injected subcutaneously into mice, is rapidly cleared in a process that requires neutrophil activity. To better elucidate the phagocytosis of light chain fibrils, a potential method of cell-mediated dissolution, amyloid-like fibrils were labeled with the pH-sensitive dye pHrodo red and a near infrared fluorophore. After injecting this material subcutaneously in mice, optical imaging was used to quantitatively monitor phagocytosis and dissolution of fibrils concurrently. Histologic evaluation of the residual fibril masses revealed the presence of CD68+, F4/80+, ionized calcium binding adaptor molecule 1- macrophages containing Congo red-stained fibrils as well as neutrophil-associated proteins with no evidence of intact neutrophils. These data suggest an early infiltration of neutrophils, followed by extensive phagocytosis of the light chain fibrils by macrophages, leading to dissolution of the mass. Optical imaging of this novel murine model, coupled with histologic evaluation, can be used to study the cellular mechanisms underlying dissolution of synthetic amyloid-like fibrils and human amyloid extracts. In addition, it may serve as a test bed to evaluate investigational opsonizing agents that might serve as therapeutic agents for light chain-associated amyloidosis.

Brain PET Imaging: Value for Understanding the Pathophysiology of HIV-associated Neurocognitive Disorder (HAND).

PURPOSE OF REVIEW: The purpose of this review is to summarize recent developments in PET imaging of neuropathologies underlying HIV-associated neurocognitive dysfunction (HAND). We concentrate on the recent post antiretroviral era (ART), highlighting clinical and preclinical brain PET imaging studies. RECENT FINDINGS: In the post ART era, PET imaging has been used to better understand perturbations of glucose metabolism, neuroinflammation, the function of neurotransmitter systems, and amyloid/tau protein deposition in the brains of HIV-infected patients and HIV animal models. Preclinical and translational findings from those studies shed a new light on the complex pathophysiology underlying HAND. The molecular imaging capabilities of PET in neuro-HIV are great complements for structural imaging modalities. Recent and future PET imaging studies can improve our understanding of neuro-HIV and provide biomarkers of disease progress that could be used as surrogate endpoints in the evaluation of the effectiveness of potential neuroprotective therapies.

Amyloid causes intermittent network disruptions in cognitively intact older subjects.

Recent findings in AD models but also human patients suggest that amyloid can cause intermittent neuronal hyperactivity. The overall goal of this study was to use dynamic fMRI analysis combined with graph analysis to a) characterize the graph analytical signature of two types of intermittent hyperactivity (spike-like (spike) and hypersynchronus-like (synchron)) in simulated data and b) to attempt to identify one of these signatures in task-free fMRIs of cognitively intact subjects (CN) with or without increased brain amyloid. The toolbox simtb was used to generate 33 data sets with 2 short spike events, 33 with 2 synchron and 33 baseline data sets. A combination of sliding windows, hierarchical cluster analysis and graph analysis was used to characterize the spike and the synchron signature. Florbetapir-F18 PET and task-free 3 T fMRI was acquired in 49 CN (age = 70.7 ± 6.4). Processing the real data with the same approach as the simulated data identified phases whose graph analytical signature resembled that of the synchron signature in the simulated data. The duration of these phases was positively correlated with amyloid load (r = 0.42, p < 0.05) and negatively with memory performance (r = -0.43, p < 0.05). In conclusion, amyloid positivity is associated with intermittent hyperactivity that is caused by short phases of hypersynchronous activity. The negative association with memory performance suggests that these disturbances have the potential to interfere with cognitive processes and could lead to cognitive impairment if they become more frequent or more severe with increasing amyloid deposition.

Different effects of lipid on conformational conversion of chicken and murine prion proteins.

Prion diseases are characterized by the conformational conversion of the cellular prion protein (PrPC) to the pathogenic isoform (PrPSc). Lipids have been found to interact with PrPC and contribute to the efficient formation of PrPSc. Non-mammalian PrPs are not readily to undergo the conversion process into an infectious isoform, yet the effect of lipid on the conformational conversion of non-mammalian PrPC remains to be explored. Herein, the effects of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) on full-length recombinant chicken PrP (ChPrP) 24-249 and murine PrP (MoPrP) 23-230 were investigated. Firstly, it was found that in the presence of chemical denaturant, POPG remarkably inhibited MoPrP amyloid fibril growth, while had slight effect on that of ChPrP as estimated by amyloid fibril growth and transmissible electronic microscope assays. Secondly, under physiological condition, POPG induced conformation changes in both MoPrP and ChPrP using Thioflavin T (ThT) fluorescence, circular dichroism, proteinase K digestion and transmission electron microscopy assays. With a POPG:PrP molar ratio of 30:1, the ThT fluorescence of MoPrP was found to be lower than that of ChPrP, however, the POPG-induced MoPrP had higher ß-sheet content and was more proteinase K-resistant than POPG-induced ChPrP. In summary, the present results suggested that the effects of POPG on conformational conversion of MoPrP and ChPrP were different under both denaturation and physiological conditions.

A new era for understanding amyloid structures and disease.

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-ß structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention.

Amyloid assembly and disassembly.

Amyloid fibrils are protein homopolymers that adopt diverse cross-ß conformations. Some amyloid fibrils are associated with the pathogenesis of devastating neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Conversely, functional amyloids play beneficial roles in melanosome biogenesis, long-term memory formation and release of peptide hormones. Here, we showcase advances in our understanding of amyloid assembly and structure, and how distinct amyloid strains formed by the same protein can cause distinct neurodegenerative diseases. We discuss how mutant steric zippers promote deleterious amyloidogenesis and aberrant liquid-to-gel phase transitions. We also highlight effective strategies to combat amyloidogenesis and related toxicity, including: (1) small-molecule drugs (e.g. tafamidis) to inhibit amyloid formation or (2) stimulate amyloid degradation by the proteasome and autophagy, and (3) protein disaggregases that disassemble toxic amyloid and soluble oligomers. We anticipate that these advances will inspire therapeutics for several fatal neurodegenerative diseases.

Semen-derived amyloidogenic peptides-Key players of HIV infection.

Misfolding and amyloid aggregation of intrinsically disordered proteins (IDPs) are implicated in a variety of diseases. Studies have shown that membrane plays important roles on the formation of intermediate structures of IDPs that can initiate (and/or speed-up) amyloid aggregation to form fibers. The process of amyloid aggregation also disrupts membrane to cause cell death in amyloid diseases like Alzheimer's disease and type-2 diabetes. On the other hand, recent studies reported the membrane fusion properties of amyloid fibers. Remarkably, amyloid-fibril formation by short peptide fragments of highly abundant prostatic acidic-phosphatase (PAP) in human semen and are capable of boosting the rate of HIV infection up to 400,000-fold during sexual contact. Unlike the least toxic fully matured fibers of most amyloid proteins, the semen-derived enhancer of virus infection (SEVI) amyloid-fibrils of PAP peptide fragments are highly potent in rendering the maximum rate of HIV infection. This unusual property of amyloid fibers has witnessed increasing number of studies on the biophysical aspects of fiber formation and fiber-membrane interactions. NMR studies have reported a highly disordered partial helical structure in a membrane environment for the intrinsically disordered PAP peptide that promotes the fusion of the viral membrane with that of host cells. The purpose of this review article is to unify and integrate biophysical and immunological research reported in the previous studies on SEVI. Specifically, amyloid aggregation, dramatic HIV infection enhancing properties, membrane fusion properties, high resolution NMR structure, and approaches to eliminate the enhancement of HIV infection of SEVI peptides are discussed.