Structure, function and antagonism of semen amyloids

Röcker, Annika; Roan, Nadia R.; Yadav, Jay Kant; Fändrich, Marcus; Münch, Jan

doi:10.1039/c8cc01491d

Cited by 35 publications

(49 citation statements)

References 102 publications

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“…While our study was performed in vitro with seminal plasma‐free sperm, ejaculated sperm bathing with seminal plasma may even have a higher rate of carrying HIV‐1 on their surface. Amyloid fibrils SEVI (Semen‐derived Enhancer of Viral Infection), present in seminal plasma, accelerate the HIV‐1 transport to target cells including sperm . In addition, since sperm can swim upwards in the tract and bind to other epithelial cells (e.g., the endometrium), sperm‐associated HIV‐1 virions are likely able to infect additional epithelial cells in the female reproductive tract.…”

Section: Discussionmentioning

confidence: 99%

Sperm can act as vectors for HIV‐1 transmission into vaginal and cervical epithelial cells

Young

Tatieng

Kongmanas

et al. 2019

American J Rep Immunol

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Problem Sperm are the major cells in semen. Human sperm possess a number of HIV‐1 gp120 binding ligands including sulfogalactosylglycerolipid (SGG). However, the mechanisms of how sperm capture HIV‐1 onto their surface are unclear. Furthermore, the ability of sperm to deliver HIV‐1 to vaginal/cervical epithelial cells lining the lower female reproductive tract, as a first step in HIV‐1 transmission, needs to be determined. Method of study Sperm from healthy donors were incubated with dual‐tropic HIV‐1CS204 (clinical isolate), and virus capture was determined by p24 antigen ELISA. The involvement of SGG in HIV‐1 capture was assessed by determining Kd values of HIV‐1 gp120‐SGG binding as well as computational docking of SGG to the gp120 V3 loop. The ability of sperm‐associated HIV‐1 to infect peripheral blood mononuclear cells (PBMCs) and TZM‐bl indicator cells was determined. Lastly, infection of vaginal (Vk2/E6E7), ectocervical (Ect1/E6E7), and endocervical (End1/E6E7) epithelial cells mediated by HIV‐1–associated sperm was evaluated. Results Sperm were able to capture HIV‐1 in a dose‐dependent manner, and the capture reached a maximum within 5 minutes. Captured HIV‐1, however, could be removed from sperm by Percoll‐gradient centrifugation. Affinity of gp120 for SGG was substantial, implicating sperm SGG in HIV‐1 capture. Sperm‐associated HIV‐1 could productively infect PBMCs and TZM‐bl cells, and was capable of being transmitted into vaginal/cervical epithelial cells. Conclusion Sperm are able to capture HIV‐1, which remains infectious and is able to be transmitted into vaginal/cervical epithelial cells, a result indicating the importance of sperm in HIV transmission.

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Section: Discussionmentioning

confidence: 99%

Sperm can act as vectors for HIV‐1 transmission into vaginal and cervical epithelial cells

Young

Tatieng

Kongmanas

et al. 2019

American J Rep Immunol

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“…The changes in the secondary structure and those in the properties of semen amyloids have been reported to be associated with reproductive health and sexually transmitted diseases, such as acquired immune deficiency syndrome (AIDS) . In order to understand the structural determinants of PAP 248‐286 and its C‐terminal domain (CTD), at the molecular level, the interaction of both the peptides with DOPC was assessed by employing CD spectroscopy, and it was confirmed that the interaction of PAP 248‐286 with DOPC does not drive the formation of β‐sheets, indicating inhibition of fibril formation.…”

Section: Discussionmentioning

confidence: 99%

The mechanism of phosphatidylcholine‐induced interference of PAP (248‐286) aggregation

Kumar

Gour

Verma

et al. 2019

Journal of Peptide Science

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Seminal amyloids are well known for their role in enhancing HIV infection. Among all the amyloidogenic peptides identified in human semen, PAP 248-286 was found to be the most active and was termed as semen-derived enhancer of viral infection (SEVI). Although amyloidogenic nature of the peptide is mainly linked with enhancement of the viral infection, the most active physiological conformation of the aggregated peptide remains inconclusive. Lipids are known to modulate aggregation pathway of a variety of proteins and peptides and constitute one of the most abundant biomolecules in human semen. PAP 248-286 significantly differs from the other known amyloidogenic peptides, including Aβ and IAPP, in terms of critical concentration, surface charge, fibril morphology, and structural transition during aggregation. Hence, in the present study, we aimed to assess the effect of a lipid, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), on PAP 248-286 aggregation and the consequent conformational outcomes. Our initial observation suggested that the presence of the lipid considerably influenced the aggregation of PAP 248-286 . Further, ZDOCK and MD simulation studies of peptide multimerization have suggested that the hydrophobic residues at C-terminus are crucial for PAP 248-286 aggregation and are anticipated to be major DOPC-interacting partners. Therefore, we further assessed the aggregation behaviour of C-terminal (PAP 273-286 ) fragment of PAP 248-286 and observed that DOPC possesses the ability to interfere with the aggregation behaviour of both the peptides used in the current study. Mechanistically, we propose that the presence of DOPC causes considerable inhibition of the peptide aggregation by interfering with the peptide's disordered state to β-sheet transition.

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“…More recently, it led to the discovery of an endogenous CXCR4 antagonist that blocks CXCR4-tropic HIV infection (Zirafi et al, 2015). Moreover, screening a semen derived peptide library identified amyloidforming peptides as enhancers of HIV-1 infection (Münch et al, 2007a;Arnold et al, 2012;Röcker et al, 2018) and antibacterial agents (Easterhoff et al, 2013). Thus, the concept of isolating novel AMPs from body fluids resulted in the identification of peptides that inhibited bacterial and viral infections by novel and unexpected mechanisms.…”

Section: Introductionmentioning

confidence: 99%

A Placenta Derived C-Terminal Fragment of β-Hemoglobin With Combined Antibacterial and Antiviral Activity

et al. 2020

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The placenta acts as physical and immunological barrier against the transmission of viruses and bacteria from mother to fetus. However, the specific mechanisms by which the placenta protects the developing fetus from viral and bacterial pathogens are poorly understood. To identify placental peptides and small proteins protecting from viral and bacterial infections, we generated a peptide library from 10 kg placenta by chromatographic means. Screening the resulting 250 fractions against Herpes-Simplex-Virus 2 (HSV-2), which is rarely transmitted through the placenta, in a cellbased system identified two adjacent fractions with significant antiviral activity. Further rounds of chromatographic purification and anti-HSV-2 testing allowed to purify the bioactive peptide. Mass spectrometry revealed the presence of a 36-mer derived from the C-terminal region of the hemoglobin β subunit. The purified and corresponding chemically synthesized peptide, termed HBB(112-147), inhibited HSV-2 infection in a dose-dependent manner, with a mean IC 50 in the median µg/ml range. Full-length hemoglobin tetramer had no antiviral activity. HBB(112-147) did not impair infectivity by direct targeting of the virions but prevented HSV-2 infection at the cell entry level. The peptide was inactive against Human Immunodeficiency Virus Type 1, Rubella and Zika virus infection, suggesting a specific anti-HSV-2 mechanism. Notably, HBB(112-147) has previously been identified as broad-spectrum antibacterial agent. It is abundant in placenta, reaching concentrations between 280 and 740 µg/ml, that are well sufficient to

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Structure, function and antagonism of semen amyloids

Cited by 35 publications

References 102 publications

Sperm can act as vectors for HIV‐1 transmission into vaginal and cervical epithelial cells

Sperm can act as vectors for HIV‐1 transmission into vaginal and cervical epithelial cells

The mechanism of phosphatidylcholine‐induced interference of PAP (248‐286) aggregation

A Placenta Derived C-Terminal Fragment of β-Hemoglobin With Combined Antibacterial and Antiviral Activity

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