Enigmatic viral promotion

An enigmatic component of human semen, SEVI, semen-derived enhancer of virus infection, boosts infectivity of the human immunodeficiency virus (HIV) which causes AIDS. Since its discovery in 2007, researchers have been hoping to learn more about its structure with the aim of inhibiting its infection-promoting activity; NMR spectroscopy has now produced new clues.

Sexual intercourse is the major route to HIV transmission, but identifying the various biochemical and physical factors that allow some people to become infected with the virus more readily than others is an important focus of research into this potentially lethal disease.

In 2007, Frank Kirchhoff of the Institute of Virology, University Clinic of Ulm, in Germany, and colleagues reported in Cell (2007, 131, 1059-1071; 10.1016/j.cell.2007.10.014) screened a complex peptide/protein library derived from human semen and demonstrated that naturally occurring fragments of the abundant biomarker prostatic acidic phosphatase (PAP) can form tiny fibres of amyloid material.

They called these fibrils SEVI and explained how the fibres can capture HIV virions and promote their attachment to the target cells of the virus, and so enhancing its infectivity by several orders of magnitude. The presence of physiological concentrations of SEVI boosts HIV infection of T cells, macrophages, and human tonsil tissues in the laboratory. They concluded that SEVI plays an important role in sexual transmission of HIV and so represents a novel therapeutic target for efforts to combat the spread of HIV infection.

Now, scientists at the University of Michigan, in Ann Arbor, with support from the National Institutes of Health have determined the atomic-level, three-dimensional structure of a SEVI precursor known as PAP248-286. Their results show how the substance can damage cell membranes and so make them more vulnerable to HIV infection. The results appear in two parallel research papers in November issues of the Journal of the American Chemical Society and the Biophysical Journal.

PAP248-286 is a peptide with a tendency to form fibrous aggregates, SEVI. Readers familiar with the aetiology of various neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, as well as age-related type-2 diabetes may recognise these amyloid fibrils as the problematic substance in those diseases too.

However, Ayyalusamy Ramamoorthy and co-workers have now used NMR spectroscopy to determine not only the molecular structure but to show how the molecule nestles into the membrane with which it interacts. The data show that the structure of PAP248-286 is unlike that of most other amyloid-forming peptides and proteins.

In solution, they explain, SEVI is completely unstructured and would have no effect on HIV infection. It binds to the cell membrane in a disorganized, loose coil form. The neurodegenerative amyloids form relatively ordered, helical structures, explains Ramamoorthy. Moreover, SEVI does not penetrate deep into the hydrophobic region of the cell membrane, but remains located near the surface. It is this behaviour that Ramamoorthy and colleagues, believe explains how SEVI fibres can enhance HIV infection as this arrangement offers a greater surface area with which the virus can interact.

Moreover, they also discovered that PAP248-286 shocks the membrane, forming a dimple that then seems to allow HIV to attach to and subsequently enter the cell.

The researchers are now looking at the structures in more detail. They are also planning to screen a range of antioxidant compounds, such as green tea extract, curcumin (from the spice turmeric), and resveratrol (from red wine) to see whether such compounds will inhibit the SEVI effect on HIV infection.

Ramamoorthy worked with graduate student Ravi Nanga, post-doctoral fellows Jeffrey Brender and Nataliya Popovych and NMR specialist Subramanian Vivekanandan on the research published in JACS. Co-workers on the Biophys J paper were Brender, graduate student Kevin Hartman, former post-doctoral fellow Lindsey Gottler, former graduate student Marchello Cavitt and biophysics undergraduate Daniel Youngstrom.

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.