Semen-derived Enhancer Of Viral Infection Research Articles

Semen-derived enhancer of virus infection (SEVI)

Semen-derived enhancer of virus infection (SEVI)

Fibrils of Prostatic Acid Phosphatase Fragments Boost Infections with XMRV (Xenotropic Murine Leukemia Virus-Related Virus), a Human Retrovirus Associated with Prostate Cancer

The xenotropic murine leukemia virus-related virus (XMRV) has recently been detected in prostate cancer tissues and may play a role in tumorigenesis. It is currently unclear how this virus is transmitted and which factors promote its spread in the prostate. We show that amyloidogenic fragments known as semen-derived enhancer of virus infection (SEVI) originating from prostatic acid phosphatase greatly increase XMRV infections of primary prostatic epithelial and stromal cells. Hybrid simian/human immunodeficiency chimeric virus particles pseudotyped with XMRV envelope protein were used to demonstrate that the enhancing effect of SEVI, or of human semen itself, was at the level of viral attachment and entry. SEVI enhanced XMRV infectivity but did not bypass the requirement for the xenotropic and polytropic retrovirus receptor 1. Furthermore, XMRV RNA was detected in prostatic secretions of some men with prostate cancer. The fact that the precursor of SEVI is produced in abundance by the prostate indicates that XMRV replication occurs in an environment that provides a natural enhancer of viral infection, and this may play a role in the spread of this virus in the human population.

An α-Helical Conformation of the SEVI Peptide, a Dramatic Enhancer of HIV Infectivity, Promotes Lipid Aggregation and Fusion

A peptide ubiquitous in human seminal fluid has been recently described that dramatically enhances the infectivity of the HIV virus (3-5 orders of magnitude by some measures). Previous studies have shown that this peptide, a fragment of human Prostatic Acid Phosphatase (PAP248-286) referred to as SEVI (Semen-derived Enhancer of Viral Infection), is amyloidogenic and the enhancement of viral infectivity is dependent on the aggregation state of the peptide. To complement these previous in vivo studies we have performed in vitro assays to investigate the physical mechanisms by which the PAP248-286 promotes the interaction with lipid bilayers. Our results indicate a strong interaction of freshly dissolved PAP248-286 with lipid bilayers but a weaker interaction with the amyloid form of PAP248-286, as measured by the tendency of freshly dissolved PAP248-286 to induce aggregation of lipid vesicles and membrane fusion. The amyloid form of PAP248-286 had little effect on either vesicle aggregation or fusion. To further investigate this effect we have solved the structure of PAP248-286 in SDS micelles. A largely α-helical conformation of PAP248-286, lying parallel to the membrane surface, is implicated in promoting bridging interactions between membranes by the screening of the electrostatic repulsion that occurs when two membranes are brought into close contact. This suggests non-specific binding of small oligomeric forms of SEVI in an α-helical conformation to lipid membranes may be an additional mechanism by which SEVI enhances the infectivity of the HIV virus.

Semen-Derived Amyloid Fibrils Drastically Enhance HIV Infection

Münch J, Rücker E, Ständker L, et al. Cell. 2007;131(6):1059–1071 Seminal Plasma Reduces the Effectiveness of Topical Polyanionic Microbicides Patel S, Hazrati E, Cheshenko N, et al. J Infect Dis. 2007;196(9):1394–1402 PURPOSE OF THE STUDIES. Heterosexual intercourse is the major route of HIV transmission throughout the world. A variety of factors have been identified that are associated with increased transmission, including virus load, lack of circumcision, and the presence of sexually transmitted diseases. One approach to the reduction of male-to-female transmission has been the use of microbicides, and a major effort has been put forth to identify a safe and effective topical microbicide. The purpose of the Münch et al study was to identify factors in semen that might enhance HIV transmission, and the purpose of the Patel et al study was to examine why one of the most promising microbicides tested has failed thus far to reduce transmission in a large controlled trial. STUDY POPULATION. Normal human seminal plasma was studied. METHODS AND RESULTS. In the Münch et al study, investigators screened a complex peptide/protein library derived from human seminal fluid. The authors looked for novel inhibitors and enhancers of HIV infection. They identified fragments of prostatic acidic phosphatase that drastically enhanced HIV infection. Functional and structural analysis showed that these peptides formed amyloid fibrils that captured HIV particles and strongly enhanced the number of productively infected cells in vitro by promoting virion-cell attachment. The authors termed this product “semen-derived enhancer of virus infection” (SEVI). Rats transgenically expressing human CD4 and chemokine receptor 5 (CCR5) are susceptible to HIV infection. In this model, SEVI significantly enhanced the infectivity of HIV in vivo. In the Patel et al study, seminal plasma was shown to dramatically reduce the activity of polyanionic microbicides to reduce infectivity of herpes simplex virus type 2. Further study demonstrated that fibronectin 1 and lactoferrin were the specific factors in seminal plasma that were responsible for this process. In a murine model, this interference in vitro translated to a loss of protection in vivo. CONCLUSIONS. Components of seminal plasma increase HIV infectivity and reduce the effectiveness of topical polyanionic microbicides. REVIEWER COMMENTS. That host factors are involved in HIV replication and transmission is not surprising. However, that amyloid fibrils associated with seminal plasma dramatically increase HIV infectivity was not expected. An increased understanding of the mechanism of this enhancement might assist in overcoming the obstacles noted by Patel et al. An extraordinary effort was put forth to identify a safe and effective microbicide that would prevent transmission of HIV. In vitro and in vivo models indicated that the compound, PRO 2000, would dramatically reduce HIV transmission in vivo. The failure of this approach and the finding that seminal plasma directly interferes with this function dramatically illustrate the need to evaluate seminal plasma as a potential interfering agent in the search for effective microbicides.

The Cationic Properties of SEVI Underlie Its Ability To Enhance Human Immunodeficiency Virus Infection

Human semen contains peptides capable of forming amyloid fibrils termed semen-derived enhancer of viral infection (SEVI) that can greatly increase human immunodeficiency virus (HIV) infection. While SEVI appears to enhance virion attachment to target cells, its underlying mechanism of action is unknown. We now demonstrate that the intrinsic positive charges of SEVI (pI = 10.21) facilitate virion attachment to and fusion with target cells. A mutant form of SEVI in which lysines and arginines are replaced with alanines retains the ability to form amyloid fibrils but is defective in binding virions and enhancing infection. In addition, the interaction of wild-type SEVI with virions and the ability of these fibrils to increase infection are abrogated in the presence of various polyanionic compounds. These anionic polymers also decrease the enhancement of HIV infection mediated by semen. These findings suggest that SEVI enhances viral infection by serving as a polycationic bridge that neutralizes the negative charge repulsion that exists between HIV virions and target cells. Combinations of agents that neutrale SEVI action and produce HIV virucidal effects are an attractive future direction for microbicide development.

Semen-Derived Amyloid Fibrils Drastically Enhance HIV Infection

Sexual intercourse is the major route of HIV transmission. To identify endogenous factors that affect the efficiency of sexual viral transmission, we screened a complex peptide/protein library derived from human semen. We show that naturally occurring fragments of the abundant semen marker prostatic acidic phosphatase (PAP) form amyloid fibrils. These fibrils, termed Semen-derived Enhancer of Virus Infection (SEVI), capture HIV virions and promote their attachment to target cells, thereby enhancing the infectious virus titer by several orders of magnitude. Physiological concentrations of SEVI amplified HIV infection of T cells, macrophages, ex vivo human tonsillar tissues, and transgenic rats in vivo, as well as trans-HIV infection of T cells by dendritic or epithelial cells. Amyloidogenic PAP fragments are abundant in seminal fluid and boost semen-mediated enhancement of HIV infection. Thus, they may play an important role in sexual transmission of HIV and could represent new targets for its prevention.