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

Abstract

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.Human immunodeficiency virus (HIV) was identified more than 25 years ago but remains a pressing threat to public health worldwide, particularly in developing nations. Sub-Saharan Africa is home to 68% of all adults and nearly 90% of all children infected with HIV; in 2007, 76% of AIDS deaths occurred in this region (UNAIDS 2007). In both developing and developed nations, semen is the principal vector mediating transmission of the virus.Semen provides a protective environment for HIV virions that may act to enhance transmission. Seminal fluid contains basic amines such as spermine, spermidine, putrescine, and cadaverine that can protect HIV virions from inactivation by the acidic secretions present in the vaginal tract (2,7,14). Recently, Münch and colleagues identified a factor in semen that greatly enhances HIV infection (9). This factor, which they termed SEVI (semen-derived enhancer of viral infection), is composed of a proteolytic peptide encompassing residues 248 to 286 of prostatic acid phosphatase (PAP), a highly abundant protein in semen. Synthetic versions of SEVI enhance HIV infection up to 10 5 -fold under conditions of limiting viral inoculums (9). These observations suggest that SEVI may play an important role in promoting semen-mediated transmission of HIV.In this study, we sought to identify the mechanism by which SEVI enhances infection. SEVI exists as amyloid fibrils, and only this fibrillar form of the PAP248-286 peptide enhances HIV infection (9). In addition, we noted that PAP248-286 contains a high abundance of positively charged lysine and arginine residues. We hypothesized that SEVI enhances infection by serving as a cationic polymer that shields the electrostatic repulsion that normally occurs between the membranes of HIV virions and their target cells. To test this hypothesis,...

Rôle des fibrilles amyloïdes dans la transmission du VIH

“…Les cellules peuvent s'engager dans des migrations solitaires ou collectives. Ces dernières impliquent une certaine coordination et une coopération des cellules [3,4]. Jusqu'à présent, les migrations collectives étaient, pensait-on, restreintes aux cellules de type épithélial [4].…”

“…La dégradation d'A-3G par la voie du protéasome n'est pas le seul mécanisme par lequel Vif contrecarre ce facteur de restriction : Vif réduit également l'expression d'A-3G en inhibant sa traduction [8] (Figure 1, voie C) et agit de façon directe pour inhiber son incorporation dans les particules virales, sans doute par compétition [3] (Figure 1, voie A). Ces deux derniers mécanismes restent encore mal connus et pourraient, eux-aussi, déboucher sur de nouvelles stratégies d'inhibition du VIH-1.…”

“…Plusieurs groupes ont publié que la présence de sperme augmente dramatiquement l'infection de lignées cellulaires et de cellules primaires par le VIH [2][3][4][5][6]. Quels sont les facteurs présents dans le sperme responsables de cet effet ?…”

“…Une dose de VIH qui serait donc insuffisante pour être infectieuse pourrait devenir, dans ce contexte, hautement infectieuse. Les [3,5]. De plus, le sperme traité avec ces polymères anioniques ou duquel on a éliminé les facteurs chargés positivement, perd lui aussi son activité facilitatrice de l'infection [3,5].…”

“…Les [3,5]. De plus, le sperme traité avec ces polymères anioniques ou duquel on a éliminé les facteurs chargés positivement, perd lui aussi son activité facilitatrice de l'infection [3,5]. Ces fibrilles semblent donc favoriser l'infection en diminuant la répulsion électros-tatique entre les membranes chargées négativement du virus et de la cellule cible (Figure 1).…”