Article

Semen-Derived Amyloid Fibrils Drastically Enhance HIV Infection

Institute of Virology, University Clinic of Ulm, 89081 Ulm, Germany.
Cell (Impact Factor: 33.12). 01/2008; 131(6):1059-71. DOI: 10.1016/j.cell.2007.10.014
Source: PubMed

ABSTRACT 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.

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    • "One mechanism by which semen could enhance sexual transmission of HIV was demonstrated by Munch and colleagues in 2007 [70]. To identify natural agents that might play a role in sexual transmission of HIV, Munch and colleagues developed a complex peptide/protein library derived from human seminal plasma which was screened for novel inhibitors and enhancers of HIV infection. "
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    ABSTRACT: Theconnection between human papillomavirus (HPV) infection and the consequent sequelae which establishes cervical neoplastic transformation and invasive cervical cancer has redefined many aspects of cervical cancer research. However there is still much that we do not know. In particular, the impact of external factors, like seminal fluid in sexually active women, on pathways that regulate cervical inflammation and tumorigenesis, have yet to be fully understood. HPV infection is regarded as the initiating noninflammatory cause of the disease; however emerging evidence points to resident HPV infections as drivers of inflammatory pathways that play important roles in tumorigenesis as well as in the susceptibility to other infections such as human immunodeficiency virus (HIV) infection.Moreover there is emerging evidence to support a role for seminal fluid, in particular, the inflammatory bioactive lipids, and prostaglandins which are present in vast quantities in seminal fluid in regulating pathways that can exacerbate inflammation of the cervix, speed up tumorigenesis, and enhance susceptibility to HIV infection.This review will highlight some of our current knowledge of the role of seminal fluid as a potent driver of inflammatory and tumorigenic pathways in the cervix and will provide some evidence to propose a role for seminal plasma prostaglandins in HIV infection and AIDS-related cancer.
    08/2014; 2014. DOI:10.1155/2014/748740
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    • "The enhancing effect of Aβ(1–42) fibrils on HIV-1 infectivity was observed at a concentration of 2 μg/ml and augments with increasing Aβ(1–42) fibril concentrations, whereas Aβ(1–42) fibrils alone had no effect on luciferase expression of TZM-bl cells (Figure 1C). In agreement with Münch et al. [3], but in contrast to Wojtowicz et al. [2], we did not observe any enhancing effect on HIV-1 infection when using Aβ(1–40) fibrils (Innovagen; Lund, Sweden) irrespective of whether these were incubated for four or six days of oligomerization under the same conditions as described above (Figure 2). The reason for this discrepancy was already discussed by Münch et al. arguing that amyloid fibrils composed of the same protein can show different conformations with distinct phenotypes [12]. "
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    ABSTRACT: Amyloid fibrils such as Semen-Derived Enhancer of Viral Infection (SEVI) or amyloid-beta-peptide (Abeta) enhance HIV-1 attachment and entry. Inhibitors destroying or converting those fibrils into non-amyloidogenic aggregates effectively reduce viral infectivity. Thus, they seem to be suitable as therapeutic drugs expanding the current HIV-intervening repertoire of antiretroviral compounds. In this study, we demonstrate that the small D-amino acid peptide D3, which was investigated for therapeutic studies on Alzheimer's disease (AD), significantly reduces both SEVI and Abeta fibril boosted infectivity of HIV-1. Since amyloids could play an important role in the progression of AIDS dementia complex (ADC), the treatment of HIV-1 infected individuals with D3, that inhibits Abeta fibril formation and converts preformed Abeta fibrils into non-amyloidogenic and non-fibrillar aggregates, may reduce the vulnerability of the central nervous system of HIV patients for HIV associated neurological disorders.
    AIDS Research and Therapy 01/2014; 11(1):1. DOI:10.1186/1742-6405-11-1 · 1.84 Impact Factor
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    • "This enhancing effect correlates with the levels of amyloidogenic fragments of prostatic acid phosphatase and semenogelins that are abundant in human semen [12,13]. These semen-derived peptides rapidly form amyloid fibrils that facilitate virion attachment and may increase the infectiousness of HIV-1 in in vitro infection assays by several orders of magnitude [10-12]. Several agents that block this enhancing activity have been reported [14-18] and related fibril-forming peptides were developed for efficient lentiviral gene delivery [19]. "
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    ABSTRACT: Semen and semen-derived amyloid fibrils boost HIV infection in vitro but their impact on sexual virus transmission in vivo is unknown. Here, we examined the effect of seminal plasma (SP) and semen-derived enhancer of virus infection (SEVI) on vaginal virus transmission in the SIV/rhesus macaque (Macacca mulatta) model. A total of 18 non-synchronized female rhesus macaques (six per group) were exposed intra-vaginally to increasing doses of the pathogenic SIVmac239 molecular clone in the presence or absence of SEVI and SP. Establishment of productive virus infection was assessed by measuring plasma viral RNA loads at weekly intervals. We found that the first infections occurred at lower viral doses in the presence of SP and SEVI compared to the control group. Furthermore, the average peak viral loads during acute infection were about 6-fold higher after exposure to SP- and SEVI-treated virus. Overall infection rates after a total of 27 intra-vaginal exposures to increasing doses of SIV, however, were similar in the absence (4 of 6 animals) and presence of SP (5 of 6), or SEVI (4 of 6). Furthermore, the infectious viral doses required for infection varied considerably and did not differ significantly between these three groups. Semen and SEVI did not have drastic effects on vaginal SIV transmission in the present experimental setting but may facilitate spreading of virus infection after exposure to low viral doses that most closely approximate the in vivo situation.
    Retrovirology 12/2013; 10(1):148. DOI:10.1186/1742-4690-10-148 · 4.77 Impact Factor
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