No SEVI-mediated enhancement of rectal HIV-1 transmission of HIV-1 in two humanized mouse cohorts

Abstract

Amyloid fibrils from semen-derived peptide (SEVI) enhance HIV-1 infectivity in vitro but the ability of SEVI to mediate enhancement of HIV infection in vivo has not been tested. In this study we used immunodeficient mice reconstituted with human immune systems to test for in vivo enhancement of HIV-1 transmission. This mouse model supports mucosal transmission of HIV-1 via the intrarectal route leading to productive infection. In separate experiments with humanized mouse cohorts reconstituted with two different donor immune systems, high dose HIV-1JR-CSF that had been incubated with SEVI amyloid fibrils at physiologically relevant concentrations did not show an increased incidence of infection compared to controls. In addition, SEVI failed to enhance rectal transmission with a reduced concentration of HIV-1. Although we confirmed potent SEVI-mediated enhancement of HIV infectivity in vitro, this model showed no evidence that it plays a role in the much more complex situation of in vivo transmission.

Epigallocatechin Gallate Inhibits Macaque SEVI-Mediated Enhancement of SIV or SHIV Infection

“…Importantly, we demonstrated that the macaque PAP248-286-derived SEVI fibrils could enhance SIV or SHIV infection of macaque PBMC. These findings in conjunction with the studies by others 25,26,35 argue for future investigations particularly in vivo studies to determine whether macaque SEVI fibrils can facilitate SIV or SHIV mucosal transmission in the macaques. In addition, given the findings that EGCG could remodel seminal amyloid fibrils and effectively suppress SEVI-mediated HIV enhancement in vitro , it is necessary to examine whether EGCG can protect macaques from SIV or SHIV infection through rectal or reproductive tract mucosa.…”

“…Thus, the PAP248-286 amyloid fibril was termed as Semen-derived Enhancer of Viral Infection (SEVI) 19 . Although in vitro studies have clearly shown that SEVI could enhance HIV infection/replication, in vivo investigations on the role of SEVI in enhancing intravaginal or intrarectal HIV infection in the animal models have generated the conflicting results 25,26 . The difference in epithelial integrities of rectal or reproductive mucosa of difference animal species 35 could contribute the discrepancy.…”

“…While human SEVI could enhance HIV infection of hCD4/hCCR5-transgenic rats by tail vein injection 19 , there was little effect of human SEVI on the rectal HIV transmission in the humanized mice 26 . Also, SEVI showed little effect on the vaginal simian immunodeficiency virus (SIV) transmission in rhesus macaques 25 .…”

“…As compared with the in vitro findings that human SEVI could enhance HIV or SIV infection 19,25 , the in vivo studies with the animals resulted in the conflicting data 25,26 . While human SEVI could enhance HIV infection of hCD4/hCCR5-transgenic rats by tail vein injection 19 , there was little effect of human SEVI on the rectal HIV transmission in the humanized mice 26 .…”

Pathogenicity of Ebola and Marburg Viruses Is Associated With Differential Activation of the Myeloid Compartment in Humanized Triple Knockout-Bone Marrow, Liver, and Thymus Mice

“…Humanized mouse models of viral infection require careful interpretation because antigen recognition and effector functions of the human compartment will not always be able to model a fully immune competent animal. Regardless, HIS mice have been successfully used to study human immune responses to many pathogens [39], and the TKO-BLT model in particular has been regularly used for human immunodeficiency virus (HIV)-1 studies [40][41][42]. In contrast to HIV-1 where only human CD4 + cells serve as targets of viral infection, in the case of filoviruses human leukocyte subsets and several murine cell types all support filovirus replication in these animals.…”