Genital Herpes Simplex Virus Type 2 Infection in Humanized HIV-Transgenic Mice Triggers HIV Shedding and Is Associated With Greater Neurological Disease

Abstract

JR-CSF/hu-cycT1 mice provide a valuable model to study HIV/HSV-2 coinfection and identify potential mechanisms by which HSV-2 facilitates HIV-1 transmission and HIV modulates HSV-2-mediated disease.

The Vaginal Acquisition and Dissemination of HIV-1 Infection in a Novel Transgenic Mouse Model Is Facilitated by Coinfection with Herpes Simplex Virus 2 and Is Inhibited by Microbicide Treatment

“…One possible mechanism that may have contributed to the increased HIV-1 infection in HSV-2-infected hCD4/R5/cT1 mice after intravaginal inoculation is HSV-2-mediated secretion of chemokines and cytokines, which recruited CD4 ϩ T cells, dendritic cells, and/or macrophages to the submucosal site of HSV-2 infection (11,12). An influx of HIV-1-susceptible cells into the submucosal tissues would provide more infectible targets for HIV-1, thereby facilitating both the establishment and dissemination of HIV-1 infection.…”

“…In our transgenic mouse model, HSV-2-challenged hCD4/R5/cT1 mice displayed increased levels of HIV-1 infection in the lower genital tract mucosa and increased dissemination of HIV-1 infection into the draining lymph nodes. We previously reported that HSV-2 infection of C57BL/6 mice induced an increase in interleukin-1␤ (IL-1␤), tumor necrosis factor alpha (TNF-␣), IL-1␣, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1␤ (MIP-1␤), and RANTES gene expression in the lower genital tract mucosa 2 days after infection (12). MCP-1, MIP-1␤, and RANTES are chemokines that stimulate the recruitment of T cells and monocytes (54,55).…”

“…hCD4/R5/cT1 mice (8 to 10 weeks old) were pretreated with 2.5 mg of DMPA 5 days before intravaginal inoculation of HSV-2 (clinical isolate 4674; 10 5 PFU), UV-inactivated HSV-2, or phosphate-buffered saline (PBS), as described previously (12). The UV-inactivated HSV-2 virus was produced by exposing the HSV-2 inoculum to the UV light source for 7 min at a distance of 10 cm, as previously described (16).…”

“…Investigating the molecular and cellular mechanisms underlying the synergistic relationships between HIV-1 and HSV-2 infection has been limited by the absence of an in vivo model to study coinfection with these two viruses. Primary HSV-2 infection creates genital ulcerations that disrupt the epithelial surface and compromise the mucosal barrier; this facilitates HIV-1 passage into the submucosa where it encounters mucosal CD4 ϩ T cells, macrophages, and dendritic cells, infects initial target cells, and forms local foci of infected cells which disseminate through-out the lymphoid tissue (10)(11)(12)(13). In addition, HSV-2 infection alters the mucosal microenvironment by increasing the local production of proinflammatory cytokines and chemokines that recruit and activate CD4 ϩ T lymphocytes, macrophages, and dendritic cells, thereby enhancing the probability that HIV-1 will encounter and infect target cells (14)(15)(16).…”

Herpes simplex virus 2 infection: molecular association with HIV and novel microbicides to prevent disease

“…Thanks to the implementation of a murine model that recapitulates the higher susceptibility to acquire HIV after HSV-2 infection, new molecular mechanisms that relate both viruses will likely be identified in the near future [124].…”