title: 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.
abstract: Epidemiological studies have demonstrated that herpes simplex virus 2 (HSV-2) infection significantly increases the risk of HIV-1 acquisition, thereby contributing to the expanding HIV-1 epidemic. To investigate whether HSV-2 infection directly facilitates mucosal HIV-1 acquisition, we used our transgenic hCD4/R5/cT1 mouse model which circumvents major entry and transcription blocks preventing murine HIV-1 infection by targeting transgenic expression of human CD4, CCR5, and cyclin T1 genes to CD4(+) T cells and myeloid-committed cells. Productive infection of mucosal leukocytes, predominantly CD4(+) T cells, was detected in all hCD4/R5/cT1 mice intravaginally challenged with an HIV-1 infectious molecular clone, HIV-Du151.2env-NLuc, which expresses an env gene (C.Du151.2) cloned from an acute heterosexually infected woman and a NanoLuc luciferase reporter gene. Lower genital tract HIV-1 infection after HIV-Du151.2env-NLuc intravaginal challenge was increased ~4-fold in hCD4/R5/cT1 mice coinfected with HSV-2. Furthermore, HIV-1 dissemination to draining lymph nodes was detected only in HSV-2-coinfected mice. HSV-2 infection stimulated local infiltration and activation of CD4(+) T cells and dendritic cells, likely contributing to the enhanced HIV-1 infection and dissemination in HSV-2-coinfected mice. We then used this model to demonstrate that a novel gel containing tenofovir disoproxil fumarate (TDF), the more potent prodrug of tenofovir (TFV), but not the TFV microbicide gel utilized in the recent CAPRISA 004, VOICE (Vaginal and Oral Interventions to Control the Epidemic), and FACTS 001 clinical trials, was effective as preexposure prophylaxis (PrEP) to completely prevent vaginal HIV-1 infection in almost half of HSV-2-coinfected mice. These results also support utilization of hCD4/R5/cT1 mice as a highly reproducible immunocompetent preclinical model to evaluate HIV-1 acquisition across the female genital tract.
  
  
  OBJECTIVE
  Multiple epidemiological studies have reported that genital herpes simplex virus 2 (HSV-2) infection increases the risk of HIV-1 sexual acquisition by severalfold. Understanding the underlying mechanisms by which HSV-2 facilitates HIV-1 infection and optimizing the efficacy of therapies to inhibit HIV-1 infection during HSV-2 coinfection should contribute to reducing HIV-1 transmission. Using our novel transgenic hCD4/R5/cT1 mouse model infectible with HIV-1, we demonstrated that HSV-2 infection enhances vaginal transmission and dissemination of HIV-1 infection while stimulating recruitment and activation of CD4(+) T cells and dendritic cells in the lower genital tract. HIV acquisition by hCD4/R5/cT1 mice vaginally coinfected with HSV-2 could be completely prevented in almost half the mice by preexposure prophylaxis (PrEP) with a novel gel containing tenofovir disoproxil fumarate (TDF), the tenofovir prodrug, but not with the tenofovir microbicide gel utilized in CAPRISA-004, VOICE, and FACTS-001 clinical trials. The hCD4/R5/cT1 mice represent a new preclinical mouse model to evaluate vaginal HIV-1 acquisition.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Kieran
authors.initials: K
authors.lastname: Seay
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Nazanin
authors.initials: N
authors.lastname: Khajoueinejad
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Zheng
authors.affiliation: Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, Illinois, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kiser
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA Birmingham Veterans Affairs Medical Center, Research Service, Birmingham, Alabama, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Betsy
authors.initials: B
authors.lastname: Herold
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA harris.goldstein@einstein.yu.edu.
authors.forename: Harris
authors.initials: H
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D060085:Coinfection / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology*; D006558:Herpes Genitalis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018258:Herpesvirus 2, Human / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014621:Vagina / Q000276:immunology / Q000473:pathology / Q000821:virology; D014622:Vaginal Creams, Foams, and Jellies / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D014622:Vaginal Creams, Foams, and Jellies