Genital herpes is one of the most prevalent sexually transmitted infections worldwide and its synergistic relationship with HIV amplifies its public health implications. Oral suppressive acyclovir failed to reduce the risk of HIV acquisition or prevent transmission of HIV from HIV/HSV-2 co-infected individuals to their HIV-naive partners highlighting the need to further define the biological mechanisms by which these two pathogens interact. Studies supported by this R01 identified several potential mechanisms, focusing on interactions between HSV and mucosal immunity. Results demonstrate that female genital tract secretions inhibit HIV and HSV in vitro, reflecting the activities of antimicrobial peptides. However, HSV interferes with this defense by downregulating protective mediators, which could lead to a loss in the anti-HIV activity of genital tract secretions. In addition, immature dendritic cells respond to HSV by releasing inflammatory cytokines and chemokines sufficient to increase HIV replication, but paradoxically, fail to mature. The HSV infected and uninfected bystander dendritic cells are rendered incapable of responding to subsequent antigenic stimuli. Thus, in the presence of overt or subclinical HSV infection, mucosal dendritic cells would be incapable of presenting HIV peptides to T cells. HSV also interferes with anatomic host defenses. HSV disrupts epithelial cell tight junctions, greatly facilitating migration of HIV across the epithelial barrier. These results complement the clinical observation that activated T cells persist at sites of HSV-2 reactivation for months after healing of genital ulcers. Together, these findings support the overall paradigm that HSV renders the genital tract mucosal environment more permissive for HIV acquisition and transmission. To test this paradigm with the overall goal of identifying novel strategies to disrupt the synergy between HSV and HIV, we will expand the humanized bone marrow-liver-thymus (BLT) mouse model of HIV to a model of HIV-1/HSV-2 mucosal co- infection and examine the impact HSV has on mucosal immunity, investigate how these changes promote HIV acquisition and increase HIV replication, and determine whether sustained acyclovir delivery using implants similar to intravaginal ring devices will be more effective than intermittent acyclovir dosing at blocking the mucosal responses to HSV that promote HIV infection. In parallel with the proposed mouse studies, we will conduct a prospective study among HIV-1/HSV-2 co-infected and HIV-1?2- women. We will use self- collected vaginal swabs to measure the impact of HSV reactivation on endogenous anti-HIV and anti-HSV activity in genital tract secretions and correlate results with genital tract HIV and HSV viral loads. Additional clinical samples (cytobrush and biopsy) will be collected during episodes of clinical reactivation to assess changes in immune cell populations in response to viral reactivation.
Epidemiological studies highlight the importance of genital herpes in fueling the HIV epidemic, yet strategies to disrupt this synergy have been unsuccessful. This proposal addresses this gap by establishing a mucosal model of HIV-1/HSV-2 co-infection and conducting a parallel clinical study in co-infected women. Clinical samples will enable us to validate mechanistic findings to the physiologically relevant course of infection in humans.
|Nixon, Briana; Jandl, Thomas; Teller, Ryan S et al. (2014) Vaginally delivered tenofovir disoproxil fumarate provides greater protection than tenofovir against genital herpes in a murine model of efficacy and safety. Antimicrob Agents Chemother 58:1153-60|
|Murphy, Kerry; Irvin, Susan C; Herold, Betsy C (2014) Research gaps in defining the biological link between HIV risk and hormonal contraception. Am J Reprod Immunol 72:228-35|
|Nixon, Briana; Fakioglu, Esra; Stefanidou, Martha et al. (2014) Genital herpes simplex virus type 2 infection in humanized HIV-transgenic mice triggers HIV shedding and is associated with greater neurological disease. J Infect Dis 209:510-22|
|Ghartey, Jeny P; Smith, Benjamin C; Chen, Zigui et al. (2014) Lactobacillus crispatus dominant vaginal microbiome is associated with inhibitory activity of female genital tract secretions against Escherichia coli. PLoS One 9:e96659|
|Herold, Betsy C; Dezzutti, Charlene S; Richardson, Barbra A et al. (2014) Antiviral activity of genital tract secretions after oral or topical tenofovir pre-exposure prophylaxis for HIV-1. J Acquir Immune Defic Syndr 66:65-73|
|Seay, Kieran; Qi, Xiaohua; Zheng, Jian Hua et al. (2013) Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. PLoS One 8:e63537|
|Pellett Madan, Rebecca; Herold, Betsy C (2013) HIV, sexual violence and special populations: adolescence and pregnancy. Am J Reprod Immunol 69 Suppl 1:61-7|
|Herold, Betsy C; Keller, Marla J; Shi, Qiuhu et al. (2013) Plasma and mucosal HIV viral loads are associated with genital tract inflammation in HIV-infected women. J Acquir Immune Defic Syndr 63:485-93|
|Scott, Mark E; Wilson, Sarah S; Cosentino, Lisa A et al. (2011) Interlaboratory reproducibility of female genital tract cytokine measurements by Luminex: implications for microbicide safety studies. Cytokine 56:430-4|
|Herold, Betsy C; Mesquita, Pedro M; Madan, Rebecca P et al. (2011) Female genital tract secretions and semen impact the development of microbicides for the prevention of HIV and other sexually transmitted infections. Am J Reprod Immunol 65:325-33|
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