Herpes simplex virus type 2 (HSV-2) infections is one of the driving forces behind the HIV epidemic In sub- Saharan Africa. This is especially true for adolescent/young women who acquire both infections rapidly after sexual debut. We hypothesize that genital inflammation among young women in sub-Saharan Africa is largely driven by HSV-2 acquisition. Our Sp.
Aim 1 will determine if HSV-2 acquisition among young African women results in persistent (>1 year) genital inflammation. The primary outcome will be the change in concentrations of the three pro-inflammatory factors MIP-ip, IL-1 a, and IL-8, measured by Luminex assays in cervicovaginal lavage (CVL) samples from adolescent women before and after initiation of sexual activity, and after HSV-2 seroconversion. We will test for other sexually transmitted infections, and for sexual activity by PSA, to determine their relative contribution to genital inflammation. A secondary clinical outcome will be the density of vulvar infiltration with HIV target cells, as measured by absolute densities of CCR5+ T cells, macrophages and dendritic cells (DCs), quantified by immunofluorescence staining vulvar biopsies obtained from women before and after HSV-2 acquisition. We will compare these biopsies to matched control women who are sexually active but remain HSV-2 seronegative. In year 1 we will conduct an exploratory microarray transcriptome study in an ex vivo vulvovaginal explant tissue model of HSV-2 infection. Our Sp Aim 2 will test whether the frequency of HSV-2 reactivation at set point correlates with the degree of inflammatory changes. We will establish a cohort of HSV-2/HIV negative adolescent women in Thika, Kenya. The women who acquire HSV-2 infection will be enrolled into a 60-day intensive study of HSV-2 shedding, during which they self-collect daily genital swabs for HSV-2 detection. The results on this study will define the role of HSV-2 in mucosal priming of young women for HIV acquisition upon exposure, provide insights into the mechanism, and lay foundation for future interventions for HSV-2 such as chemoprophylaxis, microbicides or vaccines.

Public Health Relevance

In Africa, young women acquire genital herpes and then HIV in rapid succession. The mechanism by which having genital herpes increases the risk of HIV is not clear. We will follow a group of young Kenyan women from the time before they become sexually active and look at the effect on the genital tract of sexual activity and acquisition of genital herpes. This study is important for design of effective HSV-2 and HIV prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI030731-24
Application #
8696989
Study Section
Special Emphasis Panel (ZAI1-LR-M)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
24
Fiscal Year
2014
Total Cost
$572,248
Indirect Cost
$105,426
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Magaret, A; Dong, L; John, M et al. (2016) HLA Class I and II alleles, heterozygosity and HLA-KIR interactions are associated with rates of genital HSV shedding and lesions. Genes Immun 17:412-418
Jing, Lichen; Laing, Kerry J; Dong, Lichun et al. (2016) Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses. J Immunol 196:2205-18
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Ramchandani, Meena; Kong, Marlene; Tronstein, Elizabeth et al. (2016) Herpes Simplex Virus Type 1 Shedding in Tears and Nasal and Oral Mucosa of Healthy Adults. Sex Transm Dis 43:756-760
Milman, Neta; Zhu, Jia; Johnston, Christine et al. (2016) In Situ Detection of Regulatory T Cells in Human Genital Herpes Simplex Virus Type 2 (HSV-2) Reactivation and Their Influence on Spontaneous HSV-2 Reactivation. J Infect Dis 214:23-31
Tjernlund, Annelie; Burgener, Adam; Lindvall, Jessica M et al. (2016) In Situ Staining and Laser Capture Microdissection of Lymph Node Residing SIV Gag-Specific CD8+ T cells--A Tool to Interrogate a Functional Immune Response Ex Vivo. PLoS One 11:e0149907
Nason, Martha C; Patel, Eshan U; Kirkpatrick, Allison R et al. (2016) Immunological Signaling During Herpes Simplex Virus-2 and Cytomegalovirus Vaginal Shedding After Initiation of Antiretroviral Treatment. Open Forum Infect Dis 3:ofw073
Bender Ignacio, Rachel A; Goldman, Jason D; Magaret, Amalia S et al. (2016) Patterns of human herpesvirus-8 oral shedding among diverse cohorts of human herpesvirus-8 seropositive persons. Infect Agent Cancer 11:7

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