Abstract
Vaginal inoculation of rhesus macaques (RM) with simian immunodeficiency virus (SIV) has been used to study the biology of HIV transmission. Although the results of vaginal SIV transmission experiments could be affected by vaginal inflammation, studies to date have been conducted without regard to levels of pre-existing genital inflammation present in RM. We collected cevicovaginal secretions (CVS) from 33–36 RM during the mid menstrual cycle (day 10–20) at 2 time points approximately 8 months apart and characterized the mRNA and protein levels of inflammatory cytokines, chemokines and interferon-stimulated genes. There was extreme variability in the levels of inflammatory mediators (IFN-α, IFN-γ, IL-6, TNF, IL-1b, IP-10, MIG, IL-12 and IL-17). In most animals, the mRNA levels of the inflammatory mediators were similar in the 2 CVS samples collected 8 months apart, suggesting that genital inflammation is stable in a subset of captive female RM. At both time points the cervicovaginal microbiota had low levels of Lactobacillus and was relatively diverse with an average of 13 genera in the samples from the first time point (median 13, range 7–21) and an average of 11.5 genera in the samples from the second time point (median 11, range 5–20). Many of the macaques had similar microbiota in the samples collected 8 months apart. However, we found no correlation between specific bacterial genera and the mRNA or protein levels of the inflammatory mediators in the genital tract of RM in this study. It seems likely that results of published vaginal SIV transmission experiments in RM have been influenced by pre-existing inflammation in the animals used for the experiments.
Highlights
Most HIV-1 infections occur by sexual transmission and the presence or absence of genital inflammation is of fundamental importance in HIV transmission [1] since epidemiologic studies suggest that HIV-1 acquisition is increased in women with bacterial vaginosis (BV) or sexually transmitted infections (STIs), especially herpes simplex virus type 2 (HSV-2) [2,3,4,5,6,7,8]
Of the 15 molecules assessed in the first set of cevicovaginal secretions (CVS) samples collected from 36 rhesus macaques in March 2011 (Time point 1), the mRNA levels of 12 molecules (IFN-a, PKR, RIG-I, IL-17, VISA, oligoadenylate synthetase (OAS) CXCL10, TNF, IL-6, IL-12, monokine-induced by gamma (MIG) and IFN-c) were higher than the GAPDH mRNA levels in every sample (Figure 1)
The levels of genital inflammation influence the efficiency of sexual HIV transmission [1] and HIV acquisition is enhanced by the presence BV [6,10,12,28] [3,10] The simian immunodeficiency virus (SIV)/rhesus macaque system is a well-developed animal model that has been used to study the biology of vaginal HIV transmission, to date the transmission studies using this model have not taken the levels of preexisting cervicovaginal inflammation into account
Summary
Most HIV-1 infections occur by sexual transmission and the presence or absence of genital inflammation is of fundamental importance in HIV transmission [1] since epidemiologic studies suggest that HIV-1 acquisition is increased in women with bacterial vaginosis (BV) or sexually transmitted infections (STIs), especially herpes simplex virus type 2 (HSV-2) [2,3,4,5,6,7,8]. The genital microbiota influences the expression of proinflammatory cytokines [9,10]. A consistent finding is that levels of IL-1b are increased in women with bacterial vaginosis compared to women with a genital microbiota that is dominated by Lactobacillus. Activated NFkB drives transcription of cytokine and adhesion molecule genes, dramatically enhancing expression levels and activating T cells. The infiltrates of activated CCR5+ CD4+ T cells and dendritic cells in the genital mucosa of women with BV and HSV-2 [14,15,16,17,18,19,20] provide more target cells for HIV infection
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