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. 2015 Dec;42(12):694-701.
doi: 10.1097/OLQ.0000000000000367.

Relationship of Estimated SHIV Acquisition Time Points During the Menstrual Cycle and Thinning of Vaginal Epithelial Layers in Pigtail Macaques

Ellen N Kersh  1 , Jana Ritter, Katherine Butler, Sharon Dietz Ostergaard, Debra Hanson, Shanon Ellis, Sherif Zaki, Janet M McNicholl
Affiliations

Relationship of Estimated SHIV Acquisition Time Points During the Menstrual Cycle and Thinning of Vaginal Epithelial Layers in Pigtail Macaques

Ellen N Kersh et al. Sex Transm Dis. 2015 Dec.

Abstract

Background: HIV acquisition in the female genital tract remains incompletely understood. Quantitative data on biological HIV risk factors, the influence of reproductive hormones, and infection risk are lacking. We evaluated vaginal epithelial thickness during the menstrual cycle in pigtail macaques (Macaca nemestrina). This model previously revealed increased susceptibility to vaginal infection during and after progesterone-dominated periods in the menstrual cycle.

Methods: Nucleated and nonnucleated (superficial) epithelial layers were quantitated throughout the menstrual cycle of 16 macaques. We examined the relationship with previously estimated vaginal SHIVSF162P3 acquisition time points in the cycle of 43 different animals repeatedly exposed to low virus doses.

Results: In the luteal phase (days 17 to cycle end), the mean vaginal epithelium thinned to 66% of mean follicular thickness (days 1-16; P = 0.007, Mann-Whitney test). Analyzing 4-day segments, the epithelium was thickest on days 9 to 12 and thinned to 31% thereof on days 29 to 32, with reductions of nucleated and nonnucleated layers to 36% and 15% of their previous thickness, respectively. The proportion of animals with estimated SHIV acquisition in each cycle segment correlated with nonnucleated layer thinning (Pearson r = 0.7, P < 0.05, linear regression analysis), but not nucleated layer thinning (Pearson r = 0.6, P = 0.15).

Conclusions: These data provide a detailed picture of dynamic cycle-related changes in the vaginal epithelium of pigtail macaques. Substantial thinning occurred in the superficial, nonnucleated layer, which maintains the vaginal microbiome. The findings support vaginal tissue architecture as susceptibility factor for infection and contribute to our understanding of innate resistance to SHIV infection.

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Figures

Fig. 1
Fig. 1
Menstrual cycle starting time determination in example macaque BB0499. Menstrual cycle start and duration were determined retrospectively using daily observation of bleeding (open circles), sex skin swelling (recorded on a scale of 1-4, left axis, grey bars), and plasma progesterone (right axis, filled circles). In this example, onset of menstrual bleeding defined day one of the cycle. Biopsies (cross symbol) were collected on days 8 and 29 of the cycle for this animal.
Fig. 2 A
Fig. 2 A
Example H&E stained vaginal biopsies from two pigtail macaques at two different time points each (10x magnification). Text inserts refer to macaque identification numbers and menstrual cycle day. B: Top: Illustration of non-nucleated and nucleated vaginal epithelial layers. Intermediate layers refer to s. granulosum and spinosum. Bottom: Analysis parameters applied using software as described in the text, measuring epithelial thickness at 50 micron intervals across all mounted parts of the biopsies. A mean 142 measurements were analyzed for each biopsy occasion.
Fig. 3
Fig. 3
Dynamic changes in the vaginal epithelium during the menstrual cycle. A: Mean epithelial thickness and SD (standard deviation, error bars) of the layers in animals with measurements in the indicated 4-day cycle segments. B: The dynamic changes are graphed using smoothed curves for epithelial thickness layers as indicated.
Fig. 4
Fig. 4
Relationship of epithelial thickness and susceptibility to SHIV infection A. The graph shows the percentage of 43 female pigtail macaques with est. (=estimated) SHIV acquisition time point at the indicated menstrual cycle segments of four days. The macaques became SHIVSF162P3 infected after repeated vaginal exposure at low virus dose, as published . Data were analyzed and plotted for 4-day intervals. B, C: Scatter plots of the thickness of mean vaginal epithelial layers during 4-day menstrual cycle segments, and the estimated SHIV acquisition in corresponding 4-day segments in 43 different macaques. The line represent linear regression analysis; R = Pearson co-efficient; p-value results from hypothesis test of non-zero slope. The right Y axis refers to the number of infections as reported in . D. Smoothed data were graphed to further examine the relationship of non-nucleated layer thickness and susceptibility to infection throughout the menstrual cycle.
Fig. 5
Fig. 5
Age, vaginal epithelial thickness, and susceptibility to infection. A, B. Scatterplots show the distribution of mean vaginal layer thickness and age of 16 macaques, ranging from 4.5 to 14.2 years. Thickness was evaluated between days 5-20, i.e., when thickness was high, and not thinned by hormonal influences. The line represents the linear relationship; p-value tests the hypothesis of non-zero slope in a multivariable model that controlled for changing levels of thickness over the course of the menstrual cycle C. Scatterplot shows the age of 19 macaques when they became vaginally infected with repeated, low doses of SHIVSF162P3 as described in .
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