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Menopause Is Associated With Immune Activation in Women With HIV
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The Journal of Infectious Diseases 15 January 2022 Brandilyn A. Peters,1, Xiaonan Xue,1 Lila A. Sheira,2 Qibin Qi,1 Anjali Sharma,3 Nanette Santoro,4 Maria L. Alcaide,5 Igho Ofotokun,6 Adaora A. Adimora,7 Heather S. McKay,8 Phyllis C. Tien,9,10 Katherine G. Michel,11 Deborah Gustafson,12 Bulent Turan,13,aAlan L. Landay,14 Robert C. Kaplan,1,15 and Sheri D. Weiser2,10,
"Compounded effects of HIV, aging, and menopause on immune activation could put aging women with HIV at particularly high risk of non-AIDS-related disease and mortality. Thus, research on the health of women with HIV during and after the menopausal transition is of paramount importance, including clinical research on the effectiveness of interventions (eg, health monitoring, lifestyle modifications, hormone therapy) to reduce disease risk."
In this study of women with HIV, we observed higher levels of innate immune activation, measured by plasma sCD14 and sCD163, in postmenopausal compared to premenopausal women. Additionally, our results suggested that plasma sCD14 increases specifically during the menopausal transition, consistent with changes driven by ovarian rather than chronological aging. However, menopause was not associated with IFAB, a biomarker of gut barrier dysfunction, or IL-6 and TNFR1, biomarkers of systemic inflammation. Due to the short follow-up in this study of up to 2 years, we did not have sufficient sample size to explore within-woman change in biomarkers as women transition from pre- to postmenopause-only 8 women transitioned during follow-up. Nevertheless, our results suggest a risk of increased immune activation during the menopausal transition in women with HIV. Plasma sCD14 and sCD163 are nonspecific markers of monocyte and macrophage activation [35, 36]. A plausible mechanism for the observed menopause-related increase in innate immune activation may be preventive effects of sex hormones on gut permeability and microbial translocation. Experimental evidence indicates that estrogen and progesterone maintain the gut barrier [14-18], and in human studies progesterone has been inversely correlated with microbial translocation [38, 39]. Thus, declines in estrogen and progesterone during the menopausal transition could impair the gut barrier and increase microbial translocation and immune activation. Aside from effects of menopause on the gut barrier, there may be other mechanisms for menopausal effects on immune activation in HIV. Estradiol and progesterone can inhibit HIV replication and regulate HIV latency [22, 23], suggesting that HIV reactivation may occur during menopause and cause immune activation. The effect of menopause on sCD14 in our study was only observed in women with controlled HIV, suggesting that HIV control may be an important effect modifier although the mechanism is unclear. Estrogens also interact with the gut microbiota [42], which in turn may modulate host immunity in HIV [43, 44]. We did not find an association of menopause with biomarkers of systemic inflammation: IL-6, an inflammatory cytokine, and TNFR1, receptor for the cytokine tumor necrosis factor-α (TNF-α).
In summary, postmenopausal women with HIV had evidence of increased innate immune activation relative to premenopausal women, with this increase occurring during the menopausal transition. However, menopause was not associated with increases in key markers of systemic inflammation, making the consequences of the menopause-related immune activation unclear. Additional longitudinal research following women with HIV through the pre- and postmenopausal stages is necessary to explore whether women who experience an increase in immune activation during menopause also experience increased inflammation and other disease risks. Compounded effects of HIV, aging, and menopause on immune activation could put aging women with HIV at particularly high risk of non-AIDS-related disease and mortality. Thus, research on the health of women with HIV during and after the menopausal transition is of paramount importance, including clinical research on the effectiveness of interventions (eg, health monitoring, lifestyle modifications, hormone therapy) to reduce disease risk.
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Menopause Is Associated With Immune Activation in Women With HIV
The Journal of Infectious Diseases 15 January 2022 Brandilyn A. Peters,1, Xiaonan Xue,1 Lila A. Sheira,2 Qibin Qi,1 Anjali Sharma,3 Nanette Santoro,4 Maria L. Alcaide,5 Igho Ofotokun,6 Adaora A. Adimora,7 Heather S. McKay,8 Phyllis C. Tien,9,10 Katherine G. Michel,11 Deborah Gustafson,12 Bulent Turan,13,aAlan L. Landay,14 Robert C. Kaplan,1,15 and Sheri D. Weiser2,10,
Abstract
Background
Persistent immune activation due to gut barrier dysfunction is a suspected cause of morbidity in HIV, but the impact of menopause on this pathway is unknown.
Methods
In 350 women with HIV from the Women's Interagency HIV Study, plasma biomarkers of gut barrier dysfunction (intestinal fatty acid binding protein; IFAB), innate immune activation (soluble CD14 and CD163; sCD14, sCD163), and systemic inflammation (interleukin-6 and tumor necrosis factor receptor 1; IL-6, TNFR1) were measured at 674 person-visits spanning ≤2 years.
Results
Menopause (post- vs premenopausal status) was associated with higher plasma sCD14 and sCD163 in linear mixed-effects regression adjusting for age and other covariates (β = 161.89 ng/mL; 95% confidence interval [CI], 18.37-305.41 and 65.48 ng/mL, 95% CI, 6.64-124.33, respectively); but not with plasma IFAB, IL-6, or TNFR1. In piece-wise linear mixed-effects regression of biomarkers on years before/after the final menstrual period, sCD14 increased during the menopausal transition by 250.71 ng/mL per year (95% CI, 16.63-484.79; P = .04), but not in premenopausal or postmenopausal periods.
Conclusions
In women with HIV, menopause may increase innate immune activation, but data did not support an influence on the gut barrier or inflammation. Clinical implications of immune activation during menopausal transition warrant further investigation.
Human immunodeficiency virus (HIV) infection leads to persistent immune activation and inflammation even with antiretroviral therapy (ART), which may contribute to higher risk of non-AIDS-related conditions (eg, cardiovascular disease [CVD], cancer) [1]. There are several hypothesized causes of immune activation in HIV, including low-level viral replication, coinfections, lymphoid fibrosis, and microbial translocation [2]. Microbial translocation is a process in which damage to the gut epithelial barrier, caused by HIV infection, allows microbial products to translocate from gut to circulation, activating an innate immune response [3]. Gut barrier dysfunction and innate immune activation have been associated with CVD and mortality in treated HIV infection [4-10]. Understanding drivers of immune activation and inflammation in HIV is important for prevention of non-AIDS-related diseases [11].
A recent report of 65 women without HIV found that biomarkers of gut barrier dysfunction, microbial translocation, and immune activation increased during the menopausal transition [12]. Menopause marks the end of the reproductive phase of a woman's life, when complete depletion of ovarian follicles leads to loss of ovarian production of sex hormones estradiol and progesterone [13]. Both hormones appear important for gut barrier integrity [14-18], and estradiol also has well known cardioprotective properties [19-21]. In the context of HIV infection, estradiol and progesterone can inhibit HIV replication and are thought to maintain HIV latency [22, 23]. Women with HIV have lower estradiol and ovarian reserve [24, 25], higher levels of microbial translocation and immune activation [26], and higher cardiovascular risks [27-29] than women without HIV, suggesting that menopause-related decline in sex hormones may pose unique morbidity risks. However, the effect of the menopausal transition on microbial translocation, immune activation, and inflammation is unknown in women with HIV.
Here, we examined the association of menopause status with plasma biomarkers of gut barrier dysfunction, innate immune activation, and systemic inflammation in women with HIV from the Women's Interagency HIV Study (WIHS). Additionally, we explored changes in these biomarkers over time relative to the final menstrual period, to understand effects of the menopausal transition above those of chronological aging alone [30].
Postmenopausal women had an estimated 161.89 ng/mL (95% CI, 18.37-305.41) and 65.48 ng/mL (95% CI, 6.64-124.33) higher plasma sCD14 and sCD163, respectively, than premenopausal women (P = .03 for both). A significant association of menopause status with plasma IFAB was attenuated upon adjustment for age, while menopause status was not associated with plasma IL-6 or TNFR1 in unadjusted or adjusted models (Table 3). Results were similar in a sensitivity analysis matching pre- and postmenopausal person-visits on age (Supplementary Table 2), despite reduced sample size due to exclusion of person-visits that could not be matched on age. Results were also similar in sensitivity analyses excluding premenopausal person-visits for women that later had surgical menopause, or excluding premenopausal person-visits for women who did not have a menstrual period within the last 3 months (Supplementary Tables 3 and 4). Interestingly, the association of menopause with sCD14 was only observed among women with controlled HIV (undetectable viral load and CD4 count ≥ 500 cells/mm3; P interaction = .03; Supplementary Table 5).
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