Abstract
The estrogen receptor (ER) is hypothesized to directly influence HIV transcription and latency but is also critical for immune signaling. However, the mechanisms of action of the ER in immune cells in the context of HIV are limited, and relevant to HIV cure strategies, the influence of latency reversal agents (LRAs) on the ER pathway are unknown. We evaluated (a) the effect of estrogen (E2) on the nuclear translocation of ERα in CD4+ T cells; (b) the ability of Fulvestrant, a selective estrogen receptor degrader (SERD), and ARV-471, a potent, PROteolysis TArgeting Chimera (PROTAC) selective ERα degrader to modulate ERα; and c) the effect of different classes of LRAs on ERα signaling. In contrast to what has been demonstrated in oncology, E2 did not induce ERα nuclear translocation in CD4+ T cells. Similarly, neither Fulvestrant nor ARV-471 induced degradation of ERα in CD4+ T cells. LRAs significantly downregulated ERα gene and protein expression in both PBMCs and CD4+ T cells. Collectively, our results suggest that estrogen influences on HIV transcription are not likely a consequence of canonical nuclear ERα mechanisms. The consequences of LRA downregulation of ERα, a protein important for immune signaling, warrant further investigation.
Authors
Cristina Ceriani, Priya Khetan, Anthony Abeyta-Lopez, Kena J. Lemu, Prachi Meher, Brigitte Allard, Katherine S. James, Anne-Marie W. Turner, David M. Margolis, Nancie M. Archin
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