Treatment with High Estrogen, Progesterone Concentrations Downregulate Replication in HIV-1-Infected Cells

Indira Hewlett, PhD, FDA, US Food and Drug Administration

Indira Hewlett, PhD

A new study published in PLoS One demonstrated that the pretreatment of monocyte derived macrophages (MDMs) with high concentrations of estrogen and progesterone results in the downmodulation of proinflammatory cytokine and chemokine expression as well as the downregulation of HIV-1 replication.¹

“[Our] data implies that the inhibitory effect of estrogen and progesterone may be mediated through the engagement of estrogen and progesterone receptors,” according to study investigator Indira Hewlett, PhD, et al. “A probable mechanism for the regulatory effect exerted by estrogen and progesterone could be due to modulation of chemokine receptors that serve as co-receptors for HIV-1 entry.”

Investigators of this study sought to determine the molecular mechanisms of HIV-1 replication downregulation and associated antiviral responses following exposure to estrogen and progesterone treatment. After leukapheresis, the researchers isolated human monocytes from peripheral blood mononuclear cells of male and female donors who were seronegative for HIV-1.

All primary MDMs were cultured for a total of 5 days and subsequently infected with HIV-1 Ba-L, isolates of HIV-1 subtype B-NSI, and HIV-1 subtype C-NSI. Infected MDMs were pretreated with 0.6 nM mifepristone or 5 μM tamoxifen and then exposed to 110 nM estrogen or 64 nM progesterone. The researchers also used varying concentrations of the 2 hormones to determine the effect of low versus high concentrations on replication/modulation.

A modest increase in HIV-1 BaL replication was found among all MDMs that were pretreated with 140 pM and 40 pM of estrogen as well as 2.5 nM and 1 pM of progesterone. Similar findings were observed among HIV-1 subtype B and HIV-1 subtype C MDMs who were exposed to low estrogen and progesterone concentrations. Based on these findings, the investigators decided to increase the administered estrogen and progesterone concentrations.

Using 1.75 μM estrogen, an approximately 60% decrease in HIV-1 replication was observed among HIV-1 BaL-infected MDMs. Additionally, the investigators discovered that a 64 nM progesterone pretreatment of HIV-1 BaL-infected MDMs was associated with a 45% downregulation of HIV-1 replication. These results indicated a clear advantage of using higher hormone concentrations for facilitating downregulation.

Following quantification of chemokine and cytokine concentrations in culture supernatant, the investigators observed downregulation of IL-1β, IL-6 cytokines as well as CXCL9, CXCL10, and CXCL11 chemokines in HIV-1-infected cells following exposure to high estrogen and progesterone concentrations. Among the cells treated with high progesterone concentrations, cytokines IL-18, IL-6, IL-1β, TNF-α, and interferon-responsive genes CXCL9 and CXCL10 were downregulated.

In addition, pre-treatment of infected cells with mifepristone and tamoxifen resulted in a reversal of inhibitor mechanisms mediated by treatment with estrogen and progesterone.

“The HIV-1 long terminal repeat is known to contain hormone-response elements and the activation of hormone receptors by ligands could modulate HIV-1 transcription through direct interaction with these elements, or by regulating DNA binding and transcriptional activation of other cellular transcription factors,” concluded the investigators. “Thus, the regulation of HIV-1 replication by steroid hormones may be a result of the interplay between transcriptional activation of the HIV-1 LTR and modulation of cytokine and chemokine expression and secretion.”

REFERENCE

1. Devadas K, Biswas S, Ragupathy V, et al. Modulation of HIV replication in monocyte derived macrophages (MDM) by steroid hormones. PLoS One. 2018;13(1):e0191916.

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