Luteal phase progesterone levels increase HIV-1 replication ex vivo by a mechanism different to immune cell activation as induced by MPA, used in injectable contraception
Alexis J. Bick1, Chanel Avenant1, Michele Tomasicchio2 & Janet P. Hapgood1,3 1Department of Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa; 2Centre for Lung Infection and Immunity, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa; 3Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa
Relatively high levels of endogenous progesterone (P4) found in the luteal phase (LP) of the menstrual cycle have been linked to increased HIV-1 acquisition in several models. Current epidemiological data showing that the use of the injectable contraceptive Depo-medroxyprogesterone acetate (Depo-MPA) is associated with increased HIV-1 acquisition is controversial. Recently, MPA has been shown to increase immune cell activation and expression of the HIV-1 co-receptor CCR5, on CD4+ T-cells. It has been hypothesized that the mechanisms of increased HIV-1 infection may be similar in women during the LP compared to women using DMPA. To investigate this hypothesis, peripheral blood mononuclear cells (PBMCs) and TZM-bl cervical cells were stimulated with P4 and estrogen at concentrations mimicking the LP, follicular phase (FP) or with levels of MPA at the upper range of peak serum levels detected in DMPA users. Cells were infected with the R5-tropic HIV-1 infectious molecular clone, HIV-1Bal_Renilla and the amount of Renilla was measured as a proxy for HIV-1 infection. Levels of HIV-1 CCR5 co-receptor protein or mRNA expression were measured by flow cytometry or qPCR, respectively, while activation of CD4+ T-cells was measured by flow cytometry in PBMCs. MPA increased HIV-1 replication in both PBMCs and TZM-bl cells, while LP hormones did so to a lower extent. However, while MPA increased CCR5 expression on CD4+ T-cells in PBMCs, as well as increased total CCR5 mRNA expression in TZM-bl cells, LP hormones did not change CCR5 levels in either model. In addition, MPA, but not LP hormones, increased the frequency of activated (CD69+) CD4+ T-cells in PBMCs. Lastly, using a GR antagonist or GR siRNA, it was shown that the GR is required for MPA-, but not LP hormone-induced increased HIV-1 replication in PBMCs and TZM-bls. FP hormones did not increase HIV-1 infection, CCR5 mRNA or protein or activation of PBMCs. Taken together, MPA increases HIV-1 infection in a manner different from that of LP hormones, which likely involves activation and increased expression of the HIV-1 co-receptor CCR5 on CD4+ T-cells.
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