Progesterone augments cell susceptibility to HIV-1 and HIV-1/HSV-2 co-infections

Abstract

In human immunodeficiency virus type 1 (HIV-1)-infected women, oral or injectable progesterone containing contraceptive pills may enhance HIV-1 acquisition in vivo, and the mechanism by which this occurs is not fully understood. In developing countries, Herpes simplex virus type-2 (HSV-2) co-infection has been shown to be a risk for increase of HIV-1 acquisition and, if co-infected women use progesterone pills, infections may increase several fold. In this study, we used an in vitro cell culture system to study the effects of progesterone on HIV-1 replication and to explore the molecular mechanism of progesterone effects on infected cells. In our in vitro model, CEMss cells (lymphoblastoid cell line) were infected with either HIV-1 alone or co-infected with HSV-2. HIV-1 viral load was measured with and without sex hormone treatment. Progesterone-treated cells showed an increase in HIV-1 viral load (1411.2 pg/mL) compared with cells without progesterone treatment (993.1 pg/mL). Increased cell death was noted with HSV-2 co-infection and in progesterone-treated cells. Similar observations were noted in peripheral blood mononuclear cells (PBMC) cells derived from three female donors. Progesterone-treated cells also showed reduced antiviral efficacy. Inflammatory cytokines and associations with biomarkers of disease progression were explored. Progesterone upregulated inflammatory cytokines and chemokines conversely and downregulated anti-apoptotic Bcl-2 expression. Nuclear protein analysis by electrophoretic mobility shift assay showed the association of progesterone with progesterone response element (PRE), which may lead to downregulation of Bcl-2. These data indicate that progesterone treatment enhances HIV-1 replication in infected cells and co-infection with HSV-2 may further fuel this process.

Sex Drives Dimorphic Immune Responses to Viral Infections

“…Studies in ovariectomized mouse models have indicated that progesterone treatment increases the susceptibility of females to genital HSV-2 infection whereas estrogen treatment helps clear the infection rapidly. Interestingly, combined treatment of estrogen and progesterone in ovariectomized mice depicted increases the infection spread accompanied by persistent inflammation and neutrophil infiltration (125, 126). Although studies do not directly indicate the organizational effect but effect of estrogen and progesterone in ovariectomized animals suggests effect of sex hormones in HSV-2 infection.…”

Association of Genetic Polymorphisms in TLR3, TLR4, TLR7, and TLR8 with the Clinical Forms of Dengue in Patients from Veracruz, Mexico

“…In women infected with HIV-1, contraceptive pills containing progesterone increase the susceptibility to the infection in vivo. It has also been observed that the treatment with progesterone increases the replication of HIV-1 in cells [40]. The reduced expression of PR and a high viral load result in a precarious pregnancy in hepatitis E [41].…”

Changes to the World Health Organization guideline on hormonal contraceptive eligibility for women at high risk of HIV: South African perspective and response

“…The possible mechanisms are: • architectural changes in female genital tract [2][3][4] • epithelial thinning or disruption • alteration in tight junctions • alteration of adhesions • alteration in microbiome, e.g. vaginal flora [3,4] • enhanced HIV replication [5] • increase in HIV susceptibility markers in the genital tract [5] • impact on immune response [4,6] • increased frequency of activated HIV targets cells at the cervix. [7]…”