Background:  The course of HIV-1 infection in women differs from that in men, most likely because of the influences of female sex steroid hormones on both viral replication and immune responses to HIV-1. Evidence to support this comes from findings that HIV-1-infected women have a lower plasma viral load and a higher CD4 cell count than HIV-1-infected men. Moreover, women have a greater risk of developing AIDS with the same viral load and CD4 count than men. Our hypothesis is that hormonal fluctuations in endogenous levels of estradiol and progesterone during a woman’s reproductive cycle can influence a woman’s susceptibility to infection by HIV-1 and their subsequent immune responses to virus. We studied the effects of these sex hormones on HIV-1 replication in cultures of peripheral blood mononuclear cells (PBMC).

Methods:  We compared HIV-1 replication in peripheral blood mononuclear cells (PBMC) infected in the presence of mid-secretory (high concentrations of estradiol and progesterone), mid-proliferative (low concentrations of estradiol and progesterone), or in the absence of sex hormones. With PBMC from men, we used concentrations of estradiol and progesterone that are normally present in their plasma.

Results:  Mid-secretory phase concentrations of estradiol and progesterone decreased HIV-1 replication in PBMC from women (p <0.05, Student’s t-test). In contrast, mid-proliferative phase concentrations of these hormones significantly enhanced HIV-1 replication in PBMC from both women and men (p <0.05, Student’s t-test). These effects were not due to changes in cell viability or to CCR5 expression. The addition of an estrogen receptor antagonist restored HIV-1 production to control levels, suggesting that estradiol regulates HIV-1 replication through the estrogen receptor. Using real-time polymerase chain reaction (PCR) and PCR assays, we saw no effects of estradiol and progesterone on HIV-1 reverse transcription or integration. However, mid-secretory phase concentrations of these hormones decreased the constitutive expression of the HIV-1-LTR in TZM-bl cells, a HeLa cell derivative transfected to express CD4, CCR5, and CXCR4, and a luciferase reporter gene under the control of the HIV-1-LTR. In contrast, mid-proliferative phase concentrations increased expression of the LTR, suggesting a transcriptional effect of these hormones.

Conclusions:  These findings suggest that in PBMC, estradiol and progesterone regulate HIV-1 replication, most likely at the level of HIV-1 transcription.