Our results demonstrate that LIF is a potent inhibitor of HIV-1 with an inhibitory concentration in PBMCs at least 1,000-fold less than the reportedly observed inhibitory concentration of the much-studied β-chemokines (RANTES, MIP-1α, MIP-1β) (31
). We also demonstrated that LIF maintains HIV-1 inhibitory activity in three distinct tissue compartments: placenta, PBMCs, and thymus.
Since LIF is constitutively expressed throughout normal pregnancy in the placenta, but not the peripheral blood of pregnant women, the placenta may have an innate ability to inhibit HIV-1 infection. This is supported by the decrease in HIV-1 mRNA and DNA (though only approaching statistical significance) in placenta tissue from nontransmitting women compared with placenta tissue from transmitting women in the present study and by the relatively low placenta levels of HIV-1 DNA in the absence of HIV-1 p24 or gp160 antigen in nontransmitting women from a previous study (25
). This pattern of decreased HIV-1 DNA and mRNA is consistent with the pre-reverse transcription mechanism of LIF anti–HIV-1 activity and consistent with the results seen in our placenta-explant culture model.
Here, we propose an HIV-inhibition model in the placenta based on the natural role of the placenta in preventing fetal allograft rejection. Establishment and maintenance of pregnancy is thought to be regulated at least in part by the balance of type 1 (Th1) and type 2 (Th2) cytokine responses (32
). Strong Th2 responses inhibit fetal allograft rejection whereas Th1 responses are associated with recurrent abortions (16
). Progesterone, one of the hormones essential for pregnancy, promotes the development of T-helper cells that produce Th2-type cytokines such as IL-4 and IL-10 (33
). IL-4, in turn, upregulates the production of LIF by T cells. Defective production of LIF by decidual T cells has also been linked to unexplained recurrent abortion (16
). The high incidence of recurrent abortion in HIV-infected women (35
) is consistent with a defect in IL-4, IL-10, and LIF production (16
). Moreover, the identification of increased HIV-1–infected cells in abortuses from HIV-1–infected women (35
) suggests an inverse relationship between LIF, Th2 cytokine expression, and HIV-1 infection.
Our findings demonstrate that placentae from nontransmitting women maintained a strong Th2 cytokine milieu whereas placentae from transmitting women showed a Th1 predominance. Consistent with previous reports, our data demonstrate a linkage between Th2 cytokine (IL-4) expression and LIF production. As reported here, LIF produces a potent, HIV coreceptor–independent inhibition of HIV-1 replication. Furthermore, the IC50
of LIF in PBMCs and in tissue-explant cultures is well below the level of LIF produced by CD4+
T-cell clones derived from deciduae of normal women (16
Based on analysis of specific HIV-1 gene products, LIF-induced HIV-1 suppression is exerted before reverse transcription. LIF binds to gp130, a common receptor for a family of cytokines that also includes ciliary neurotropic factor (CNTF), IL-11, oncostatin M, and, paradoxically, the HIV-1–inducing cytokine IL-6 (36
). The activities of these cytokines on HIV-1 most likely differ due to the dimerization of secondary components that transduce different signal cascades. Consequently, LIF binding to gp130-LIFRβ activates the JAK1/STAT signal transduction pathway. IL-6, however, induces homodimerization of gp130 and activates a signal transduction pathway different from LIF (39
). Further study is necessary to elucidate the exact mechanism in this novel HIV-inhibitory pathway.
We cannot conclude, as yet, whether LIF is the CD8-derived (40
), allo-induced (41
), or the hCG-associated (14
) unidentified antiviral factors described previously; however, cell types expressing LIF, including bone marrow stromal cells (42
), CD4 and CD8 T cells (43
), and monocytes/macrophages (44
) are ubiquitous. The pre-reverse transcription site of LIF anti-HIV activity most closely resembles the site of allo-induced anti-HIV activity (41
). This similarity is intriguing given that HLA class I concordance increases perinatal HIV-1 transmission (6
). Though protection in HLA class I discordant pregnancies was suggested to be mediated by a protective allogeneic immune response, the findings from this previous study are consistent with allo-induced LIF expression.
Most importantly, our findings have significant therapeutic implications since progesterone, which can upregulate the positive LIF regulator IL-4, is commonly and safely administered to women with reduced fertility to increase the chances of implantation and term pregnancy. Progesterone has also been shown to be decreased in HIV-1–infected placenta (23
), so progesterone therapy may also be important in order to restore critical hormonal levels in HIV-1–infected women.