Induction of HIV-1 Replication in Latently Infected Syncytiotrophoblast Cells by Contact with Placental Macrophages: Role of Interleukin-6 and Tumor Necrosis Factor-α

Abstract

The syncytiotrophoblast (ST) layer of the human placenta has an important role in limiting transplacental viral spread from mother to fetus. Although certain strains of human immunodeficiency virus type 1 (HIV-1) may enter ST cells, the trophoblast does not exhibit permissiveness for HIV-1. The present study tested the possibility that placental macrophages might induce replication of HIV-1 carried in ST cells and, further, that infected ST cells would be capable of transmitting virus into neighboring macrophages. For this purpose, we investigated HIV-1 replication in ST cells grown alone or cocultured with uninfected placental macrophages. The macrophage-tropic Ba-L strain of HIV-1, capable of entering ST cells, was used throughout our studies. We demonstrated that interactions between ST cells and macrophages activated HIV-1 from latency and induced its replication in ST cells. After having become permissive for viral replication, ST cells delivered HIV-1 to the cocultured macrophages, as evidenced by detection of virus-specific antigens in these cells. The stimulatory effect of coculture on HIV-1 gene expression in ST cells was mediated by marked tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release from macrophages, an effect caused by contact between the different placental cells. Results of this study suggest an interactive role for the ST layer and placental macrophages in the dissemination of HIV-1 among placental tissue. Data reported here may also explain why macrophage-tropic HIV-1 strains are transmitted preferentially during pregnancy.

The Promiscuous CC Chemokine Receptor D6 Is a Functional Coreceptor for Primary Isolates of Human Immunodeficiency Virus Type 1 (HIV-1) and HIV-2 on Astrocytes

“…Trophoblastic cells can be productively infected with HIV as well as mediating the transplacental transport of virus (2,4,31,33). Therefore, any role of D6 in prenatal mother-to-child transmission should be investigated.…”

“…Once the virus infects its host, usually through the genital or rectal mucosa, it can colonize distinct anatomical sites (4). In addition to the lymphoid tissue, viral infection can be found in astrocytes and microglia in the brain, where it can induce neuropathy and dementia.…”

The Low Viral Production in Trophoblastic Cells Is Due to a High Endocytic Internalization of the Human Immunodeficiency Virus Type 1 and Can Be Overcome by the Pro-inflammatory Cytokines Tumor Necrosis Factor-α and Interleukin-1

“…Second, pretreatment of trophoblastic cells with TNF-␣ and IL-1␤ increased lymphocytic cell adhesion to trophoblastic cells (51). Third, cell contact between macrophages and trophoblasts resulted in up-regulation of HIV-1 expression that was mediated by the release of TNF-␣ and IL-6 by macrophages (52). Based on these published data together with the present findings, it can be proposed that TNF-␣ and IL-1 are produced by HIV-1-infected trophoblastic cells and/or macrophages upon cell contact with trophoblasts.…”

Role of Placental Cytokines in Transcriptional Modulation of HIV Type 1 in the Isolated Villous Trophoblast

“…Previously, it has been reported that cytokines may be involved in the regulation of HIV in the placental trophoblast. 9,11 To obtain further insight into the locally produced factors involved in the control of HIV replication in the trophoblast, we have comprehensively analyzed the complement of cytokines typically present at the maternal-fetal interface for the capacity to modulate transient expression from the HIV long terminal repeat (LTR). In addition, to test for the possibility that virus-specific factors may play a part, we employed two phylogenetically distant HIV strains, which belong to subtype B (HIV-1 LAI) and D (HIV-1 NDK) variants.…”