Interactions between human immunodeficiency virus type 1 and human cytomegalovirus in human term syncytiotrophoblast cells coinfected with both viruses

Abstract

Human cytomegalovirus (HCMV) and human immunodeficiency virus type 1 (HIV-1) may interact in the pathogenesis of AIDS. The placental syncytiotrophoblast layer serves as the first line of defense of the fetus against viruses. We analyzed the patterns of replication of HIV-1 and HCMV in singly an dually infected human term syncytiotrophoblast cells cultured in vitro. Syncytiotrophoblast cells exhibited restricted permissiveness for HIV-1, while HCMV replication was restricted at the level of immediate-early and early gene products in the singly infected cells. We found that the syncytiotrophoblasts as an overlapping cell population could be coinfected with HIV-1 and HCMV. HIV-1 replication was markedly upregulated by previous or simultaneous infection of the cells with HCMV, whereas prior HIV-1 infection of the cells converted HCMV infection from a nonpermissive to a permissive one. No simultaneous enhancement of HCMV and HIV-1 expression was observed in the dually infected cell cultures. Major immediate-early proteins of HCMV were necessary for enhancement of HIV-1 replication, and interleukin-6 production induced by HCMV and further increased by replicating HIV-1 synergized with these proteins to produce this effect. Permissive replication cycle of HCMV was induced by the HIV-1 tat gene product. We were unable to detect HIV-1 (HCMV) or HCMV (HIV-1) pseudotypes in supernatant fluids from dually infected cell cultures. Our results suggest that interactions between HIV-1 and HCMV in coinfected syncytiotrophoblast cells may contribute to the transplacental transmission of both viruses.

Placental trophoblasts resist infection by multiple human immunodeficiency virus (HIV) type 1 variants even with cytomegalovirus coinfection but support HIV replication after provirus transfection

“…Our results show that CT and ST, although readily infected by CMV, did not become susceptible to HIV-1 when challenged with both viruses. These results differ from those of Toth et al (64), who found that ST were unable to support late stages of CMV replication but coinfection of ST with CMV and HIV-1 greatly enhanced HIV-1 production. The reasons for these discrepancies are unclear.…”

“…These observations suggest that trophoblasts with even low levels of stromal cell contamination may manifest infection not only because stromal cells may be selective targets for HIV infection but also because, if infected, they may deliver virus efficiently to adjacent trophoblasts in a cell-mediated manner. Pure trophoblast preparations have been previously reported to be infected by HIV-1, albeit at low levels (27,64). There are several possible reasons for differences in results.…”

“…In this regard, vertical transmission has been shown to be primarily associated with NSI macrophage-tropic variants (66) as well as with specific minor subtypes within the maternal HIV repertoire as determined by V3 region typing (3). However, there are no reports of in vitro HIV infection of placental cells with primary HIV-1 isolates, and most studies of HIV infection of placental cells in vitro have used well-characterized laboratory strains (24,47,64). Here we examined the possibility that differences in viral type accounted for the disparity in reports of trophoblast infection.…”

Permissive Cytomegalovirus Infection of Primary Villous Term and First Trimester Trophoblasts

“…Possible reasons include the following: (i) there is a disadvantageous target ratio (there are Ͼ4,000-fold more trophoblasts); (ii) infected vimentin-positive cells may lyse and not be detected, although lack of high titers of infectious virus in supernatants during the first week of culture argues against this; (iii) fibroblasts, which strongly adhere to tissue culture plastic, may lie beneath the trophoblasts and be protected from virus challenge; and (iv) EGF down modulates CMV production from infected placental fibroblasts as it does with other human fibroblasts (30). Our results differ from those of Toth et al (59), who found that CMV infection of syncytialized term trophoblasts was abortive and became fully permissive only if the cells were preinfected with HIV-1. The reasons for the different results are not clear, but it is possible that different CT subpopulations were isolated by the slightly different negative selection methods used in the two laboratories: elimination of MHC class I, MHC class II, and CD9-expressing cells in our laboratory (28) and elimination of MHC class I and II cells in their laboratory (59).…”

HIV-1 Tat protein: A target for the development of anti-AIDS therapies

“…Therefore, extracellular Tat has been implicated in the development of hypervascularized KS (7). Furthermore, extracellular Tat transactivates the genome of human herpes virus 8 (15), hepatitis virus C (16) and human cytomegalovirus (17), thus favoring secondary infections. And finally, extracellular Tat induces upregulation of a wide spectrum of cytokines, chemokines, growth factors and their receptors (4).…”