Potential Mechanisms for Increased HIV-1 Transmission Across the Endocervical Epithelium During C. trachomatis Infection

Among the now pandemic sexually transmitted infections (STIs), Chlamydia trachomatis (C. trachomatis) is the predominant bacterial pathogen and human immunodeficiency virus type 1 (HIV-1) is the most lethal of the viral pathogens. The female genital tract is the primary site for heterosexual transmission of both C. trachomatis and HIV-1. Infection with C. trachomatis, and with a variety of other STIs, increases the risk for transmission of HIV-1, although the mechanisms for this finding remain unclear. We have used in vitro modeling to assess the mechanisms by which infection with genital C. trachomatis serovars might increase the transmission of HIV-1 across the female genital tract. C. trachomatis infection of an immortalized endocervical epithelial cell line (A2EN) increases the cell surface expression of the HIV-1 alternative primary receptor, galactosyl ceramide (GalCer), and of the HIV-1 co-receptors, CXCR4 and CCR5. C. trachomatis infection also increases the binding of HIV-1 to A2EN cells, and, subsequently, increases levels of virus in co-cultures of HIV-exposed A2EN and susceptible MT4-R5 T cells. Finally, in vivo endocervical cell sampling reveals a dramatic increase in the number of CD4+, CXCR4 and/or CCR5 positive T cell targets in the endocervix of C. trachomatis positive women when compared to those who are C. trachomatis negative. This combination of in vitro and in vivo results suggests several mechanisms for increased transmission of HIV-1 across the endocervices of C. trachomatis-infected women.