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Abstract & Commentary
Activation of HIV by STI Pathogens
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Synopsis: HSV-1/2, N. gonorrhoeae, and TLR ligands directly induced HIV-LTR activation in T cells in cell culture. Additionally, supernatants obtained from genital epithelial cells (GEC) exposed to TLR ligands and sexually transmitted infection (STI) pathogens also induced LTR activation in T cells. Inhibition of nuclear factor kB (NFkB) and activator protein-1 (AP-1) signaling pathways abrogated HIV-LTR activation.
Sources: Ferreira VH, et al. Endometrial epithelial cell responses to coinfecting viral and bacterial pathogens in the genital tract can activate the HIV-1 LTR in an NFkB- and AP-1- dependent manner. J Infect Dis 2011;204:299-308.
The authors conducted a series of experiments in which HIV-1 transfected 1G5 T cells were exposed to either a series of known long terminal repeat (TLR) ligands (FimH/TLR-4, flagellin/TLR-5, and poly I:C/TLR-3) or STI pathogens (HSV-1, HSV-2, and N. gonorrhoeae). Direct LTR activation in 1G5 cells was measured with a luciferase assay. Indirect activation of the HIV-LTR in 1G5 cells by these substances was assessed as follows: Primary human GECs growing confluently as a monolayer in culture were treated with the same TLR ligands and STI pathogens as the T-cell line in the initial experiments, then washed five times with PBS after incubation and replaced with fresh media. After 24 hours, the supernatant from the GECs was added to the 1G5 cells. The cells were lysed after an additional 24 hours of incubation and luciferase activity was measured. LTR activation was demonstrated both directly by application of the antigens to the T-cell line and indirectly by incubation of the T-cells in supernatant from the GECs. Both direct and indirect activation of HIV-LTR was shown to be abrogated by pretreatment of the T-cell line with PDTC (an inhibitor of NFkB activation) and with both a MAP kinase inhibitor and a JNK inhibitor (the latter two pathways activate AP-1).
While this study is very much a "basic science" paper, it nicely sheds light on the inter-relationship between co-infection with STI pathogens and activation of HIV replication in the presence of these pathogens. The LTR is a promoter region present at both the 5' and 3' end of the 9.4 kB HIV-1 genome. As with most regions of retrovirus genomes, these promoter regions picked up genes from their hosts over centuries of time. The HIV-LTR is particularly interesting since it contains numerous mammalian promoter/enhancer genes including AP-1, SP-1, NFAT, and NFkB. The experiments nicely demonstrate that TLR ligands, HSV-1, HSV-2, and N. gonorrhoeae can both directly activate HIV-LTR and indirectly activate HIV-LTR by their effect on GECs via pro-inflammatory signaling pathways. This increased HIV-1 replication, resulting from increased viral transcription, may enhance sexual and vertical HIV transmission.