The role of the long terminal repeat (LTR) in the pathogenesis of human immunodeficiency virus type 2 (HIV-2)
Recent data has indicated that the prolonged asymptomatic phase and freedom from clinical illness experienced by the majority of HIV-2 infected individuals results from a lower level of virus production during infection than that observed in either HIV-1 infection or in the small number of HIV-2 infected individuals displaying relatively rapid progression to disease. The rate at which viral gene products are transcribed is one mechanism by which the rate of virus production can be controlled and is mediated by the Long Terminal Repeat (LTR) regions of the HIV-2 genome. A limiting dilution sensitive nested PCR has been developed to amplify the HIV-2 LTR from clinically and phenotypically characterised infected sources, including a number of HIV-2 isolates and uncultured PBMC samples derived from Gambian HIV-2 infected long-term non-progressor (LTNP) and rapid progressor (RP) patients. Using a highly efficient cloning system LTR amplicons have been cloned into a firefly luciferase reporter vector. A dual luciferase reporter assay has been used to determine LTR-directed basal and Tat transactivated levels of transcription in physiologically relevant cell lines. LTRs derived from LTNP patients tended to direct lower levels of basal and Tat transactivated transcription when compared to LTRs derived from RP patients. The difference between the two groups was more pronounced in the T cell-like Jurkat cell-line. Nucleotide sequence analyses of the LTR clones has revealed that the rate of general and G-to-A mutations at single functional sites within the LTR is higher in sequences derived from LTNP patients compared to RP patients. Taken together our data implies a relationship between LTR activity, sequence variation, and overall levels of virus expression in HIV-2 as evidenced by higher levels of circulating peripheral HIV-2 RNA in the patients with progressive disease profiles. Therefore, different LTR responsiveness may relate to different rates of virus production and disease progression rates and hence be a determinant in viral pathogenesis.