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138 Evolution of Promoter Activities of Attenuated Strains of HIV-1
M. J. Churchill*, I. de Castella, D. Rhodes, D. McPhee, and N. Deacon
Macfarlane Burnet Ctr. for Med. Res., Fairfield, Victoria, Australia
Background: A group of HIV-1-infected long-term symptomless persons were reported in 1992 and subsequently found to be infected with a nef-defective strain of HIV-1. This group comprised a common blood donor and 8 transfusion recipients known as the Sydney Blood Bank Cohort (SBBC). The viral quasi species present within several of these cohort members has been investigated. Two of the cohort members, C98 and D36, have shown changes in the nef/LTR sequences over the past 5 years with the more recent evolved species having larger deletions. Both C98 and D36, have lost approximately 200 bp of additional sequence from the nef/LTR region during this period and changes have now been observed within the basal promoter. More recently recipients C54 and C64 have also shown further deletion in this region.
Methods: A sensitive viral fitness assay has been established to examine the role of the nef/LTR changes on viral replication. Transcription assays have been used to examine the effects of LTR mutations on viral promoter activities.
Results: Chimeric viruses containing smaller nef/LTR sequences are fitter than chimeras containing the larger nef/LTR forms in both T-cell tropic and macrophage tropic backgrounds. Whereas the Nef protein associated with these sequences remains constant, the nef/LTR sequences have evolved. The promoter activities of the various LTR sequences have now been analysed, and results suggest there has been an evolution to a more transcriptionally active promoter sequences for all of the cohort members examined. The most recent D36 isolate having a promoter activity similar to wild-type virus.
Conclusions: Viral fitness and transcription studies are in agreement that 2 of the SBBC HIV-1 strains are evolving into fitter viral strains through viral promoter improvement although they remain less replication competent than wild-type HIV-1.
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