IDENTIFICATION OF A REPLICATION-COMPETENT PATHOGENIC HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 WITH A DUPLICATION IN THE TCF-1-ALPHA REGION BUT LACKING NF-KAPPA-B BINDING-SITES

Multiple human immunodeficiency virus type 1 (HTV-1) sequences with de letions of NF-kappa B binding sites at both the 5' and 3' long termina l repeats (LTRs) were identified in serial samples collected from an i nfected individual. The effect of this deletion on the level of transc ription was studied by transient transfection of an LTR-driven lucifer ase reporter gene and by infection with a full-length recombinant HIV- 1 containing a luciferase reporter (HIVHXBluc). Detectable levels of g ene expression were found in both systems, in the presence or absence of the viral transactivator Tat. Interestingly, a duplication of a put ative TCF-1 alpha motif was found in place of the NF-kappa B elements in these viruses. Higher transcriptional activity was observed with HX BLTR (NF-kappa B intact) than with the patient's LTR (NF-kappa B delet ed), suggesting that the NF-kappa B binding sites may promote optimal levels of viral gene transcription. The ability of these viruses with NF-kappa B deleted to replicate and cause substantial decline in CD4 c ell counts demonstrates that the NF-kappa B binding sites are not abso lutely required for viral replication or pathogenicity in vivo. These results are consistent with the notion that the HIV-1 LTR possesses fu nctional redundancy which allows it to interact with multiple transcri ption factors, thereby ensuring viral replication in a variety of cell types.