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Background  Pandemic strains of HIV-1 (group M) encode a total of nine structural ( gag ,  pol ,  env ), regulatory ( rev ,  tat ) and accessory ( vif ,  vpr ,  vpu ,  nef ) genes. However, some subtype A and C viruses exhibit an unusual gene arrangement in which the first exon of  rev  ( rev1 ) and the  vpu  gene are placed in the same open reading frame. Although this  rev1 - vpu  gene fusion is present in a considerable fraction of HIV-1 strains, its functional significance is unknown.    Results  Examining infectious molecular clones (IMCs) of HIV-1 that encode the  rev1-vpu  polymorphism, we show that a fusion protein is expressed in infected cells. Due to the splicing pattern of viral mRNA, however, these same IMCs also express a regular Vpu protein, which is produced at much higher levels. To investigate the function of the fusion gene, we characterized isogenic IMC pairs differing only in their ability to express a Rev1-Vpu protein. Analysis in transfected HEK293T and infected CD4+ T cells showed that all of these viruses were equally active in known Vpu functions, such as down-modulation of CD4 or counteraction of tetherin. Furthermore, the polymorphism did not affect Vpu-mediated inhibition of NF-кB activation or Rev-dependent nuclear export of incompletely spliced viral mRNAs. There was also no evidence for enhanced replication of Rev1-Vpu expressing viruses in primary PBMCs or  ex vivo  infected human lymphoid tissues. Finally, the frequency of HIV-1 quasispecies members that encoded a  rev1 - vpu  fusion gene did not change in HIV-1 infected individuals over time.    Conclusions  Expression of a  rev1-vpu  fusion gene does not affect regular Rev and Vpu functions or alter HIV-1 replication in primary target cells. Since there is no evidence for increased replication fitness  of rev1-vpu  encoding viruses, this polymorphism likely emerged in the context of other mutations within and/or outside the  rev1-vpu  intergenic region, and may have a neutral phenotype.

A Naturally Occurring rev1-vpu Fusion Gene Does Not Confer a Fitness Advantage to HIV-1