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Susceptibility of Feline Immunodeficiency Virus/Human Immunodeficiency Virus Type 1 Reverse Transcriptase Chimeras to Non-Nucleoside RT Inhibitors

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium (J.A., E.D.C., J.B.); and the Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Oxford, United Kingdom (R.E.)

To map the determinants of the lack of susceptibility of feline immunodeficiency virus (FIV) reverse transcriptase (RT) to anti human immunodeficiency virus type 1 (HIV-1) non-nucleoside RT inhibitors (NNRTIs), a variety of chimeric HIV-1/FIV RTs were constructed. The majority of chimeric RTs had an affinity (K_m) for their natural substrates comparable with that of the wild-type HIV-1 and FIV RTs, but their catalytic efficacy was decreased. Whereas HIV-1 RT could be made entirely insensitive to NNRTIs by exchanging the amino acid sequence 97 through 205 of FIV RT, none of the reverse FIV/HIV-1 RT chimeras gained susceptibility to NNRTIs. The amino acids that are thought to be involved in NNRTI susceptibility and that are different from those in HIV-1 RT have also been introduced in FIV RT. These mutant RTs gained virtually no susceptibility to efavirenz or capravirine. Vice versa, when these HIV-1-specific amino acids were replaced by their FIV RT counterparts in HIV-1 RT, susceptibility to the NNRTIs was lost. Thus, replacing segments or substituting relevant amino acids in FIV RT by their HIV-1 RT counterparts did not suffice to make FIV RT sensitive toward NNRTIs and was often accompanied by a decrease or even total loss of polymerase activity. It is postulated that, in contrast to the results found for HIV-1/HIV-2 RT chimeras and supported by the crystal structure of HIV-2 RT, there exist significant differences in the structure and/or flexibility of FIV RTs that may prevent NNRTIs from interacting with the FIV RT.

Address correspondence to: Jan Balzarini, Rega Institute for Medical Research, Minderbroedersstraat 10, 3000 Leuven, Belgium. E-mail: jan.balzarini{at}rega.kuleuven.ac.be

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