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The reverse transcriptase sequence of human immunodeficiency virus type 1 is under positive evolutionary selection within the central nervous system

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Abstract

The human immunodeficiency virus type 1 (HIV-1) enters the central nervous system (CNS) during the acute phase of infection and causes AIDS-related encephalitis and dementia in 30% of individuals. Previous studies show that HIV-1 sequences derived from the CNS of infected patients, including the sequence encoding reverse transcriptase (RT), are genetically distinct from sequences in other tissues. The hypothesis of the current study is that the RT sequence of HIV-1 is under positive selection within the CNS. Multiple alignments of non-CNS-derived and CNS-derived HIV-1 RT sequences were constructed using the ClustalW 1.8 program. The multiple alignments were analyzed with the Synonymous/Nonsynonymous Analysis Program. Codon positions 122–125, 135–149, and 166–212 of the CNS-derived RT sequences underwent a greater accumulation of nonsynonymous than synonymous substitutions, which was markedly different from the analysis results of the non-CNS-derived RT sequences. These residues are located in the finger and palm subdomains of the RT protein structure, which encodes the polymerase active site. The analysis of CNS-derived partial-length RT sequences that encompass these regions yielded similar results. A comparison of CNS-derived RT sequences to a non-CNS-derived RT consensus sequence revealed that a majority of the nonsynonymous substitutions resulted in a specific amino acid replacement. These results indicate that reverse transcriptase is under positive selection within the CNS. The amino acid replacements were visualized on a three-dimensional structure of HIV-1 RT using the Sybyl software suite. The protein structure analysis revealed that the amino acid replacements observed among the CNS-derived sequences occurred in areas of known structural and functional significance.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Wright State University School of Medicine, 3640 Colonel Glenn Highway, 45435, Dayton, Ohio, USA

    Kelly J. Huang, Gerald M. Alter & Dawn P. Wooley

  2. Center for Retrovirus Research, The Ohio State University, Columbus, Ohio, USA

    Dawn P. Wooley

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  1. Kelly J. Huang
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  2. Gerald M. Alter
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  3. Dawn P. Wooley
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Correspondence to Dawn P. Wooley.

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The Biomedical Sciences PhD Program supported KJH. Public Health Service Grant CA72239 from the National Institutes of Health and a Research Challenge Grant from the state of Ohio supported this research.

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Huang, K.J., Alter, G.M. & Wooley, D.P. The reverse transcriptase sequence of human immunodeficiency virus type 1 is under positive evolutionary selection within the central nervous system. Journal of NeuroVirology 8, 281–294 (2002). https://doi.org/10.1080/13550280290100716

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