hiv-1 subtype b protease and reverse transcriptase amino acid covariationhiv - 1亚型b蛋白酶和逆转录酶氨基酸共变.pdfVIP

HIV-1 Subtype B Protease and Reverse Transcriptase Amino Acid Covariation 1 1 2 1* Soo-Yon Rhee , Tommy F. Liu , Susan P. Holmes , Robert W. Shafer 1 Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, California, United States of America, 2 Department of Statistics, Stanford University, Stanford, California, United States of America Despite the high degree of HIV-1 protease and reverse transcriptase (RT) mutation in the setting of antiretroviral therapy, the spectrum of possible virus variants appears to be limited by patterns of amino acid covariation. We analyzed patterns of amino acid covariation in protease and RT sequences from more than 7,000 persons infected with HIV-1 subtype B viruses obtained from the Stanford HIV Drug Resistance Database (). In addition, we examined the relationship between conditional probabilities associated with a pair of mutations and the order in which those mutations developed in viruses for which longitudinal sequence data were available. Patterns of RT covariation were dominated by the distinct clustering of Type I and Type II thymidine analog mutations and the Q151M-associated mutations. Patterns of protease covariation were dominated by the clustering of nelfinavir- associated mutations (D30N and N88D), two main groups of protease inhibitor (PI)–resistance mutations associated either with V82A or L90M, and a tight cluster of mutations associated with decreased susceptibility to amprenavir and the most recently approved PI darunavir. Different patterns of covariation were frequently observed for different mutations at the same position including the RT mutations T69D versus T69N, L74V versus L74I, V75I versus V75M, T215F versus T215Y, and K219Q/E versus K219N/R, and the protease mutations M46I