TFL and SPH contributed reagents/materials/analysis tools

TFL and SPH contributed reagents/materials/analysis tools. mutation pairs and the ten strongest negatively connected protease mutation pairs. Table S1 shows the complete list of 161 statistically significant mutation pairs. Table 1 Forty Highest Positively Correlated Protease Mutation Pairs and Ten Highest Negatively Correlated Protease Mutation Pairs from PI-Experienced Individuals Open in a separate windowpane For the positively connected mutation pairs, Table 1 also contains two columns with data within the temporal order in which correlated mutations occurred in sequences with both mutations from individuals in which an earlier sequence was available that contained only one of the two mutations. For example, the 1st row demonstrates among individuals with both I54V and V82A in whom an earlier sequence contained only one of these two mutations was available, I54V occurred 1st in nine (26%) of 34 people, and V82A occurred 1st in 25 (74%) of 34 people ( 0.01). In contrast, the fourth row demonstrates among individuals with both A71V and L90M, each of the mutations was as likely to happen 1st (26 of 51 versus 25 of BMS-599626 51; = NS). Number S1 plots the relationship between the log of the ratio of the conditional probability of two mutations versus the log of the ratio in which two mutations develop, indicating that the conditional dependence between mutations is definitely highly correlated with the order in which the mutations develop when they happen collectively (r2 = 0.56, 0.001). Among the 18 positively connected pairs in Table 1 containing a major and an accessory PI-resistance mutation (as defined in Methods), the accessory mutation appeared 1st more often in 12 of the 18 pairs. There were several impressive patterns of temporal association among these 18 pairs of correlated major and accessory mutations. The major mutation L90M preceded the accessory mutation G73S in 31 of 34 individuals for whom temporal data were available. In contrast, the accessory mutation L63P preceded L90M in 160 of 172 individuals, and the accessory mutations L10I and A71V preceded the major mutation I84V in 51 of 59 and 35 of 38 individuals, respectively. The Jaccard dissimilarity coefficients associated with 595 pairs of 35 mutations were utilized for a multidimensional scaling. The mutations included in this analysis were the 22 positively connected mutations in Table 1 and 13 additional clinically relevant PI-resistance mutations (L10F, V32I, L33F, I47V, I50V/L, F53L, I54L/M, Q58E, L76V, V82T, and N88S). Number 1 plots the mutations along axes representing the 1st BMS-599626 two principal parts. The first principal component accounted for 10% of the total inertia and separates the nelfinavir-resistance mutations D30N and N88D from the main group of PI-resistance mutations. The second principal component accounted for 7% of the total inertia and separates V82A-connected mutations (I54V, L24I, and M46L) from L90M-connected mutations (M46I, G73S, and I84V). Finally, the lower-left part of the number consists of a cluster with seven of the 11 mutations recently reported to be BMS-599626 associated with phenotypic and medical resistance to the newest PI, darunavir (V32I, L33F, I47V, I50V, I54L/M, and L76V). Open in a separate window Number 1 Multidimensional Scaling of 35 HIV-1 Protease MutationsIncludes the 22 mutations from the mutation pairs with the highest positive association (Table 1) in daring, and 13 additional BMS-599626 clinically relevant protease inhibitor resistance mutations (L10F, V32I, L33F, I47V, I50V/L, F53L, I54L/M, Q58E, L76V, V82T, and N88S). The graph is definitely a 2-D projection of the distances among the 35 mutations, in which the FHF1 range between any two mutations is definitely measured by their Jaccard dissimilarity coefficient among individuals who have received at least one protease inhibitor. At several positions, there was adequate data to contrast covariation patterns for different mutations. For example, M46I/L were each significantly associated with L10I, L24I, V32I, L33F, I54V, V82A, and L90M. However, M46I was distinctively associated with F53L, G73S/T, V82F/T, I84V, and N88S. I54V was significantly associated with L10F, L24I, L33F, M46I/L, G48V, F53L, V82A/F/T, I84V, and L90M. In contrast, I54L/M were significantly connected only with L33F, M46I, I47V, I84V, and L90M. N88D was positively associated with D30N and negatively associated with M46I, whereas N88S was negatively associated with D30N BMS-599626 and positively associated with M46I. Of notice, the divergent associations of different mutations at positions 46 and 88 have previously been reported by Hoffman and coworkers [5]. Among 7,131 pairs of mutations.

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