Sequence analysis of the HIV-1 protease coding region of 18 HIV-1-infected patients prior to HAART and possible implications on HAART

Fitness Landscape of Human Immunodeficiency Virus Type 1 Protease Quasispecies

“…This diversity allows the quick adaptation of viral quasispecies to environmental changes. For instance, primary (V82A) or secondary (L10I, G16E, K20R, M36VT, D60E, I62V, L63P, A71T, V77I, and N83D) mutations conferring resistance to PIs, as previously described by others (21,28,32), were found in the three quasispecies (Fig. 2) (21, 28, 32).…”

“…To determine the enzymatic activities of the different identified proteases (21,42, and 42 for the M, N, and O quasispecies, respectively), a bacteriophage lambda-based genetic screen was used. This genetic screen is based on the phage lambda regulatory circuit in which the viral repressor cI is specifically cleaved to initiate the lysogenic-tolytic switch (55).…”

Rapid Enzymatic Test for Phenotypic HIV Protease Drug Resistance

“…Even if proteases with a moderate increase of inhibition constants would cause no clinically significant resistance, these proteases are more likely to develop a relevant mutation pattern (Gehringer et al, 2000). Moreover, low phenotypic resistance factors can also be caused by highly resistant 'quasispecies' (Domingo et al, 1985(Domingo et al, , 1995 present in a low percentage of the whole HIV population.…”

Activities of Atazanavir (BMS-232632) against a Large Panel of Human Immunodeficiency Virus Type 1 Clinical Isolates Resistant to One or More Approved Protease Inhibitors

“…However, the extensive use of PIs has led to the emergence of resistant human immunodeficiency virus type 1 (HIV-1) variants that possess various degrees of cross-resistance to other members in the class (13,33). PI-resistant HIV-1 can be isolated from patients treated with current PIs (35) as well as from patients who have not received any treatment with current PIs (5,10,20,21), indicating that transmission of PI-resistant HIV-1 can occur during primary infection. Drug-resistant HIV-1 variants have been detected in as many as 26% of newly infected, treatment-naïve patients.…”

“…Since predicting the susceptibility of atazanavir based solely on the presence of specific amino acids was equally challenging, an attempt was made to correlate the overall number of key substitutions with decreased susceptibility to atazanavir. For this analysis, substitutions at amino acid residues 10,20,24,33,36,46,48,54,63,71,73,82,84, and 90 were considered "key" atazanavir resistance changes because of their strong correlation with loss of susceptibility to atazanavir. Figure 3 is a plot of FC in atazanavir susceptibility for each of the 943 isolates evaluated against the number of the 14 key atazanavir substitutions present.…”