Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV-1-infected patients

Abstract

Clonal analysis strongly suggests that the two main genetic pathways, 155 and 148, involved in the development of resistance to raltegravir are independent and exclusive. Moreover, the switch of the resistance profile from 155 to 148 may be related to the higher level of resistance to raltegravir conferred by the 148 pathway and also to the higher instability of the 155 pathway.

Substitutions at Amino Acid Positions 143, 148, and 155 of HIV-1 Integrase Define Distinct Genetic Barriers to Raltegravir Resistance In Vivo

“…Together, the data reported here and in previous studies (8,20) demonstrate that RAL-resistant viruses emerge via multiple pathways within and among individual patient virus populations. Furthermore, shifts from one pathway to another occur in the presence of continued RAL pressure (23) and are driven by the relative selective advantages conferred by the specific constellation of primary and secondary mutations that emerge within a patient virus population.…”

“…Additional resistance mutations resulting in amino acid substitutions V72I, L74I or L74M, E92Q, T97A, F121Y, E138K, G140S or G140A, V151I, E157Q, G163R, I203M, and S230R have also been described (D. Cooper and B. Nguyen, presented at the 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, CA, 25 to 28 February 2007) (19,21). Recent studies have reported that the primary resistance mutations N155H and Q148R, Q148H, or Q148K represent mutually exclusive and nonoverlapping pathways (8,20). With the exception of T66I, viruses that acquire resistance to EVG exhibit similar mutation profiles (N155H, Q148R, H, or K, as well as E92Q); thus, EVG-resistant viruses generally exhibit cross-resistance to RAL and vice versa (10,11,28).…”

“…For the most part, RAL-and EVG-resistant variants remain susceptible to DLG (S/GSK1349572), which, in vitro, selects for a distinct mutation profile that includes L101I, T124A, and S153F or Y (16). A notable exception may be viruses containing mutations at position 148, which in vitro can exhibit reduced susceptibility to DLG when they also contain specific secondary mutations (16) Studies evaluating sequential virus samples have reported shifts in primary IN inhibitor resistance mutation patterns in subjects remaining on RAL following virologic treatment failure (3,5,9,20,22,23). Specifically, in RAL phase II and III clinical trials, investigators noted that N155H variants detected at the first fail-ure time point were frequently replaced by Q148H, K, or R variants at later time points in the presence of ongoing RAL exposure (22,23).…”

Selective-Advantage Profile of Human Immunodeficiency Virus Type 1 Integrase Mutants Explains In Vivo Evolution of Raltegravir Resistance Genotypes

“…The development of such resistance has been best studied for raltegravir, which is currently the only INSTI that has been approved for clinical use. Virological studies conducted in HIV-1-infected patients developing resistance to raltegravir have shown that resistance to this drug can follow three main genetically distinct mutational pathways (6,11,17). The N155 pathway is based on emergence of mutation N155H, which can be followed by selection of other integrase mutations such as E92Q.…”

“…(i) The N155 pathway is generally observed early in the evolution of resistance and, after several weeks of HIV-1 evolution under pharmacological pressure by raltegravir, is replaced in most instances by emergence of mutations belonging to the Q148 or to the Y143 pathway (6,17). (ii) Clonal analyses of viral quasispecies present in patients failing raltegravir have shown that viral genomes carrying mutations from different resistance pathways can coexist and coevolve in parallel in the same patient (6,7,11). (iii) Finally, these studies have revealed that the three raltegravir resistance pathways are mutually exclusive, since they are always found to evolve on separate viral genomes (6,11).…”