Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

Abstract

Differences in baseline polymorphisms between subtypes may result in development of diverse mutational pathways during antiretroviral treatment. We compared drug resistance in patients with human immunodeficiency virus subtype C (referred to herein as "subtype-C-infected patients") versus subtype-B-infected patients following protease inhibitor (PI) therapy. Genotype, phenotype, and replication capacity (Phenosense; Virologic) were determined. We evaluated 159 subtype-C-and 65 subtype-B-infected patients failing first PI treatment. Following nelfinavir treatment, the unique nelfinavir mutation D30N was substantially less frequent in C (7%) than in B (23%; P ‫؍‬ 0.03) while L90M was similar (P < 0.5). Significant differences were found in the rates of M36I (98 and 36%), L63P (35 and 59%), A71V (3 and 32%), V77I (0 and 36%), and I93L (91 and 32%) (0.0001 < P < 0.05) in C and B, respectively. Other mutations were L10I/V, K20R, M46I, V82A/I, I84V, N88D, and N88S. Subtype C samples with mutation D30N showed a 50% inhibitory concentration (IC 50 ) change in susceptibility to nelfinavir only. Other mutations increased IC 50 correlates to all PIs. Following accumulation of mutations, replication capacity of the C virus was reduced from 43% ؎ 22% to 22% ؎ 15% (P ‫؍‬ 0.04). We confirmed the selective nature of the D30N mutation in C, and the broader cross-resistance of other common protease inhibitor mutations. The rates at which these mutational pathways develop differ in C and subtype-B-infected patients failing therapy, possibly due to the differential impact of baseline polymorphisms. Because mutation D30N is not preferentially selected in nelfinavir-treated subtype-C-infected patients, as it is in those infected with subtype B, the consideration of using this drug initially to preserve future protease inhibitor options is less relevant for subtype-C-infected patients.

The Challenge of HIV-1 Subtype Diversity

“…49 Nelfinavir resistance appears to occur primarily through L90 → M mutations in subtypes G and C and other non-B subtypes, whereas subtype B acquires either D30 → N or L90 → M nelfinavir-resistance mutations. 81,82 Overall, it appears that most antiretroviral resistance in non-B subtypes is accounted for within the current resistance databases. 83 Further studies of treated cohorts infected with non-B HIV-1 are needed to determine whether other subtype-specific pathways to resistance exist (Table 3).…”

The Effect of Clade-Specific Sequence Polymorphisms on HIV-1 Protease Activity and Inhibitor Resistance Pathways

“…For the most part, resistance mutation patterns are very similar in HIV-1 clade B and non-B clade proteases (19). However, several alternative resistance pathways have been observed for non-B clade proteases compared with those of clade B protease (1,12,13,26). Limited data are available on how sequence polymorphisms, some of which are associated with drug resistance in clade B protease, might influence the pathway to drug resistance in non-B clade proteases.…”

Most HIV Type 1 Non-B Infections in the Spanish Cohort of Antiretroviral Treatment-Naïve HIV-Infected Patients (CoRIS) Are Due to Recombinant Viruses

“…HIV-1 non-B variants present clade-specific substitutions in positions related to drug resistance (26,52). They could accelerate the emergence of drug-resistant viruses, change or induce alternative pathways of resistance (17,19), influence viral replicative capacity in vitro (25), impair the interpretation of genotypic resistance algorithms (9,43,52), reduce the genetic barrier of certain protease inhibitors (47), and affect drug-binding affinity (27). Additionally, patients infected by certain HIV-1 non-B subtypes present accelerated disease pro-gression (2, 48) and higher cognitive impairment (40).…”