Patterns of Point Mutations Associated With Antiretroviral Drug Treatment Failure in CRF01_AE (Subtype E) Infection Differ From Subtype B Infection

Abstract

An increasing number of HIV-1-infected patients living in developing countries now have access to antiretroviral drugs. Information regarding the drug-resistant mutations of non-B subtype HIV-1 remains limited, however. The authors cross-sectionally compared patterns of the drug-resistant point mutations in patients infected with either subtype B or CRF01_AE (subtype E) among patients who acquired HIV by sexual transmission in Japan. Protease sequence data were available from 216 patients with a detectable level of RNA copies in plasma. Based on phylogenetic analysis of the protease and the C2V3 regions, 162 subtype B and 45 CRF01_AE cases were identified; 82 subtype B and 24 CRF01_AE patients had a treatment failure with nucleoside reverse transcriptase inhibitors; and 69 subtype B and 19 CRF01_AE patients had a treatment failure with a protease inhibitor. Antiretroviral drug history was similar in subtype B-infected and CRF01_AE-infected patients. The mutations T69N and V75M in reverse transcriptase and L10F, K20I, L33I, and N88S in protease were seen more frequently in patients infected with CRF01_AE than in patients with subtype B. The mutations, D30N, A71V, and N88D were found exclusively in patients with subtype B. Most of the characteristic mutation patterns were associated with a history of receiving nelfinavir. The pattern of drug resistance mutations differs between the subtypes. Data derived from subtype B drug-resistant genotypes may not always be applicable to non-B subtypes.

Thymidine Analogue Resistance Suppression by V75I of HIV-1 Reverse Transcriptase

“…Mutations at codon 75 have been also detected in treated patients infected with other clades of HIV-1. Thus, V75M has been found in CRF01_AE-infected patients (30), whereas V75A and V75M have been selected in the absence and in the presence of TAMs, respectively, in stavudine-treated patients infected with HIV-1 group O (31).…”

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.…”

“…1A). Interestingly, AE protease develops a different resistance pathway from that of clade B protease to confer resistance to the protease inhibitor nelfinavir (NFV) (1). In patients infected with AE, the protease acquires predominantly the N88S mutation in response to NFV therapy, whereas in patients with clade B infection, the protease acquires the D30N/N88D mutations.…”

Structural Analysis of Human Immunodeficiency Virus Type 1 CRF01_AE Protease in Complex with the Substrate p1-p6

“…HIV-1 protease is one of the major proteins targeted for anti-HIV drug development. The pol gene, which codes for protease, differs by 10 to 15% between clades (7), and sequence diversity within HIV-1 clades has been an important area of study in recent years due to its possible role in altering resistance pathways within the protease (1,10). In particular, the HIV-1 CRF01_AE protease acquires nelfinavir resistance via an alternative mutational pathway (1), making the detailed study of non-B proteases strongly warranted.…”