Abstract
Human immunodeficiency virus type 2 (HIV-2) is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors and exhibits reduced susceptibility to several of the protease inhibitors used for antiretroviral therapy of HIV-1. Thus, there is a pressing need to identify new classes of antiretroviral agents that are active against HIV-2. Although recent data suggest that the integrase strand transfer inhibitors raltegravir and elvitegravir may be beneficial, mutations that are known to confer resistance to these drugs in HIV-1 have been reported in HIV-2 sequences from patients receiving raltegravir-containing regimens. To examine the phenotypic effects of mutations that emerge during raltegravir treatment, we constructed a panel of HIV-2 integrase variants using site-directed mutagenesis and measured the susceptibilities of the mutant strains to raltegravir and elvitegravir in culture. The effects of single and multiple amino acid changes on HIV-2 replication capacity were also evaluated. Our results demonstrate that secondary replacements in the integrase protein play key roles in the development of integrase inhibitor resistance in HIV-2. Collectively, our data define three major mutational pathways to high-level raltegravir and elvitegravir resistance: i) E92Q+Y143C or T97A+Y143C, ii) G140S+Q148R, and iii) E92Q+N155H. These findings preclude the sequential use of raltegravir and elvitegravir (or vice versa) for HIV-2 treatment and provide important information for clinical monitoring of integrase inhibitor resistance in HIV-2–infected individuals.
Highlights
Human immunodeficiency virus type 2 (HIV-2) is believed to have originated in West Africa, where the virus is endemic, and has spread to other areas with socio-economic ties to the region [1]
We previously showed that the single amino acid changes Q148R and N155H in HIV-2 integrase confer moderate resistance to raltegravir, whereas the Y143C change had a minimal effect on raltegravir sensitivity [11]
The Y143C, N155H, and Q148H, K, and R changes each conferred statistically-significant declines in infectious virus production, with mean titers 3–15-fold lower than that of wild-type ROD9 (Figure 1). These data demonstrate that treatment-associated mutations at the three key sites involved in raltegravir resistance in HIV-1 (Y143, Q148 and N155; [19]) are deleterious to viral replication in HIV-2, whereas secondary changes alone do not measurably diminish HIV-2 replication capacity
Summary
Human immunodeficiency virus type 2 (HIV-2) is believed to have originated in West Africa, where the virus is endemic, and has spread to other areas with socio-economic ties to the region [1]. Newer ARV drugs that exhibit potent and durable anti–HIV-1 activity (i.e., tenofovir disoproxil fumarate/emtricitabine and ritonavir-boosted lopinavir) have only recently become available in West Africa. The use of suboptimal ARVs for HIV-2 treatment has resulted in a high frequency of multiclass drug resistance in the region [4]. Non-protease inhibitor-based first-line options are needed for HIV-2, in addition to new second-line ARVs, because resistance and adverse effects have left many HIV2–infected individuals with few (if any) options for effective treatment
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