Abstract
Approximately 20 years has passed since the first human trial with HIV-1 protease inhibitors. Protease inhibitors set the stage for combination therapy in the mid-1990s but are now rarely used in first-line combination therapy and reserved for salvage therapy. Initially, resistance to protease inhibitors was deemed unlikely due to the small enzymatic target with limited genetic diversity, the extended drug binding site in protease, and the need to cleave multiple sites in the HIV-1 precursor proteins. However, a highly protease inhibitor-resistant virus can emerge during treatment and is found to harbor a collection of primary drug-resistant mutations near the drug and/or substrate binding site as well as secondary mutations that compensate for fitness loss. For years, the research field has debated the impact of these secondary mutations on the emergence rates of high-level protease inhibitor resistance. A recent study poses a more pertinent question, related to disease progression in patients newly infected with a virus harboring secondary protease inhibitor-associated polymorphisms. The authors of that study show that increased rates of disease progression, inferred by increased viral loads and decreased CD4 cell counts, correlate with a fitness score of the infecting virus. The modeled fitness scores increased with an accumulation of these secondary protease inhibitors mutations, and not because of any one specific polymorphism.
Highlights
In 1992, I attended a Gordon Conference entitled the ‘Chemotherapy of AIDS’ in Oxnard, California
The effects of these secondary protease inhibitors (PI) mutations has been a subject of debate for years but a recent paper by Theys et al in Retrovirology [8] sheds new light on how these polymorphisms may impact disease progression in newly infected patients. How do these mutations emerge under PI selection? Most primary PI-resistance mutations may pre-exist at low frequency in the intrapatient human immunodeficiency virus type 1 (HIV-1) population but their dominance with PI treatment or selection comes with a significant fitness cost [9]
A more important role for these secondary mutations may relate to replicative fitness and the ability to compensate for the fitness loss associated with primary PI-resistance mutations
Summary
Variant almost immediately with monotherapy [5,6]. Oh, how times have changed. A triple drug combination therapy, based on a non-NRTI (NNRTI)backbone, is the norm for first-line therapy and anything less than complete virus suppression is deemed a treatment failure (reviewed in [7]) Aside from their antiviral potency on HIV in tissue culture, PIs were perceived as better than the rest because of their small enzymatic target with a pleotropic cleavage pattern. Primary drug-resistance mutations are positioned below the ‘flap’ and near the substrate or inhibitor binding groove (red dots in the wire frame protease structure; Figure 1A) whereas secondary mutations (for example, L10I/V, I13V, K20I/M/R, M36I, D60E, I62V, L63P, A71T/V, V77I and I93L) are present primarily on solvent accessible regions near the surface of the dimer. The effects of these secondary PI mutations has been a subject of debate for years but a recent paper by Theys et al in Retrovirology [8] sheds new light on how these polymorphisms may impact disease progression in newly infected patients
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