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Multidrug-resistant (MDR) HIV-1 viruses are thought to be less pathogenic than wild-type viruses because of the fitness costs of drug-resistance mutations. However, we identified an individual infected with MDR virus associated with rapid disease progression referred to as MDR-1. To study the contribution of virologic factors to rapid disease progression, we constructed molecular clones that demonstrated high replication fitness and cytopathicity. To dissect determinants of enhanced fitness of a cytopathic clone, pMDR-1c, we divided its genome into 2 parts: the envelope (gp160) and the remaining backbone genome, and constructed mutual chimeric viruses with a reference, wild-type virus clone, pNL4-3. The growth competition assay indicated that pMDR-1c has high fitness (1.62), although its envelope confers remarkably enhanced fitness (2.29) and its backbone confers reduced fitness (0.56) as compared with pNL4-3. We also performed a similar study with a less cytopathic pMDR-5a, a molecular clone derived from another subject MDR-5, infected with MDR HIV-1, and associated with slower clinical progression. The results indicated that pMDR-5a has reduced fitness (0.82), although its envelope confers enhanced fitness (1.64) and its backbone confers reduced fitness (0.49), a fitness pattern compatible with envelope-mediated fitness compensation. These results suggest that the viral envelope may be a major determinant of the enhanced fitness of the MDR HIV-1 variant isolated from a patient with rapid disease progression. Furthermore, we speculate that compensation conferred by envelope may be a mechanism by which MDR HIV-1 maintains overall fitness despite the presence of changes in pol, which reduce replication capacity.

Viral Envelope Is a Major Determinant of Enhanced Fitness of a Multidrug-Resistant HIV-1 Variant