title: Viral envelope is a major determinant of enhanced fitness of a multidrug-resistant HIV-1 variant.
abstract: 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.
authors.affiliation: The Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY (Dr. N. Prada is now with Antiviral Immunity, Biotherapy and Vaccine Unit, Institut Pasteur, Paris, France).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mohri
authors.forename: Nicole
authors.initials: N
authors.lastname: Prada
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
mesh_terms: D018450:Disease Progression; D024921:Drug Resistance, Multiple, Viral; D019302:HIV Envelope Protein gp160 / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D011995:Recombination, Genetic; D059386:Reverse Genetics; D014779:Virus Replication
chemical_list: D019302:HIV Envelope Protein gp160