Research ArticleHIV

A Critical Subset Model Provides a Conceptual Basis for the High Antiviral Activity of Major HIV Drugs

Science Translational Medicine  13 Jul 2011:
Vol. 3, Issue 91, pp. 91ra63
DOI: 10.1126/scitranslmed.3002304

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King of the Hill

Thirty years ago, a deadly new disease burst onto the medical scene. AIDS was poorly understood, untreatable, and rapidly lethal. Today, through the herculean efforts of scientists, clinicians, and public health officers, HIV infection can be largely controlled in adherent patients with highly active antiretroviral therapy (HAART), which consists of treatment with at least three antiretroviral drugs. However, the success of HAART does not stem simply from the combined use of three drugs; indeed, some drug combinations are more successful than others. Shen et al. now show that the most successful drugs act cooperatively by binding multiple copies of the drug target.

Successful inhibition by a drug depends both on the drug dose and the concentration of the drug target: There must be sufficient amounts of the drug to inhibit the activity of the drug’s target. Individual drugs can be more effective if they act cooperatively by binding a single target multiple times, such as one observes with a multivalent receptor, which contains more than one drug-binding site. This intramolecular cooperation can be represented by the Hill coefficient, which is a measure of how inhibition increases with drug concentration. HAART drugs have univalent targets; however, they still demonstrate cooperative inhibition in a dose-response curve (Hill coefficient > 1). Shen et al. propose a critical subset model that explains this unexpected cooperation: Infectivity requires multiple copies of a drug target at an individual stage of the virus’s life cycle. This means that a certain number of the targeted molecules must remain unbound by the drug throughout the life cycle for infectivity to occur. Thus, the drug target actually functions as a virtual multivalent receptor, which results in the cooperative action of the HAART drugs. The authors confirm their model experimentally by modulating the number of functional drug targets per virus, verifying model predictions. These data not only explain the relative success of the current HAART therapy for HIV but also provide a framework for choosing new targets for antiviral drugs.


  • * Present address: Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.

  • Citation: L. Shen, S. A. Rabi, A. R. Sedaghat, L. Shan, J. Lai, S. Xing, R. F. Siliciano, A Critical Subset Model Provides a Conceptual Basis for the High Antiviral Activity of Major HIV Drugs. Sci. Transl. Med. 3, 91ra63 (2011).