Treatment with appropriate combinations of antiretroviral drugs can reduce HIV-1 viremia to below the limit of detection and allow reconstitution of the immune system. The correct choice of antiretroviral drugs is critical for achieving and maintaining suppression of viral replication. Interestingly, there is no widely accepted system for comparing the antiviral activity of different drugs. Previous studies from this lab have shown that the inhibitory potential of antiretroviral drugs is strongly dependent upon a previously ignored factor termed here the slope parameter. This parameter describes the steepness of the dose-response curve. The inhibitory potential of antiretroviral drugs, described in a new index developed by this lab, varies for different classes of antiretroviral drugs by over 10 logs (10,000,000,000 fold!) in a manner that is strongly influence by the slope parameter. Thus the slope parameter is a critical missing dimension in the analysis of the suppressive potential of antiretroviral drugs. This proposal seeks to understand the molecular mechanisms underlying this effect and to use that information to guide the development of drugs and vaccines that will maximally suppress viral replication. The first specific aim is to test a mechanistic hypothesis involving a unique form of intermolecular cooperativity which can explain the shapes of dose-response curves for antiviral drugs. This hypothesis will be tested in a very specific way using phenotypic mixing experiments with viruses carrying both wild type and mutant forms of the proteins targeted by the drugs.
The second aim i s to understand the high magnitude and drug-to-drug variability of the slope parameter for the protease inhibitor class of antiretroviral drugs. Among the drug classes tested to date, the protease inhibitors show the highest slope values. As a result, clinical concentrations of some of these drugs can inhibit single round infections by ~10 logs. This project seeks to identify the mechanism underlying this extraordinary susceptibility of HIV-1 to inhibition by some protease inhibitors. The third specific aim is to apply this method of analysis to novel classes of antiretroviral drugs. Since a high slope value is critical for achieving multi-log inhibition of single round infection, the proposed analyses could identify drug classes that are likely to be particularly effective in vivo.
The fourth aim i s to determine the effect of drug resistance mutations on dose-response curve slope. Correct prediction of the clinical consequences of drug resistance mutations requires an understanding of the effects of the mutations on the slope parameter.
The final aim i s to measure the slope parameter of neutralizing antibodies directed at the HIV-1 envelope protein since concept of dose-response curve slope also applies to vaccine-induced effector mechanisms including neutralizing antibodies.

Public Health Relevance

This project involves a new method for measuring the antiviral activity of HIV drugs in the laboratory. The method incorporates a previously unappreciated factor that contributes enormously to the ability of drugs and vaccines to inhibit HIV. The goal is to facilitate the design of drugs and vaccines that maximally inhibit HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081600-04
Application #
8204784
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Conley, Tony J
Project Start
2009-01-23
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$281,290
Indirect Cost
$109,772
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Weil, Amy F; Ghosh, Devlina; Zhou, Yan et al. (2013) Uracil DNA glycosylase initiates degradation of HIV-1 cDNA containing misincorporated dUTP and prevents viral integration. Proc Natl Acad Sci U S A 110:E448-57
Siliciano, Janet D; Siliciano, Robert F (2013) Recent trends in HIV-1 drug resistance. Curr Opin Virol 3:487-94
Goldberg, Daniel E; Siliciano, Robert F; Jacobs Jr, William R (2012) Outwitting evolution: fighting drug-resistant TB, malaria, and HIV. Cell 148:1271-83
Jilek, Benjamin L; Zarr, Melissa; Sampah, Maame E et al. (2012) A quantitative basis for antiretroviral therapy for HIV-1 infection. Nat Med 18:446-51
Sampah, Maame Efua S; Shen, Lin; Jilek, Benjamin L et al. (2011) Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance. Proc Natl Acad Sci U S A 108:7613-8
Shen, Lin; Rabi, S Alireza; Sedaghat, Ahmad R et al. (2011) A critical subset model provides a conceptual basis for the high antiviral activity of major HIV drugs. Sci Transl Med 3:91ra63
McMahon, Moira A; Parsons, Teresa L; Shen, Lin et al. (2011) Consistent inhibition of HIV-1 replication in CD4+ T cells by acyclovir without detection of human herpesviruses. J Virol 85:4618-22
Spivak, Adam M; Rabi, S Alireza; McMahon, Moira A et al. (2011) Short communication: dynamic constraints on the second phase compartment of HIV-infected cells. AIDS Res Hum Retroviruses 27:759-61
Shen, Lin; Siliciano, Robert F (2010) Achieving a quantitative understanding of antiretroviral drug efficacy. Clin Infect Dis 51:1105-6; author reply 1106-7

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