Chapter 7 : Inhibitors of the Human Immunodeficiency Virus Protease

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HIV protease inhibitors (PIs) were first introduced into clinical practice in 1996, and their use has resulted in major clinical benefits for human immunodeficiency virus (HIV) -infected people in terms of better viral suppression, improved immune restoration, reduced morbidity, and longer survival. This chapter focuses on the biochemical and molecular basis of inhibition of HIV-1 aspartic protease (PR), the virological basis of PI resistance, and implications on the therapeutics of HIV infections and proposes the research that is still needed in order to further improve on the benefits that PIs offer for HIV medicine. Drug-resistant viruses have been described for all PIs developed to date. Some strains of HIV recovered from extensively treated patients display cross-resistance to a variety of PIs. Additionally, structural data from a highly resistant PR containing 10 resistance mutations revealed an expansion in the active site, as a result of a separation of the flaps by as much as 10 Å, while this distance is only 4 Å in the case of wild-type PR. The degree of suppression of viral replication is the result of the interaction between exposure of the virus to the drug and the inherent susceptibility of the infecting virus to such drug, all this within the diverse environments of human tissues. The study of efflux transporters and their role in PI penetration into, and distribution within, so-called sanctuary sites may lead to ways of making HIV in these compartments more susceptible to antiretrovirals (ARVs).

Citation: Martinez-Cajas J, Wainberg M. 2009. Inhibitors of the Human Immunodeficiency Virus Protease, p 113-135. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch7

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Human immunodeficiency virus 1
Non-Nucleoside Reverse Transcriptase Inhibitors
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Image of Figure 1.
Figure 1.

HIV protease inhibitors arrest maturation of the virus particle by blocking the processing of Gag and Gag-Pol. This prevents reorganization of the structural proteins within the virion. Any resultant virus particles are not infectious.

Citation: Martinez-Cajas J, Wainberg M. 2009. Inhibitors of the Human Immunodeficiency Virus Protease, p 113-135. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch7
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Image of Figure 2.
Figure 2.

Schematic representation of nine cleavage sites within Gag and Gag-Pol. The PR enzyme recognizes heptamers within its natural substrates. S refers to a pocket in the protease that accepts a group P from the substrate. This nomenclature (by Schechter and Berger) is used for both natural substrates and inhibitors ( ).

Citation: Martinez-Cajas J, Wainberg M. 2009. Inhibitors of the Human Immunodeficiency Virus Protease, p 113-135. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch7
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Image of Figure 3.
Figure 3.

The crystal structure of the wild-type HIV-1 PR. The flaps are flexible structures that open to permit entrance of the large Gag-Pol polyproteins. The aspartate residues in the active site confer hydrolytic activity to the enzyme. This figure was generated from the 3HVP structure in the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) using software available from PyMol DeLano Scientific, Palo Alto, CA.

Citation: Martinez-Cajas J, Wainberg M. 2009. Inhibitors of the Human Immunodeficiency Virus Protease, p 113-135. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch7
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Image of Figure 4.
Figure 4.

Transmission electron micrographs of HIVBal-infected monocytes/macrophages incubated with or without PIs at 20 μM for 5 days. (A) Control cells. Bullet-shaped “mature” cores of virus particles in an intracytoplasmic vacuole are visible. (B) Cells incubated with pepstatin A. The virions in this cell have mature cores. (C) Cells incubated with the PI SK&F 107461; , 48 nM. Many virions are “immature”; that is, they have Gag protein plaques and no cores. Some virions have mature cores. (D) Cells incubated with the PI SK&F 108922; , <10 nM. Almost all virions have immature morphology. Reprinted from the ( ) with permission of the publisher.

Citation: Martinez-Cajas J, Wainberg M. 2009. Inhibitors of the Human Immunodeficiency Virus Protease, p 113-135. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch7
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Image of Figure 5.
Figure 5.

Secondary structures of approved HIV-1 PIs.

Citation: Martinez-Cajas J, Wainberg M. 2009. Inhibitors of the Human Immunodeficiency Virus Protease, p 113-135. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch7
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Image of Figure 6.
Figure 6.

Common PI resistance mutations. Black box, major mutation; white box, minor mutation; gray arrow, wild-type consensus sequence. (Based on the IAS-USA list of HIV drug resistance mutations [66].)

Citation: Martinez-Cajas J, Wainberg M. 2009. Inhibitors of the Human Immunodeficiency Virus Protease, p 113-135. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch7
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Table 1.

Drug resistance selection experiments with different HIV-1 PIs

Citation: Martinez-Cajas J, Wainberg M. 2009. Inhibitors of the Human Immunodeficiency Virus Protease, p 113-135. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch7
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Table 2.

Pharmacokinetic features of HIV PIs

Citation: Martinez-Cajas J, Wainberg M. 2009. Inhibitors of the Human Immunodeficiency Virus Protease, p 113-135. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch7

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