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Retroviral Integrase: Structure as a Foundation for Drug Design
Alison B. Hickman and Fred Dyda
National Institutes of Health, Bethesda, Maryland
I. Introduction
A. Retroviral Lifecycle
Page 83
The human immunodeficiency virus (HIV) is one of only a few retroviruses known to infect humans. It
is estimated that approximately twenty-two million people are now infected worldwide [1]. With only a
tiny number of exceptions, infection ultimately leads to the development of the lethal condition of
acquired immunodeficiency syndrome, or AIDS. To date, only a handful of drugs have been shown to
have any effect on the course of the disease. These are, in general, relatively ineffective at significantly
prolonging life, and drug resistance develops rapidly. Equally discouraging, vaccines have not yet been
developed to prevent infection.
The retroviral lifecycle presents several steps that can be targeted as possible sites of intervention by
inhibitors. As shown in Figure 1, when a retrovirus encounters a host cell, specific recognition between
proteins on the surface of the virus and receptors on the host cell surface leads to membrane fusion. The
viral core then enters the cell cytoplasm where the process of reverse transcription begins. The
requirement of the conversion of viral RNA to double-stranded DNA is a feature unique to retroviruses.
With the recent exception of the protease inhibitor saquinavir, ritonavir, and indinavir, the drugs
approved to date by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection
have been nucleoside analogs targeted against the viral enzyme that carries out this conversion, reverse
transcriptase.
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