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HIV & AIDS
A Promising New Therapy for HIV Infection—Integrase Inhibitor
a report by
Sidonie A Morrison, PhD
1
and Roy T Steigbigel, MD
2
1. Associate Professor of Medicine and Pharmacology; 2. Professor of Medicine, Pathology, Microbiology, and Pharmacology,
State University of New York at Stony Brook
Among the difficulties associated with the control of HIV infection is the (RAGs) responsible for gene switching in pre-B and pre-T lymphocytes.
increasing prevalence of HIV resistant to currently available therapies. The Nonetheless, early in the AIDS epidemic it was hoped that HIV-encoded
incidence of drug-resistant HIV is likely only to increase as its transmission to integrase would be sufficiently distinct from any mammalian enzyme to be a
newly infected people increases; currently, 10–15% of the newly infected good target to aim at with antiretroviral drugs. That goal has now been
acquire virus with resistance to some antiretroviral therapies (ARTs). As more reached with raltegravir (MK-0518), the first integrase-inhibiting molecule to
people are treated, some of whom do not receive CD4 cell count or viral load be approved by the US Food and Drug Administration (FDA) based on
monitoring, there is likely to be a rise in the prevalence of resistant HIV in the findings in worldwide trials.
global population. Hence, there is an urgent need for therapies directed at
new targets in the HIV replication cycle. It is highly likely that extant HIV would Integrase Structure–Function Relationships
be sensitive to such medications, as there has been no therapeutic pressure To appreciate the rationale for the pharmacological attack on HIV integrase,
for the selection of strains resistant to them. Perhaps the most exciting and it is worthwhile to look at the structure and mechanism of the enzyme.
promising of targets for therapy is the HIV-1 integrase enzyme. Integrase monomer, IN, is a 32kDa, 288-amino-acid metalloprotein encoded
together with RT and protease by the HIV-1 pol gene and lying 3’ or
downstream of them. IN monomers are released when Gag-Pol, the viral
…early in the AIDS epidemic it was translation product or polyprotein, is sliced up within nascent viral particles
by mature HIV protease.
hoped that HIV-encoded integrase would
be sufficiently distinct from any In common with other retroviral integrases, IN activity depends on an acidic
DDE (single-letter amino acid code) motif. This is formed from non-
mammalian enzyme to be a good target
contiguous amino acids in the central core domain of the IN’s folded
to aim at with antiretroviral drugs. structure. The carboxyl groups in DDE bind one or more Mg
2+
ions or, in the
experimental setting, Mn
2+
ions, which are required for enzyme activity.
1
A
Retroviral Integrase
A defining characteristic of HIV-1 and other retroviruses is their ability to
Sidonie A Morrison, PhD, is Associate Professor of Medicine
and Pharmacology at the State University of New York at
create a complementary DNA (cDNA) copy of the viral positive-strand RNA
Stony Brook School of Medicine. Her main research interest is
that is destined to be part of the infected host cell’s DNA. Once the cDNA is
evaluating the nature and extent of immune dysfunction in
created by the viral RNA-dependent DNA polymerase (reverse transcriptase,
HIV-infected subjects with or without treatment with the best
antiretroviral drugs available. She is also deeply involved in
RT), integrase cuts out the stretch of double-stranded (ds) polynucleotide
medical education, and writes extensively for trainees at all
that forms the new DNA replicon and takes it into the nucleus. Integrase
levels of the profession. Dr Morrison received her BA and
then inserts the new DNA replicon into the host cell’s genome. In this way,
PhD in biochemistry from Oxford University.
the viral DNA essentially becomes a permanent resident, remaining for as
long as the cell and its progeny survive, to be transcribed and translated from
Roy T Steigbigel, MD, is Professor of Medicine, Pathology,
its new site into proteins and, thus, more virions. The demands of these steps Microbiology, and Pharmacology in the Division of Infectious
and where they take place (RT and DNA processing in the host cell
Diseases at the State University of New York (SUNY) at Stony
Brook. His research is in the area of host defense and
cytoplasm; integration in the nucleus) are such that integrases are
antimicrobials. He has been responsible for many
sophisticated enzymes that are highly evolved to perform multiple tasks and translational initiatives in the HIV pandemic, and contributes
move freely between separate cellular compartments. Retroviral integrases
actively to the development of new antiretroviral strategies.
He received his BA from Carleton College and his MD from
are members of a superfamily of polynucleotide cutting-and-pasting
the University of Rochester. After a residency and fellowship
enzymes known as polynucleotide transferases or transposases. The family at Rochester and Stanford University, and time in the US Public Health Service, Baltimore, he
includes enzymes that manipulate both RNA and DNA, and permeates all
joined the Department of Medicine faculty at the University of Rochester, Strong Memorial
Hospital. Dr Steigbigel moved to SUNY at Stony Brook in 1983 as Founding Chief of the
branches of the biosphere. There is a superficial resemblance among family
Infectious Diseases Division.
members, for example between retroviral integrase and the ribonucleases
(RNases) of vertebrates, as well as among the recombinase-activating genes
© T OUCH BRIEFINGS 2007
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