Target cell availability and the successful suppression of hiv by hydroxyurea and didanosine
Target cell availability and the successful suppression
of HIV by hydroxyurea and didanosine
Rob J. De Boer
Keywords: Hydroxyurea, immunosuppression, target cell availability,
72 weeks of ddI–HU treatment, three out of sixpatients had no detectable plasma virus, and that there
Surprisingly, immunosuppressive treatment can
was no rebound of the plasma viral load in any patient
enhance the efficacy of conventional HIV-1 antiretro-
on uninterrupted treatment. There is also an intriguing
viral treatment, and can be beneficial for HIV-1-
anecdotal report of a patient on indinavir, ddI and HU,
infected patients. This argues for a role of target cell
who after having had HIV driven down to an unde-
availability in limiting the HIV-1 infection, and is in
tectable level stopped taking these drugs, and remained
agreement with mathematical models suggesting that
immunosuppression may limit the outgrowth of drug-resistant escape mutants. Immunosuppressive drugs like
Short-term studies report similar encouraging results of
hydroxyurea (HU) may therefore be powerful and
the ddI–HU combination in patients naive for ddI.
affordable supplements to HIV-1 antiretroviral therapy.
During the first month of treatment the viral loaddecreases sharply by 1–2 log
patients had undetectable virus levels after 3 months
another study, 1000 mg daily HU treatment added tochronic ddI therapy decreased viral load by approxi-
Recent clinical trials in HIV-1-infected patients have
investigated the long-term synergistic effect of HU on
conventional antiretroviral therapy with the nucleoside
potent than combinations with other nucleoside ana-
naive individuals with CD4 cell counts above
200 × 106/l with HU and ddI, and reported that after
monotherapy with HU failed to have a beneficial effect
1 year, 10 out of 20 patients had no detectable virus in
on plasma HIV RNA load (but may decrease CD4 cell
plasma or lymphoid tissue. Two of these patients
stopped therapy and had extracellular virus remain
monotherapy with the ddI–HU combination. They
undetectable in both lymph nodes and plasma for
nificantly stronger decrease in plasma viraemia with the
From Theoretical Biology, Utrecht University, the *Department of Virology, Eijkman-Winkler Institute, Utrecht UniversityHospital, Utrecht, The Netherlands, and the †Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico,USA.
Note: Portions of this work were performed under the auspices of the US Department of Energy and the Santa Fe Institute.
Sponsorship: This work was supported by NIH grant RR06555, NATO grant GRC960019, Dutch AIDS foundation (PccO grant1317), and the Jeanne P. and Joseph M. Sullivan Foundation.
Requests for reprints to: Dr Rob J. De Boer, Theoretical Biology, Utrecht University, Padualaan 8, 3584 CH Utrecht, TheNetherlands.
Date of receipt: 13 February 1998; revised: 13 May 1998; accepted: 19 May 1998.
Lippincott Williams & Wilkins
1998, Vol 12 No 13
decreasing target cell levels. Suppression with
ment routinely develop mutations known to confer
patients have a lower plasma virus concentration than
Analysing mathematical models in which the HIVinfection is target-cell-limited one finds that for any
Efficacy of ddI–HU
strain of HIV there exists a minimum target cell num-
Why is long-term treatment with ddI–HU effective?
This threshold number is set by various viral character-
HU blocks the cellular enzyme ribonucleotide reduc-
istics, such as its infection rate, burst size, and lifespan
tase, which thus decreases the intracellular concentra-
epidemiology stating that any infectious disease has a
By decreasing the intracellular dATP pool, HU may
critical host density below which the infection cannot
maintain itself. Because HIV-1 infection is at
steady-state target cell level should be close to this
epidemiological threshold. Target cell numbers higher
than this would allow a target-cell-limited virus to
employed in ddI–HU trials should be low enough to
expand, which is consistent with the data reviewed
above, while target cell numbers below this threshold
CD4 cell counts. This negative impact on peripheral
Analysing antiretroviral therapy in the same mathemati-
blood CD4 cell counts is an important difference
cal model, we have predicted precisely the long-term
between the ddI–HU combination and other forms of
effects that are observed now with the ddI–HU combi-
antiretroviral therapy. By killing dividing CD4+ T cells
nation: the major beneficial effect of supplementing
and by depleting intracellular dATP concentrations HU
antiretroviral therapy with target cell suppression
reduces the availability of suitable target cells for HIV.
should be a reduced expansion of drug-resistant
Using mathematical models we have shown that such a
reduction of target cell availability during antiretroviral
ing a lower fitness than the pretreatment wild-type
treatment can strongly reduce the growth rates of drug-
wild-type virus in order to expand. Likewise, novel
explains the encouraging long-term effects of the
mutants arising under drug pressure are unlikely to
attain a fitness higher than that of wild-type virus
before the onset of treatment. Thus, the recovery of
There is ample evidence that the availability of acti-
the CD4+ target cell population seems the ‘Achilles
vated CD4+ T cells limits HIV-1 levels during clinical
heel’ of conventional antiretroviral therapy: the
latency. Stimulating the immune system with inter-
increased target cell availability allows drug-resistant
leukin-2 in the absence of potent antiretroviral therapy
long-term effect of ddI–HU treatment on the viral
1-infected patients with either influenza vaccine
load, allowing in most cases only for a limited CD4 cell
recovery, is therefore in good agreement with our con-
jecture that HU decreases target cell availability and
cells, tends to increase the viral load. A similar increase
consequently reduces, or even prevents, the outgrowth
in HIV levels is seen during infection with pathogenic
straightforward explanation in the increased target cell
Finally, the high CD4+ T-cell production in children
Importantly, our results suggest that similar long-term
beneficial effects are to be expected from the combina-
tion of HU, or other immunosuppressive agents, with
able to exploit this by immunosuppressive therapies
other antiretroviral drugs. Obviously this should be
Suppression of HIV by ddI–HU
De Boer et al.
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