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
AIDS 1998, 12:1567–1570
Keywords: Hydroxyurea, immunosuppression, target cell availability,
resistance
Introduction
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 Clinical trials
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
AIDS 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 Mathematical models
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 Conclusion
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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