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Target cell availability and the successful suppression of hiv by hydroxyurea and didanosineTarget 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,
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 copies/ml, and several 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 copies/ml and decreased CD4 cell count investigated the long-term synergistic effect of HU on conventional antiretroviral therapy with the nucleoside potent than combinations with other nucleoside ana- analogue didanosine (ddI). Vila 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 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.
tested carefully because lowering CD4+ T cells may phocytic choriomeningitis virus infection. J Immunol 1995,
put patients at risk of even more opportunistic 17. Buchkovich KJ, Greider CW: Telomerase regulation during
infections, and because immunosuppression would be entry into the cell cycle in normal human T cells. Mol Biol Cell
harmful if the HIV infection is largely controlled by An overview of the clinical experience with
immune responses rather than by target cell availability.
hydroxyurea. Semin Oncol 1992, 19:11–19.
The current encouraging results with the ddI–HU 19. Rocha B, Freitas AA, Coutinho AA: Population dynamics of T
combination nevertheless supports our conjecture that lymphocytes. Renewal rate and expansion in the peripheral
lymphoid organs. J Immunol 1983, 131:2158–2164.
some degree of target cell depletion could be very ben- Renewal rates of murine T-lymphocyte subsets. Cell
Immunol 1990, 128:185–197.
out to be true, it would open up inexpensive and well- 21. De Boer RJ, Boucher CA: Anti-CD4 therapy for AIDS suggested
by mathematical models. Proc R Soc Lond B Biol Sci 1996,
tolerated new therapeutic strategies for patients not responding to current therapies, and for countries 22. Kovacs JA, Baseler M, Dewar RJ, et al.: Increases in CD4 T lym-
phocytes with intermittent courses of interleukin-2 in patients
unable to afford them.
with human immunodeficiency virus infection. A preliminary
study. N Engl J Med 1995, 332:567–575.
23. Staprans SI, Hamilton BL, Follansbee SE, et al.: Activation of
virus replication after vaccination of HIV-1-infected individu-
als. J Exp Med 1995, 182:1727–1737.
24. O'Brien WA, Grovit-Ferbas K, Namazi A, et al.: Human immun-
odeficiency virus-type 1 replication can be increased in
peripheral blood of seropositive patients after influenza vac-
1. Vila J, Biron F, Nugier F, Vallet T, Peyramond D: 1-year follow-
cination. Blood 1995, 86:1082–1089.
up of the use of hydroxycarbamide and didanosine in HIV
25. Cheeseman SH, Davaro RE, Ellison RT III: Hepatitis B vaccina-
infection. Lancet 1996, 348:203–204.
tion and plasma HIV-1 RNA [letter]. N Engl J Med 1996,
Vila J, Nugier F, Bargues G, et al.: Absence of viral rebound
after treatment of HIV-infected patients with didanosine and
26. Brichacek B, Swindells S, Janoff EN, Pirruccello S, Stevenson M: hydroxycarbamide. Lancet 1997, 350:635–636.
Increased plasma human immunodeficiency virus type 1 bur-
3. Lori F, Jessen H, Foli A, Lisziewicz J, Matteo PS: Long-term sup-
den following antigenic challenge with pneumococcal vac-
pression of HIV-1 by hydroxyurea and didanosine. JAMA
cine. J Infect Dis 1996, 174:1191–1199.
27. Stanley SK, Ostrowski MA, Justement JS, et al.: Effect of immu-
HIV suppressed long after treatment [news]. Science
nization with a common recall antigen on viral expression in
patients infected with human immunodeficiency virus type 1.
5. Biron F, Lucht F, Peyramond D, et al.: Pilot clinical trial of the
N Engl J Med 1996, 334:1222–1230.
combination of hydroxyurea and didanosine in HIV-1 infected
28. Goletti D, Weissman D, Jackson RW, et al.: Effect of
individuals. Antiviral Res 1996, 29:111–113.
Mycobacterium tuberculosis on HIV replication. Role of
6. Clotet B, Ruiz L, Cabrera C, et al.: Short term anti-HIV activity,
immune activation. J Immunol 1996, 157:1271–1278.
at three month interval, of the combination didanosine and
29. Orenstein JM, Fox C, Wahl SM: Macrophages as a source of
hydroxyurea. Antiviral Ther 1996, 1:189–193.
HIV during opportunistic infections. Science 1997,
7. De Antoni A, Foli A, Lisziewicz J, Lori F: Mutations in the pol
gene of the human immunodeficiency virus type 1 in infected
Jong MD, Veenstra J, Stilianakis NI, et al.: Host–parasite
patients receiving didanosine and hydroxyurea combination
dynamics and outgrowth of virus containing a single K70R
therapy. J Infect Dis 1997, 176:899–903.
amino acid change in reverse transcriptase are responsible
8. Montaner JS, Zala C, Conway B, et al.: A pilot study of hydrox-
for the loss of human immunodeficiency virus type 1 RNA
yurea among patients with advanced human immunodefi-
load suppression by zidovudine. Proc Natl Acad Sci USA 1996,
ciency virus (HIV) disease receiving chronic didanosine
therapy: Canadian HIV Trials Network Protocol 080. J Infect
31. McLean AR, Emery VC, Webster A, Griffiths PD: Population
Dis 1997, 175:801–806.
dynamics of HIV within an individual after treatment with
9. Lori F, Malykh A, Cara A, et al.: Hydroxyurea as an inhibitor of
zidovudine. AIDS 1991, 5:485–489.
human immunodeficiency virus-type 1 replication. Science
32. McLean AR, Nowak MA: Competition between zidovudine-
sensitive and zidovudine-resistant strains of HIV. AIDS 1992,
10. Gao WY, Johns DG, Chokekuchai S, Mitsuya H: Disparate
actions of hydroxyurea in potentiation of purine and pyrimi-
33. Stilianakis NI, Boucher CA, De Jong MD, Van Leeuwen R, dine 2',3'-dideoxynucleoside activities against replication of
Schuurman R, De Boer RJ: Clinical data sets of human immun-
human immunodeficiency virus. Proc Natl Acad Sci USA 1995,
odeficiency virus type 1 reverse transcriptase-resistant
mutants explained by a mathematical model. J Virol 1997,
11. Lori F, Malykh AG, Foli A, et al.: Combination of a drug target-
ing the cell with a drug targeting the virus controls human
34. Mackall CL, Fleisher TA, Brown MR, et al.: Age, thymopoiesis,
immunodeficiency virus type 1 resistance. AIDS Res Hum
and CD4+ T-lymphocyte regeneration after intensive
chemotherapy. N Engl J Med 1995, 332:143–149.
12. Simonelli C, Nasti G, Vaccher E, et al.: Hydroxyurea treatment
35. Steketee RW, Abrams EJ, Thea DM, et al.: Early detection of
in HIV-infected patients. J Acquir Immune Defic Syndr Hum
perinatal human immunodeficiency virus (HIV) type 1 infec-
Retrovirol 1996, 13:462–464.
tion using HIV RNA amplification and detection. New York
13. Giacca M, Zanussi S, Comar M, et al.: Treatment of human
City Perinatal HIV Transmission Collaborative Study. J Infect
immunodeficiency virus infection with hydroxyurea: virologic
Dis 1997, 175:707–711.
and clinical evaluation. J Infect Dis 1996, 174:204–209.
36. Shearer WT, Quinn TC, LaRussa P, et al.: Viral load and disease
14. Simonelli C, Comar M, Zanussi S, De Paoli P, Tirelli U, Giacca progression in infants infected with human immunodeficiency
M: No therapeutic advantage from didanosine (ddI) and
virus type 1. N Engl J Med 1997, 336:1337–1342.
hydroxyurea versus ddI alone in patients with HIV infection.
HIV population dynamics in vivo: implications for
AIDS 1997, 11:1299–1300.
genetic variation, pathogenesis, and therapy. Science 1995,
15. Meyerhans A, Vartanian JP, Hultgren C, et al.: Restriction and
enhancement of human immunodeficiency virus type 1 repli-
38. Feinberg MB, McLean AR: AIDS: decline and fall of immune
cation by modulation of intracellular deoxynucleoside
surveillance? Curr Biol 1997, 7:R136–R140.
triphosphate pools. J Virol 1994, 68:535–540.
39. Andrieu JM, Even P, Venet A, et al.: Effects of cyclosporin on T-
16. Cousens LP, Orange JS, Biron CA: Endogenous IL-2 contributes
cell subsets in human immunodeficiency virus disease. Clin
to T cell expansion and IFN-gamma production during lym-
Immunol Immunopathol 1988, 47:181–198.
AIDS 1998, Vol 12 No 13
40. Schwarz A, Offermann G, Keller F, et al.: The effect of
DD, Neumann AU, Perelson AS, Chen W, Leonard JM, cyclosporine on the progression of human immunodeficiency
Markowitz M: Rapid turnover of plasma virions and CD4 lym-
virus type 1 infection transmitted by transplantation: data on
phocytes in HIV-1 infection. Nature 1995, 373:123–126.
four cases and review of the literature. Transplantation 1993,
46. Wei X, Ghosh SK, Taylor ME, et al.: Viral dynamics in human
immunodeficiency virus type 1 infection. Nature 1995,
41. Weber J, Galpin S: HIV results in the frame. Cyclosporin A
[letter]. Nature 1995, 375:198.
47. Wein LM, D'Amato RM, Perelson AS: Mathematical analysis of
42. Martin LN, Murphey-Corb M, Mack P, et al.: Cyclosporin A
antiretroviral therapy aimed at HIV-1 eradication or mainte-
modulation of early virologic and immunologic events during
nance of low viral loads. J Theor Biol 1998, 192:81–98.
primary simian immunodeficiency virus infection in rhesus
48. Goudsmit J, De Ronde A, Ho DD, Perelson AS: Human immun-
monkeys. J Infect Dis 1997, 176:374–383.
43. Andrieu JM, Lu W, Levy R: Sustained increases in CD4 cell
odeficiency virus fitness in vivo: calculations based on a sin-
counts in asymptomatic human immunodeficiency virus type
gle zidovudine resistance mutation at codon 215 of reverse
1-seropositive patients treated with prednisolone for 1 year. J
transcriptase. J Virol 1996, 70:5662–5664.
Infect Dis 1995, 171:523–530.
49. Goudsmit J, De Ronde A, De Rooij E, De Boer RJ: Broad spec-
Reducing T cell activation as a therapy for human
trum of in vivo fitness of human immunodeficiency virus type
immunodeficiency virus infection. J Infect Dis 1995,
1 subpopulations differing at reverse transcriptase codons 41
and 215. J Virol 1997, 71:4479–4484.
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