OKT3 and IL-2 Treatment for Purging of the Latent HIV-1 Reservoir in Vivo Results in Selective Long-lasting CD4+ T Cell Depletion

Overview

Journal J Clin Immunol

Publisher Springer

Specialty Allergy & Immunology

Date 2001 Jun 14

PMID 11403229

Citations 78

Authors

R M van Praag

J M Prins

M T Roos

P T Schellekens

I J ten Berge

S L Yong

H Schuitemaker

A J Eerenberg

S Jurriaans

F de Wolf

C H Fox

J Goudsmit

F Miedema

J M Lange

Affiliations

Soon will be listed here.

Abstract

Activation of resting T cells has been proposed to purge the reservoir of HIV-1-infected resting CD4+ T cells. We therefore treated three HIV-1-infected patients on antiretroviral therapy with OKT3, a CD3 monoclonal antibody, and recombinant human IL-2. Here we report the profound and partially long-lasting host responses induced by the OKT3 and IL-2 treatment. OKT3/IL-2 induced a strong but transient release of plasma cytokines and chemokines. The percentage CD4+ and CD8+ cells in the blood expressing the activation marker CD38 transiently increased to almost 100%, and in lymph nodes we "observed" a 10-fold increase in the number of dividing Ki67+ cells and increased numbers of apoptotic cells. Following OKT3/IL-2 treatment, a long-lasting depletion of CD4+ cells in the peripheral blood and lymph nodes occurred, suggesting the physical deletion of these cells. Increases in CD4+T cell numbers during the two year followup period were due mainly to increased memory cell numbers. CD8+ cells were also depleted in the blood, but less severely in lymph nodes, and returned to baseline levels within several weeks.

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References

Bemelman F, Buysmann S, Yong S, van Diepen F, Schellekens P, ten Berge R . Biphasic granulocytopenia after administration of the first dose of OKT3. J Lab Clin Med. 1995; 126(6):571-9. View

Hamann D, Baars P, Rep M, Hooibrink B, Klein M, van Lier R . Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med. 1997; 186(9):1407-18. PMC: 2199103. DOI: 10.1084/jem.186.9.1407. View

Kovacs J, Baseler M, Dewar R, Vogel S, Davey Jr R, Falloon J . Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. A preliminary study. N Engl J Med. 1995; 332(9):567-75. DOI: 10.1056/NEJM199503023320904. View

Fraser C, Ferguson N, Ghani A, Prins J, Lange J, Goudsmit J . Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs. AIDS. 2000; 14(6):659-69. DOI: 10.1097/00002030-200004140-00005. View

Muller T, Grebe S, Neumann M, Heymanns J, Radsak K, Sprenger H . Persistent long-term changes in lymphocyte subsets induced by polyclonal antibodies. Transplantation. 1997; 64(10):1432-7. DOI: 10.1097/00007890-199711270-00010. View

Parlevliet K, Bemelman F, Yong S, Hack C, Surachno J, Wilmink J . Toxicity of OKT3 increases with dosage: a controlled study in renal transplant recipients. Transpl Int. 1995; 8(2):141-6. DOI: 10.1007/BF00344424. View

Davey Jr R, Chaitt D, Piscitelli S, Wells M, Kovacs J, Walker R . Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons. J Infect Dis. 1997; 175(4):781-9. DOI: 10.1086/513971. View

Chatenoud L, Ferran C, Legendre C, Thouard I, Merite S, Reuter A . In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids. Transplantation. 1990; 49(4):697-702. DOI: 10.1097/00007890-199004000-00009. View

Finzi D, Blankson J, Siliciano J, Margolick J, Chadwick K, Pierson T . Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999; 5(5):512-7. DOI: 10.1038/8394. View

10.

Bucy R, Hockett R, Derdeyn C, Saag M, Squires K, Sillers M . Initial increase in blood CD4(+) lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues. J Clin Invest. 1999; 103(10):1391-8. PMC: 408455. DOI: 10.1172/JCI5863. View

11.

Ellenhorn J, Woodle E, Ghobreal I, Thistlethwaite J, Bluestone J . Activation of human T cells in vivo following treatment of transplant recipients with OKT3. Transplantation. 1990; 50(4):608-12. DOI: 10.1097/00007890-199010000-00016. View

12.

Perelson A, Neumann A, Markowitz M, Leonard J, Ho D . HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996; 271(5255):1582-6. DOI: 10.1126/science.271.5255.1582. View

13.

Buysmann S, Hack C, van Diepen F, Surachno J, ten Berge I . Administration of OKT3 as a two-hour infusion attenuates first-dose side effects. Transplantation. 1998; 64(11):1620-3. DOI: 10.1097/00007890-199712150-00024. View

14.

Wong J, Eylath A, Ghobrial I, Colvin R . The mechanism of anti-CD3 monoclonal antibodies. Mediation of cytolysis by inter-T cell bridging. Transplantation. 1990; 50(4):683-9. DOI: 10.1097/00007890-199010000-00030. View

15.

Ferran C, Dy M, Merite S, Sheehan K, Schreiber R, Leboulenger F . Reduction of morbidity and cytokine release in anti-CD3 MoAb-treated mice by corticosteroids. Transplantation. 1990; 50(4):642-8. DOI: 10.1097/00007890-199010000-00023. View

16.

Janssen O, Wesselborg S, Kabelitz D . Immunosuppression by OKT3--induction of programmed cell death (apoptosis) as a possible mechanism of action. Transplantation. 1992; 53(1):233-4. View

17.

Ho D . Toward HIV eradication or remission: the tasks ahead. Science. 1998; 280(5371):1866-7. DOI: 10.1126/science.280.5371.1866. View

18.

Wong J, Hezareh M, Gunthard H, Havlir D, Ignacio C, Spina C . Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997; 278(5341):1291-5. DOI: 10.1126/science.278.5341.1291. View

19.

Luster A . Chemokines--chemotactic cytokines that mediate inflammation. N Engl J Med. 1998; 338(7):436-45. DOI: 10.1056/NEJM199802123380706. View

20.

Buysmann S, Bemelman F, Schellekens P, van Kooyk Y, Figdor C, ten Berge I . Activation and increased expression of adhesion molecules on peripheral blood lymphocytes is a mechanism for the immediate lymphocytopenia after administration of OKT3. Blood. 1996; 87(1):404-11. View