Increased CD4+ T cell levels during IL-7 administration of antiretroviral therapy-treated simian immunodeficiency virus-positive macaques are not dependent on strong proliferative responses

Amanda Leone, Mukta Rohankhedkar, Afam Okoye, Alfred Legasse, Michael Axthelm, Francois Villinger, Michael Piatak, Jeffrey D. Lifson, Brigitte Assouline, Michel Morre, Louis Picker, Donald L. Sodora

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

CD4+ T cell depletion is a fundamental component of HIV infection and AIDS pathogenesis and is not always reversed following antiretroviral therapy (ART). In this study, the SIV-infected rhesus macaque model was used to assess recombinant simian IL-7 in its glycosylated form (rsIL-7gly) to enhance regeneration of CD4+ T cells, particularly the crucial central memory compartment, after ART. We assessed the impact of rsIL-7gly administration as single injections and as a cluster of three doses. Irrespective of the dosing strategy used, the rsIL-7gly administration transiently increased proliferation of both central memory and naive cells, in both CD4+ and CD8+ subsets, without increasing SIV levels in the blood. Administration of rsIL-7gly at intervals of 4-6 wk maximized the proliferative response to therapy but resulted in only transient increases in peripheral blood T cell counts. Although more frequent rsIL-7gly "clustered" dosing (three times weekly with 2 wk of rest and then repeat) induced only an initial proliferative burst by CD4+ T cells, this dosing strategy resulted in sustained increases in peripheral blood CD4+ T cell counts. The clustered rsIL-7gly treatment regimen was shown to increase the half-life of a BrdU label among memory T cells in the blood when compared with that of macaques treated with ART alone, which is consistent with enhanced cell survival. These results indicate that dosing intervals have a major impact on the response to rsIL-7gly in SIV-positive ART-treated rhesus macaques and that optimum dosing strategies may be ones that induce CD4+ T cell proliferation initially and provide increased CD4+ T cell survival.

Original languageEnglish (US)
Pages (from-to)1650-1659
Number of pages10
JournalJournal of Immunology
Volume185
Issue number3
DOIs
StatePublished - Aug 1 2010

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Interleukin-7
Simian Immunodeficiency Virus
Macaca
T-Lymphocytes
Therapeutics
Macaca mulatta
Cell Survival
Blood Cell Count
Bromodeoxyuridine
CD4 Lymphocyte Count
HIV Infections
Half-Life
Regeneration
Acquired Immunodeficiency Syndrome
Cell Proliferation
Injections

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Increased CD4+ T cell levels during IL-7 administration of antiretroviral therapy-treated simian immunodeficiency virus-positive macaques are not dependent on strong proliferative responses. / Leone, Amanda; Rohankhedkar, Mukta; Okoye, Afam; Legasse, Alfred; Axthelm, Michael; Villinger, Francois; Piatak, Michael; Lifson, Jeffrey D.; Assouline, Brigitte; Morre, Michel; Picker, Louis; Sodora, Donald L.

In: Journal of Immunology, Vol. 185, No. 3, 01.08.2010, p. 1650-1659.

Research output: Contribution to journalArticle

Leone, Amanda ; Rohankhedkar, Mukta ; Okoye, Afam ; Legasse, Alfred ; Axthelm, Michael ; Villinger, Francois ; Piatak, Michael ; Lifson, Jeffrey D. ; Assouline, Brigitte ; Morre, Michel ; Picker, Louis ; Sodora, Donald L. / Increased CD4+ T cell levels during IL-7 administration of antiretroviral therapy-treated simian immunodeficiency virus-positive macaques are not dependent on strong proliferative responses. In: Journal of Immunology. 2010 ; Vol. 185, No. 3. pp. 1650-1659.
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AU - Legasse, Alfred

AU - Axthelm, Michael

AU - Villinger, Francois

AU - Piatak, Michael

AU - Lifson, Jeffrey D.

AU - Assouline, Brigitte

AU - Morre, Michel

AU - Picker, Louis

AU - Sodora, Donald L.

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AB - CD4+ T cell depletion is a fundamental component of HIV infection and AIDS pathogenesis and is not always reversed following antiretroviral therapy (ART). In this study, the SIV-infected rhesus macaque model was used to assess recombinant simian IL-7 in its glycosylated form (rsIL-7gly) to enhance regeneration of CD4+ T cells, particularly the crucial central memory compartment, after ART. We assessed the impact of rsIL-7gly administration as single injections and as a cluster of three doses. Irrespective of the dosing strategy used, the rsIL-7gly administration transiently increased proliferation of both central memory and naive cells, in both CD4+ and CD8+ subsets, without increasing SIV levels in the blood. Administration of rsIL-7gly at intervals of 4-6 wk maximized the proliferative response to therapy but resulted in only transient increases in peripheral blood T cell counts. Although more frequent rsIL-7gly "clustered" dosing (three times weekly with 2 wk of rest and then repeat) induced only an initial proliferative burst by CD4+ T cells, this dosing strategy resulted in sustained increases in peripheral blood CD4+ T cell counts. The clustered rsIL-7gly treatment regimen was shown to increase the half-life of a BrdU label among memory T cells in the blood when compared with that of macaques treated with ART alone, which is consistent with enhanced cell survival. These results indicate that dosing intervals have a major impact on the response to rsIL-7gly in SIV-positive ART-treated rhesus macaques and that optimum dosing strategies may be ones that induce CD4+ T cell proliferation initially and provide increased CD4+ T cell survival.

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