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

• Published in: The Journal of immunology (1950) 2010-08, Vol.185 (3), p.1650-1659
• Main Authors: Leone, Amanda, Rohankhedkar, Mukta, Okoye, Afam, Legasse, Alfred, Axthelm, Michael K, Villinger, Francois, Piatak, Jr, Michael, Lifson, Jeffrey D, Assouline, Brigitte, Morre, Michel, Picker, Louis J, Sodora, Donald L
• Format: Article
• Language: English
• Subjects: Adenine - administration & dosage; Adenine - analogs & derivatives; Animals; Antiretroviral Therapy, Highly Active - methods; CD4 Lymphocyte Count; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Cell Proliferation - drug effects; CHO Cells; Cricetinae; Cricetulus; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Emtricitabine; Interleukin-7 - administration & dosage; Macaca mulatta; Organophosphonates - administration & dosage; Simian Acquired Immunodeficiency Syndrome - drug therapy; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - pathology; Tenofovir
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0902626

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.