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.
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.
Leone
Amanda
A
Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
Rohankhedkar
Mukta
M
Okoye
Afam
A
Legasse
Alfred
A
Axthelm
Michael K
MK
Villinger
Francois
F
Piatak
Michael
M
Lifson
Jeffrey D
JD
Assouline
Brigitte
B
Morre
Michel
M
Picker
Louis J
LJ
Sodora
Donald L
DL
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D018791:CD4 Lymphocyte Count; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000068679:Emtricitabine; D015851:Interleukin-7 / Q000008:administration & dosage*; D008253:Macaca mulatta; D063065:Organophosphonates / Q000008:administration & dosage*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D000068698:Tenofovir
D015851:Interleukin-7; D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine