Blockade of T cell costimulation reveals interrelated actions of CD4+ and CD8+ T cells in control of SIV replication.
In vivo blockade of CD28 and CD40 T cell costimulation pathways during acute simian immunodeficiency virus (SIV) infection of rhesus macaques was performed to assess the relative contributions of CD4+ T cells, CD8+ T cells, and Ab responses in modulating SIV replication and disease progression. Transient administration of CTLA4-Ig and anti-CD40L mAb to SIV-infected rhesus macaques resulted in dramatic inhibition of the generation of both SIV-specific cellular and humoral immune responses. Acute levels of proliferating CD8+ T cells were associated with early control of SIV viremia but did not predict ensuing set point viremia or survival. The level of in vivo CD4+ T cell proliferation during acute SIV infection correlated with concomitant peak levels of SIV plasma viremia, whereas measures of in vivo CD4+ T cell proliferation that extended into chronic infection correlated with lower SIV viral load and increased survival. These results suggest that proliferating CD4+ T cells function both as sources of virus production and as antiviral effectors and that increased levels of CD4+ T cell proliferation during SIV infections reflect antigen-driven antiviral responses rather than a compensatory homeostatic response. These results highlight the interrelated actions of CD4+ and CD8+ T cell responses in vivo that modulate SIV replication and pathogenesis.
Garber
David A
DA
Emory Vaccine Center, Atlanta, Georgia 30329, USA.
Silvestri
Guido
G
Barry
Ashley P
AP
Fedanov
Andrew
A
Kozyr
Natalia
N
McClure
Harold
H
Montefiori
David C
DC
Larsen
Christian P
CP
Altman
John D
JD
Staprans
Silvija I
SI
Feinberg
Mark B
MB
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000378:metabolism; D008253:Macaca mulatta / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D019562:Viral Load; D014779:Virus Replication / Q000502:physiology*
D007371:Interferon-gamma