Abstract
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.
Authors
David A. Garber, Guido Silvestri, Ashley P. Barry, Andrew Fedanov, Natalia Kozyr, Harold McClure, David C. Montefiori, Christian P. Larsen, John D. Altman, Silvija I. Staprans, Mark B. Feinberg
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