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Blockade of T cell costimulation reveals interrelated actions of CD4+ and CD8+ T cells in control of SIV replication
David A. Garber, … , Silvija I. Staprans, Mark B. Feinberg
David A. Garber, … , Silvija I. Staprans, Mark B. Feinberg
Published March 15, 2004
Citation Information: J Clin Invest. 2004;113(6):836-845. https://doi.org/10.1172/JCI19442.
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Article AIDS/HIV

Blockade of T cell costimulation reveals interrelated actions of CD4+ and CD8+ T cells in control of SIV replication

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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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Figure 1

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Effects of CS blockade on SIV replication. (A) SIV viral load
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Effects of CS blockade on SIV replication. (A) SIV viral load (log10 SIV RNA copies per milliliter plasma) from macaques in the control group (left panel) or CS blockade treatment group (right panel). Indicated are times at which individual macaques were sacrificed because of clinical deterioration due to simian AIDS (circled x). Control macaques: ROz5 (black), RBm6 (blue), RVy5 (red), RYt5 (green). CS blockade macaques: REp6 (black), REo6 (blue), RIc6 (red), RCr5 (green). The gray bar denotes the treatment period. (B) Geometric mean SIV viral load (log10 SIV RNA copies per milliliter plasma) for CS blockade group (red) and control group (black). The yellow shading indicates times at which significant differences were determined between groups (P ≤ 0.05, repeated measures analysis of means). The gray bar denotes the treatment period.
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