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200 The β Chemokines MDC, TARC and I-309 are an Important Component of the Soluble anti-X4 Activity Secreted by CD4+ and CD8+ T Cells

Cocchi, F; DeVico, A; Demo, A Garzino; Latinovic, O; Gallo, R C

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 85
doi: 10.1097/01.qai.0000397382.77308.18

Institute of Human Virology, Baltimore, MD

Control of persistent viral infection relies particularly on cell-mediated immunity comprised of CD4+ and CD8+ T cells. There is accumulating evidence on the relevance of soluble factor(s) secreted by CD8+ and CD4+ T cells in controlling HIV replication in vivo. While the β chemokines RANTES, MIP1-α and MIP1-β collectively account for the suppression of R5 viruses, yet information is lacking on the identity of the molecules involved in the suppression of X4 viruses. Proteins that inhibit the replication of X4 HIV isolates were purified from the conditioned media (CM) of immortalized CD8+ and CD4+ T cell lines from HIV+ long-term non-progressors subjects (LTNPs) and identified as the β chemokines macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC) and I-309. These chemokines are secreted primarily by CD4+ T cells but also by CD8+T cells. CD4+ T cells of asymptomatic HIV+ individuals secreted significantly higher levels of MDC and TARC compared with subjects who progressed to AIDS. Recombinant human MDC, TARC and I309 induced a dose dependent inhibition of X4 viruses. A cocktail of neutralizing antibodies against MDC, TARC and I309 abrogated the inhibition of the replication of X4 viruses mediated by the endogenous chemokines in PBMC and CD8-depleted PBMC cells acutely infected in vitro. While the β chemokines RANTES, MIP1-α and MIP1-β suppress R5 viruses by blocking their entry into host cells the mechanism of inhibition of X4 viruses mediated by MDC, TARC and I-309 is a post entry mechanism of suppression. These molecules represent a major component of the soluble anti-X4 activity of T cells, suggesting that the mechanism whereby CD8+ and CD4+ T cells contribute to the control of HIV-1 replication may relate to the secretion of MDC, TARC and I-309.These results may be relevant to HIV pathogenesis.

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