[TuOrA1135] Interleukin-7 accelerates HIV X4 replication by inducing the production of β-chemokines, downregulation of CCR5 and upregulation of CXCR4

14th International AIDS Conference

Barcelona, Spain — July 7-12, 2002

[TITLE:] Interleukin-7 accelerates HIV X4 replication by inducing the production of β-chemokines, downregulation of CCR5 and upregulation of CXCR4

[AUTHOR(S):] A. Llano, J. Barretina, A. Gutierrez, B. Clotet, J. Este Fundacio IrsiCaixa¹

Int Conf AIDS. 2002 Jul 7-12;14:Abstract No. TuOrA1135

[ABSTRACT:] Interleukin-7 (IL-7) plays an important role in HIV dependent T-cell depletion and pathogenesis. There is a clear relationship between CD4 T cell number, HIV viral load and circulating IL-7 levels. We have previously identified IL-7 as a factor that may be related to the evolution of HIV from CCR5-using (R5) to CXCR4-using (X4) strains but the exact mechanism has not been elucidated. In stimulated (PHA/IL-2) T-cell blasts, IL-7 induced a dose-dependent upregulation of CXCR4 and production of RANTES. The same effect was observed when freshly isolated PBMC from HIV+ individuals were cultured in the presence of IL-7. The increased RANTES production (up to 4500 pg/ml) was sufficient to induce a detectable downregulation of CCR5. Consequently, the replication of an X4 HIV-1 strain (NL4-3) could be enhanced by the presence of IL-7 or RANTES.

These results suggest that IL-7 may regulate β-chemokine production in vivo. When we evaluated IL-7 levels in plasma of HIV+ individuals, we found that individuals with low (< 9 pg/ml) IL-7 always had low levels (<20 ng/ml) of circulating RANTES and that high (>9 pg/ml) IL-7 was necessary but not sufficient to induce high levels of circulating RANTES in vivo. There is a high correlation (r: 0.797, p<0.001) between IL-7 and RANTES in plasma of individuals with CD4 cell count > 200 cell/ml. However, this correlation is lost (r: 0.379) when individuals with low CD4 cell count are included in the analysis. These results suggest that there may be a tight control of β-chemokine production that includes IL-7 in HIV+ individuals. However, as immunedeficiency progresses the regulatory mechanism is lost.

In conclusion, our data indicate that IL-7 may directly activate mature T cells to upregulate CXCR4 and induce β-chemokine production favouring the replication of X4 HIV. Our results suggest that IL-7 is a determinant in the emergence of SI/X4 strains and further support a role of chemokine levels in HIV disease progression.

Presenting author: Anuska Llan

1Fundació irsiCaixa, Hospital Trias i Pujol, Badalona, Spain/

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