Dual effect of interleukin 4 on HIV-1 expression: Implications for viral phenotypic switch and disease progression

192

157

Chemokines play necessary and important roles in regulating the trafficking of lymphocytes to intra- or interlymphoid tissues as well as to sites of inflammation. The complex migratory patterns of lymphoid lineage cells is governed by subset-specific expression of chemokine receptors and their access to specific ligands. Several chemokine receptors and chemokine receptor-like orphan receptors also serve, in conjunction with CD4, as coreceptors for infection by human and simian immunodeficiency viruses (HIV and SIV). Here we show that the expression pattern of Bonzo/STRL33, an orphan SIV/HIV coreceptor, is highly restricted to the memory subset of T cells and is up-regulated upon stimulation of these cells with IL-2 or IL-15. Both the pattern and the regulation of Bonzo expression closely paralleled that of CC family chemokine receptors CCR5 or CCR6 and inversely correlated with CXCR4 expression. However, in striking contrast to CCR5, Bonzo expression was not down-modulated by PMA or mitogen stimulation of T cells. Targeted replacement of the Bonzo gene with a gene encoding green fluorescent protein in mice revealed that the expression and cytokine regulation of mouse Bonzo are comparable to those of its human counterpart. The similar expression and regulation patterns of Bonzo and the HIV coreceptor CCR5 may have implications for understanding the role of HIV/SIV receptors in viral evolution and pathogenesis.

Section: Figuresupporting

confidence: 92%

Section: Discussionmentioning

confidence: 92%

The Primate Lentiviral Receptor Bonzo/STRL33 Is Coordinately Regulated with CCR5 and Its Expression Pattern Is Conserved Between Human and Mouse

Unutmaz

Xiang

Sunshine

et al. 2000

192

157

“…The cytokine environment may determine susceptibility to HIV infection in part by the regulation of HIV-1 coreceptor expression (32). IL-4 down-regulates CCR5 but up-regulates CXCR4 expression on CD4 ϩ T cells and favors high replication of X4 HIV-1 strains (33). IL-4 can also increase HIV-1 replication in DC:T cell cocultures by stimulating T cell proliferation (34).…”

Section: Opposite Effects Of Il-10 On the Ability Of Dendritic Cells mentioning

confidence: 99%

Opposite Effects of IL-10 on the Ability of Dendritic Cells and Macrophages to Replicate Primary CXCR4-Dependent HIV-1 Strains

Ancuța

Bakri

Chomont

et al. 2001

We investigated the effect of IL-10 on replication of primary CXCR4-dependent (X4) HIV-1 strains by monocyte-derived dendritic cells (DCs) and macrophages (MΦs). MΦs efficiently replicated CXCR4-dependent HIV-1 (X4 HIV-1) strains NDK and VN44, whereas low levels of p24 were detected in supernatants of infected DCs. IL-10 significantly increased X4 HIV-1 replication by DCs but blocked viral production by MΦs as determined by p24 levels and semiquantitative nested PCR. IL-10 up-regulated CXCR4 mRNA and protein expression on DCs and MΦs, suggesting that IL-10 enhances virus entry in DCs but blocks an entry and/or postentry step in MΦs. The effect of IL-10 on the ability of DCs and MΦs to transmit virus to autologous CD4+ T lymphocytes was investigated in coculture experiments. DCs exhibited a greater ability than did MΦs to transmit a vigorous infection to CD4+ T cells despite their very low replication capacity. IL-10 had no effect on HIV-1 replication in DC:T cell cocultures but markedly decreased viral production in MΦ:T cell cocultures. These results demonstrate that IL-10 has opposite effects on the replication of primary X4 HIV-1 strains by DCs and MΦs. IL-10 increases X4-HIV-1 replication in DCs but does not alter their capacity to transmit virus to CD4+ T lymphocytes. These findings suggest that increased levels of IL-10 observed in HIV-1-infected patients with disease progression may favor the replication of X4 HIV-1 strains in vivo.

“…In addition, CXCR4 has been identified as a cofactor for HIV entry into T cells (4). We and others have shown previously that cell-surface expression of CXCR4 on T lymphocytes is strongly up-regulated by IL-4, rendering these cells susceptible to infection with certain strains of HIV-1 (5,6). In contrast, T cellexpressed CXCR4 is strongly down-regulated, following TCR/ CD3 complex-mediated activation, using either anti-CD3 mAbs (5,7) or specific Ag (8).…”

mentioning

confidence: 99%

Cytokines and Cell Surface Molecules Independently Induce CXCR4 Expression on CD4+ CCR7+ Human Memory T Cells

Jourdan

Vendrell²,

Huguet³

et al. 2000

106

In the present study, we show that IL-2, IL-4, IL-7, and IL-15 are able to induce functional CXCR4 surface expression on resting in vitro-generated CD4+ CXCR4− CCR7+ memory T cells. Cytokine-mediated induction of CXCR4 expression was associated with an increase in CXCR4 transcription, enhanced stromal-derived factor-1-induced T cell migration in vitro, and increased susceptibility of these cells to infection with X4 strains of HIV-1. CXCR4 expression could also be induced through an alternative pathway, following coculture of these cells with CD40-activated, autologous, CD34+ progenitor-derived dendritic cells. Although these dendritic cells express transcripts for IL-7 and IL-15, addition of neutralizing anti-IL-7R and IL-15 mAbs did not block induction of CXCR4 expression. Indeed, dendritic cell-mediated up-regulation of CXCR4 expression was found to depend on CD40/CD154 and CD134/CD134L interactions. Whereas activated autologous dendritic cells induced the expression of both CXCR4 and CD25 on a portion of CCR7+ memory T cells, concomitant CD3-mediated activation of these cells further enhanced CD25 expression, but, in contrast, prevented induction of CXCR4 expression. This observation suggests that triggering of the CD134 and CD154 molecules, in contrast to TCR/CD3 complex-mediated stimulation, results in simultaneous T cell activation and CXCR4 expression. Taken together, these results show that common γ-chain-interacting cytokines as well as signals mediated via noncognate interactions between activated dendritic cells and memory T cells are involved in the up-regulation of CXCR4 expression.