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Modulation of HIV-1 replication by the Th2 chemokine CCL18
Presented by Helena Schmidtmayerova, United States.
Schmidtmayerova H.1, Singh P.1, Chaung W.1, Giannakou A.1, Pompucci L.1, Malhotra P.2
1The Feinstein Institute for Medical Research, Manhasset, United States, 2North Shore University Hospital, Manhasset, United States
Objectives: To evaluate the effect of CCL18, a Th2 chemokine elevated in HIV-1-infected patients, on viral replication.
Methods: Primary lymphocytes isolated from the blood of healthy donors were activated with PHA/IL-2 or cultivated in the presence of IL-2 without PHA stimulation (sub-optimal activation). Cells were treated with human recombinant CCL18 before infection with HIV-1 R5 or X4 strains. Viral replication was analyzed by p24 antigen assay and synthesis of viral DNA was determined by PCR. Co-receptor expression was measured by flow cytometry. The activation of intracellular signaling pathways was analyzed by western blotting using phospho-specific antibodies against ERK42/44 and p38 MAPK.
Results: HIV-1 replication in PHA/IL-2 activated lymphocytes was not affected by CCL18. However, when cells were cultivated in the presence of IL-2 without previous PHA activation, CCL18 selectively increased replication of X4 viruses in a dose-dependent manner. Treatment with CCL18 had no effect on the expression of viral co-receptors CXCR4 or CCR5. PCR analysis revealed that CCL18 modulates early steps in the viral life cycles. It has been previously suggested that in contrast to R5 viruses, replication of X4 strains depends on the activation-induced MEK/ERK pathway. Indeed, our results showed increased activation of ERK42/44 and p38 MAPK in CCL18-treated cells.
Conclusions: CCL18 selectively enhances replication of X4 viruses in sub-optimally activated lymphocytes, most likely via activation of ERK42/44 and p38 MAPK pathways. These data suggest that increased levels of CCL18 in HIV-1patients may contribute to the enhanced replication of X4 viruses emerging during later stages of the infection.
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