Differential effects of IL-4 on HIV-1 expression suggest a role in viral phenotypic switch and disease progression

OBJECTIVES: To study the effects of the cytokine network on HIV expression and switching. DESIGN: HIV-1 isolates have been classified as rapid/high or syncytia-inducing (SI) and slow/low or non-syncytia-inducing (NSI) according to their biological phenotype. The main coreceptors for NSI and SI virus entry are the chemokine receptors CCR5 and CXCR4, respectively. NSI viruses are more likely to be transmitted and are found early after infection in most infected individuals. In contrast, SI viruses are usually found in the later stages of disease, and their appearance is associated with increased viral loads and poor prognosis. Although a switch from NSI to SI has been demonstrated in a majority of BIV-1 infected individuals, the mechanism regulating this process is poorly understood. METHODS: We measured expression of CCR5 and CXCR4 coreceptor levels and correlated these levels to virus propagation in primary lymphocytes and attached macrophages, after treatment with several cytokines including IL-2, IIL-4, IL-5, IL-10 and IL-13 under different conditions. Specific populations of primary cells were examined after fractionation and by FAX analysis. RESULTS: We found that IL-4 inhibited infection by NSI HIV-1 by downregulating the NSI coreceptor CCR5 in primary T-lymphocytes. In contrast, IL-4 increased the expression of both NSI and SI virus isolates in primary macrophages. In addition, IL-4 activated intracellular expression, in both T-cells and macrophages, of all HIV-1 isolates via a tat-dependent transcriptional mechanism. The combination of these effects results in increased propagation of SI and inhibition of NSI HIV-1 primary isolates. Research sponsored by the National Cancer Institute, DHHS, under contract with ABL. CONCLUSION: IL-4 is an important regulator of HIV-1. It is responsible for modulating the levels of critical virus coreceptors and may have a critical role in the control of viral evolution and in the phenotypic switch from CCR5 to CXCR4-using virus.

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