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

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 HIV-1 infected individuals, the mechanism regulating this process is poorly understood. We study the effects of the cytokine network on HIV expression and switching. We found that IL-4 inhibits infection by NSI HIV-1 by downregulating the NSI coreceptor in T-lymphocytes but not in primary macrophages. In addition, IL-4 activates the 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 FNSI HIV-1 primary isolates. Thus IL-4 is an important regulator of HIV-1 and may have a critical role in the control of viral evolution and in the phenotypic switch from CCR5 to CSCR4-using virus.

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