Abstract
HIV-1 relies on the host-cell machinery to accomplish its replication cycle, and characterization of these helper factors contributes to a better understanding of HIV-host interactions and can identify potential novel antiviral targets. Here we explored the contribution of CIB2, previously identified by RNAi screening as a potential helper factor, and its homolog, CIB1. Knockdown of either CIB1 or CIB2 strongly impaired viral replication in Jurkat cells and in primary CD4+ T-lymphocytes, identifying these proteins as non-redundant helper factors. Knockdown of CIB1 and CIB2 impaired envelope-mediated viral entry for both for X4- and R5-tropic HIV-1, and both cell-free and cell-associated entry pathways were affected. In contrast, the level of CIB1 and CIB2 expression did not influence cell viability, cell proliferation, receptor-independent viral binding to the cell surface, or later steps in the viral replication cycle. CIB1 and CIB2 knockdown was found to reduce the expression of surface molecules implicated in HIV-1 infection, including CXCR4, CCR5 and integrin α4β7, suggesting at least one mechanism through which these proteins promote viral infection. Thus, this study identifies CIB1 and CIB2 as host helper factors for HIV-1 replication that are required for optimal receptor-mediated viral entry.
Highlights
Human Immunodeficiency Virus type-1 (HIV-1) relies on the host-cell machinery to accomplish its replication cycle, and characterization of these helper factors contributes to a better understanding of HIV-host interactions and can identify potential novel antiviral targets
We found that CIB1 and calcium- and integrin-binding 2 (CIB2) did not influence the initial attachment of HIV-1 to target cells, but both were required for optimal CCR5- and CXCR4-dependent entry occurring through either cell-free or cell-to-cell transmission pathways
Despite the significant homology between CIB1 and CIB2, the knockdown of mRNA expression was highly specific, as expression of short hairpin RNA (shRNA) against CIB1 had no significant effect on CIB2 mRNA levels, and shRNAs against CIB2 had no significant effect on CIB1 mRNA levels
Summary
HIV-1 relies on the host-cell machinery to accomplish its replication cycle, and characterization of these helper factors contributes to a better understanding of HIV-host interactions and can identify potential novel antiviral targets. It is not surprising that CIB proteins have been implicated in processes as diverse as, for example, cell survival and proliferation[26], non-homologous end-joining DNA repair[25], integrin signaling in skeletal muscle[12], cytoskeleton and microtubule organization[28], and macropinocytic cell entry of Kaposi’s sarcoma-associated herpesvirus[29]. Given their wide intracellular distribution and polyvalent functions, it is difficult to dismiss a priori a potential role of CIB1 and CIB2 proteins at any step in the HIV-1 life cycle, and multiple distinct functions cannot be excluded. The action of CIB1 and CIB2 were restricted to the early step of receptor-mediated viral entry
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