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HIV-2 evolved ZAP resistance despite increased CpG levels

ABSTRACT: Simian immunodeficiency viruses infecting sooty mangabeys (SIVsmm) have been transmitted to humans on multiple occasions, giving rise to human immunodeficiency virus type 2 (HIV-2) groups A to I. However, only groups A and B spread significantly in humans causing an epidemic in West Africa. The reasons for this are poorly understood. Here, we show that genetically diverse SIVsmm strains efficiently infect primary human T cells. However, they are highly sensitive to type I IFN, indicating that interferon-stimulated genes (ISGs) pose a barrier to the successful spread of SIVsmm in humans. One well-known ISG is the zinc finger antiviral protein (ZAP), which specifically targets CpG dinucleotides in viral RNAs. To evade ZAP restriction, many viruses, including HIV-1, suppress their CpG content. Unexpectedly, we found that HIV-2 is less sensitive to restriction by ZAP than HIV-1 and SIVsmm despite significantly higher CpG content. Analyses of chimeric HIV-2/SIVsmm constructs, together with binding site mapping using eCLIP, revealed that the determinants of ZAP resistance map to the U3 region of the 3’ LTR that overlaps with the nef gene. Our results indicate that ZAP poses a barrier to the efficient spread of SIVsmm in humans and that epidemic HIV-2 evolved a unique mechanism to evade it.

ORGANISM(S): Human immunodeficiency virus 2 Homo sapiens Simian immunodeficiency virus

PROVIDER: GSE290608 | GEO | 2025/03/06

REPOSITORIES: GEO

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Project description:Macrophages provide an interface between innate and adaptive immunity and are important long-lived reservoirs for Human Immunodeficiency Virus Type-1 (HIV-1). Multiple genetic networks involved in regulating signal transduction cascades and immune responses in macrophages are coordinately modulated by HIV-1 infection. To evaluate complex interrelated processes and to assemble an integrated view of activated signaling networks, a systems biology strategy was applied to genomic and proteomic responses by primary human macrophages over the course of HIV-1 infection. Macrophage responses, including cell cycle, calcium, apoptosis, mitogen-activated protein kinases (MAPK), and cytokines/chemokines, to HIV-1 were temporally regulated, in the absence of cell proliferation. In contrast, Toll-like receptor (TLR) pathways remained unaltered by HIV-1, although TLRs 3, 4, 7, and 8 were expressed and responded to ligand stimulation in macrophages. HIV-1 failed to activate phosphorylation of IRAK-1 or IRF-3, modulate intracellular protein levels of Mx1, an interferon-stimulated gene, or stimulate secretion of TNF, IL-1b, or IL-6. Activation of pathways other than TLR was inadequate to stimulate, via cross-talk mechanisms through molecular hubs, the production of proinflammatory cytokines typical of a TLR response. HIV-1 sensitized macrophage responses to TLR ligands, and the magnitude of viral priming was related to virus replication. HIV-1 induced a primed, proinflammatory state, M1HIV, which increased the responsiveness of macrophages to TLR ligands. HIV-1 might passively evade pattern recognition, actively inhibit or suppress recognition and signaling, or require dynamic interactions between macrophages and other cells, such as lymphocytes or endothelial cells. HIV-1 evasion of TLR recognition and simultaneous priming of macrophages may represent a strategy for viral survival, contribute to immune pathogenesis, and provide important targets for therapeutic approaches. Affymetrix arrays were used to identify genomic macrophage response to HIV during viral spread in culture. Experiment Overall Design: An HIV-1 spreading infection was established in primary human macrophages. RNA was extracted from both viral- and mock-infected macrophages cultures over 7 days and hybridized to Affymetrix HG-U95Av2 GeneChips for analysis.

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HIV-2 evolved ZAP resistance despite increased CpG levels

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