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Genome-Wide Innate Immune Responses in HIV-1-Infected Macrophages Are Preserved Despite Attenuation of the NF-B Activation Pathway¹

Mahdad Noursadeghi^2,*, Jhen Tsang^*, Robert F. Miller, Sarah Straschewski^3,*, Paul Kellam^*, Benjamin M. Chain^* and David R. Katz^*

^* Infection and Immunity and Centre for Sexual Health and HIV Research, University College London, London, United Kingdom

Macrophages contribute to HIV-1 infection at many levels. They provide permissive cells at the site of inoculation, augment virus transfer to T cells, generate long-lived viral reservoirs, and cause bystander cell apoptosis. A body of evidence suggests that the role of macrophages in cellular host defense is also compromised by HIV-1 infection. In this respect, macrophages are potent cells of the innate immune system that initiate and regulate wide-ranging immunological responses. This study focuses on the effect of HIV-1 infection on innate immune responses by macrophages at the level of signal transduction, whole genome transcriptional profiling, and cytokine secretion. We show that in an ex vivo model, M-CSF-differentiated monocyte-derived macrophages uniformly infected with replicating CCR5-tropic HIV-1, without cytopathic effect, exhibit selective attenuation of the NF-B activation pathway in response to TLR4 and TLR2 stimulation. However, functional annotation clustering analysis of genome-wide transcriptional responses to LPS stimulation suggests substantial preservation of gene expression changes at the systems level, with modest attenuation of a subset of up-regulated LPS-responsive genes, and no effect on a selection of inflammatory cytokine responses at the protein level. These results extend existing reports of inhibitory interactions between HIV-1 accessory proteins and NF-B signaling pathways, and whole genome expression profiling provides comprehensive assessment of the consequent effects on immune response gene expression. Unexpectedly, our data suggest innate immune responses are broadly preserved with limited exceptions, and pave the way for further study of the complex relationship between HIV-1 and immunological pathways within macrophages.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Wellcome Trust fellowship (WT077161) to M.N.

² Address correspondence and reprint requests to Dr. Mahdad Noursadeghi, Infection and Immunity, University College London, Windeyer Building, 46 Cleveland Street, London W1T 4JF, U.K. E-mail address: m.noursadeghi{at}ucl.ac.uk

³ Current address: Institute for Virology, University Hospital, Ulm, Germany.

⁴ Abbreviations used in this paper: MDM, monocyte-derived macrophage; AF, Alexa Fluor; DAPI, 4',6-diamidino-2-phenylindole; FDR, false detection rate; HS, human serum; MOI, multiplicity of infection; NHS, normal HS; SAM, significance analysis of microarray; Pam₃CSK4, N-palmitoyl-S-[2,3-bis(palmitoyloxy)- (2RS)-propyl]-Cys-Ser-Lys4.

⁵ The online version of this article contains supplementary material.