HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages.

HIV establishes long-term latent infection in memory CD4 ⁺ T cells and also establishes sustained long-term productive infection in macrophages, especially in the central nervous system (CNS). To better understand how HIV sustains infection in macrophages, we performed RNAseq analysis after infection of human monocyte-derived macrophages (MDMs) with the brain-derived HIV-1 strain YU2 and compared this with acute infection of CD4 ⁺ T cells. HIV infection in MDM and CD4 ⁺ T cells altered many gene transcripts, but with few overlaps between these different cell types. We found interferon pathways upregulated in both MDM and CD4 ⁺ T cells, but with different gene signatures. The interferon-stimulated gene RSAD2/Viperin was among the most upregulated genes following HIV infection in MDMs, but not in CD4 ⁺ T cells. RSAD2/Viperin was induced early after infection with various HIV strains, was sustained over time, and remained elevated in established MDM infection even if new rounds of infection were blocked by antiretroviral treatment. Immunofluorescence microscopy revealed that RSAD2/Viperin was induced in HIV-infected cells, as well as in some uninfected neighboring cells. Knockdown of RSAD2/Viperin following the establishment of infection in MDMs reduced the production of HIV transcripts and viral p24 antigen. This correlated with the reduction in the number of multinucleated giant cells, and changes in the HIV DNA and chromatin structure, including an increased DNA copy number and loss of nucleosomes and histone modifications at the long terminal repeat (LTR). RNAseq transcriptomic analysis of RSAD2/Viperin knockdown during HIV infection of MDMs revealed the activation of interferon alpha/beta and gamma pathways and the inactivation of Rho GTPase pathways. Taken together, these results suggest that RSAD2/Viperin supports the sustained infection in macrophages, potentially through mechanisms involving the alteration of the LTR chromatin structure and the interferon response.
Importance: HIV infection of macrophages is a barrier to HIV cure and a source of neurocognitive pathology. We found that HIV induces RSAD2/Viperin during sustained infection of macrophages. While RSAD2/Viperin is an interferon-stimulated gene with known antiviral activity, we find RSAD2/Viperin promotes HIV infection in macrophages through multiple mechanisms, including interferon signaling. Therefore, RSAD2/Viperin may be a therapeutic target for the treatment of HIV-infected macrophages.
Competing Interests: Paul M. Lieberman declares his role as a founder of Vironika, LLC, as a conflict of interest that is managed by the Wistar Institute. Fang Lu is presently an employee at Wuxi Therapeutics.