Molecular Cell
Volume 78, Issue 2, 16 April 2020, Pages 197-209.e7
Journal home page for Molecular Cell

Article
A Quantitative Genetic Interaction Map of HIV Infection

https://doi.org/10.1016/j.molcel.2020.02.004Get rights and content
Under an Elsevier user license
open archive

Highlights

  • We adapted the E-MAP approach to study genetic interactions underlying viral infection

  • We studied host gene pairs as well as gene-drug and gene-viral mutant combinations

  • The HIV vE-MAP highlighted a role for the CNOT complex in mediating infection

  • CNOT mediates HIV infection in primary CD4+ T cells by suppression of innate immunity

Summary

We have developed a platform for quantitative genetic interaction mapping using viral infectivity as a functional readout and constructed a viral host-dependency epistasis map (vE-MAP) of 356 human genes linked to HIV function, comprising >63,000 pairwise genetic perturbations. The vE-MAP provides an expansive view of the genetic dependencies underlying HIV infection and can be used to identify drug targets and study viral mutations. We found that the RNA deadenylase complex, CNOT, is a central player in the vE-MAP and show that knockout of CNOT1, 10, and 11 suppressed HIV infection in primary T cells by upregulating innate immunity pathways. This phenotype was rescued by deletion of IRF7, a transcription factor regulating interferon-stimulated genes, revealing a previously unrecognized host signaling pathway involved in HIV infection. The vE-MAP represents a generic platform that can be used to study the global effects of how different pathogens hijack and rewire the host during infection.

Keywords

epistasis map
vE-MAP
CCR4-NOT
CNOT complex
IRF7
combinatorial genetics
innate immunity
interferon stimulated gene
viral infection genetic screen
host-pathogen network biology

Cited by (0)

11

These authors contributed equally

12

Lead Contact