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Castro-Gonzalez S, Chen Y, Benjamin J, et al. Residues T. Retrovirology. 2021;18(1):33doi: 10.1186/s12977-021-00576-y.
Castro-Gonzalez, S., Chen, Y., Benjamin, J., Shi, Y., & Serra-Moreno, R. (2021). Residues T. Retrovirology, 18(1), 33. https://doi.org/10.1186/s12977-021-00576-y
Castro-Gonzalez, Sergio, et al. "Residues T." Retrovirology vol. 18,1 (2021): 33. doi: https://doi.org/10.1186/s12977-021-00576-y
Castro-Gonzalez S, Chen Y, Benjamin J, Shi Y, Serra-Moreno R. Residues T. Retrovirology. 2021 Oct 28;18(1):33. doi: 10.1186/s12977-021-00576-y. PMID: 34711257; PMCID: PMC8555152.
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Retrovirology. 2021 Oct 28;18(1):33. doi: 10.1186/s12977-021-00576-y.

Residues T.

Retrovirology

Sergio Castro-Gonzalez, Yuexuan Chen, Jared Benjamin, Yuhang Shi, Ruth Serra-Moreno

Affiliations

  1. Department of Chemistry, Umeå University, Umeå, Sweden.
  2. Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.
  3. Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA. [email protected].

PMID: 34711257 PMCID: PMC8555152 DOI: 10.1186/s12977-021-00576-y

Abstract

BACKGROUND: Autophagy plays an important role as a cellular defense mechanism against intracellular pathogens, like viruses. Specifically, autophagy orchestrates the recruitment of specialized cargo, including viral components needed for replication, for lysosomal degradation. In addition to this primary role, the cleavage of viral structures facilitates their association with pattern recognition receptors and MHC-I/II complexes, which assists in the modulation of innate and adaptive immune responses against these pathogens. Importantly, whereas autophagy restricts the replicative capacity of human immunodeficiency virus type 1 (HIV-1), this virus has evolved the gene nef to circumvent this process through the inhibition of early and late stages of the autophagy cascade. Despite recent advances, many details of the mutual antagonism between HIV-1 and autophagy still remain unknown. Here, we uncover the genetic determinants that drive the autophagy-mediated restriction of HIV-1 as well as the counteraction imposed by Nef. Additionally, we also examine the implications of autophagy antagonism in HIV-1 infectivity.

RESULTS: We found that sustained activation of autophagy potently inhibits HIV-1 replication through the degradation of HIV-1 Gag, and that this effect is more prominent for nef-deficient viruses. Gag re-localizes to autophagosomes where it interacts with the autophagosome markers LC3 and SQSTM1. Importantly, autophagy-mediated recognition and recruitment of Gag requires the myristoylation and ubiquitination of this virus protein, two post-translational modifications that are essential for Gag's central role in virion assembly and budding. We also identified residues T

CONCLUSIONS: This study provides evidence that autophagy antagonism is important for virus replication and suggests that the ability of Nef to counteract autophagy may have played an important role in mucosal transmission. Hence, disabling Nef in combination with the pharmacological manipulation of autophagy represents a promising strategy to prevent HIV spread.

© 2021. The Author(s).

Keywords: Autophagy; Gag; HIV-1; Nef

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