HIV-1 Integrase Variants Retarget Viral Integration and Are Associated With Disease Progression in a Chronic Infection Cohort

Cell Host Microbe. 2014 Nov 12;16(5):651-62. doi: 10.1016/j.chom.2014.09.016. Epub 2014 Nov 12.

Abstract

Distinct integration patterns of different retroviruses, including HIV-1, have puzzled virologists for over 20 years. A tetramer of the viral integrase (IN) assembles on the two viral cDNA ends, docks onto the target DNA (tDNA), and catalyzes viral genome insertion into the host chromatin. We identified the amino acids in HIV-1 IN that directly contact tDNA bases and affect local integration site sequence selection. These residues also determine the propensity of the virus to integrate into flexible tDNA sequences. Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene-dense regions. Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort. These findings link integration site selection to virulence and viral evolution, but also to the host immune response and antiretroviral therapy, since HIV-1 IN119 is under selection by HLA alleles and integrase inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cloning, Molecular
  • Computational Biology
  • DNA, Viral / genetics
  • Disease Progression
  • Genome, Viral
  • HIV Infections / enzymology*
  • HIV Integrase / genetics
  • HIV Integrase / metabolism*
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Polymorphism, Genetic
  • Protein Conformation
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Virus Integration*
  • Virus Replication

Substances

  • DNA, Viral
  • Recombinant Proteins
  • HIV Integrase
  • p31 integrase protein, Human immunodeficiency virus 1

Associated data

  • GEO/GSE61003