HIV-1 replication is controlled at the level of T cell activation and proviral integration

EMBO J. 1990 May;9(5):1551-60.

Abstract

During progression of the Acquired Immune Deficiency Syndrome (AIDS), the human immunodeficiency virus type 1 (HIV-1) is harbored in CD4+ T cells, which act as the primary reservoir for the virus. In vitro, HIV-1 requires activated T cells for a productive infection; however, in vivo, the number of circulating T cells in the activated state that are potential targets for HIV-1 infection is low. We have investigated the ability of HIV-1 to infect resting T cells, and the consequences of such an infection. T cell activation was not required for HIV-1 infection; however, viral DNA was unable to integrate in resting T cells and was maintained extrachromosomally. Subsequent T cell activation allowed integration of extrachromosomal forms and led to a productive viral life cycle. Extrachromosomal forms of viral DNA were found to persist for several weeks after infection of resting T cells and, following T cell activation, these forms maintained their ability to integrate and act as a template for infectious virus. Several lines of evidence, including temporal analysis of HIV-1 replication and analysis of an HIV-1 integrase deletion mutant, indicated that extra-chromosomal HIV-1 DNA genomes were transcriptionally active. These results are compatible with a model whereby HIV-1 can persist in a non-productive extra-chromosomal state in resting T cells until subsequent antigen-induced or mitogen-induced T cell activation, virus integration and release. Thus agents that induce T cell activation may control the rate of HIV-1 replication and spread during AIDS progression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acquired Immunodeficiency Syndrome / microbiology*
  • DNA Nucleotidyltransferases / physiology
  • DNA, Viral / physiology
  • Gene Products, gag / biosynthesis
  • Gene Products, tat / biosynthesis
  • HIV-1 / genetics
  • HIV-1 / physiology*
  • Integrases
  • Lymphocyte Activation
  • Lysogeny
  • Models, Genetic
  • Mutation
  • Polymerase Chain Reaction
  • T-Lymphocytes / microbiology*
  • Virus Replication / immunology*
  • tat Gene Products, Human Immunodeficiency Virus

Substances

  • DNA, Viral
  • Gene Products, gag
  • Gene Products, tat
  • tat Gene Products, Human Immunodeficiency Virus
  • DNA Nucleotidyltransferases
  • Integrases