HIV-1 replication is controlled at the level of T cell activation and proviral integration.
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.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68105.
M
M
Stevenson
T L
TL
Stanwick
M P
MP
Dempsey
C A
CA
Lamonica
D000163:Acquired Immunodeficiency Syndrome / Q000382:microbiology*; D004254:DNA Nucleotidyltransferases / Q000502:physiology; D004279:DNA, Viral / Q000502:physiology; D015683:Gene Products, gag / Q000096:biosynthesis; D015696:Gene Products, tat / Q000096:biosynthesis; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D019426:Integrases; D008213:Lymphocyte Activation; D008242:Lysogeny; D008957:Models, Genetic; D009154:Mutation; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000382:microbiology*; D014779:Virus Replication / Q000276:immunology*; D054322:tat Gene Products, Human Immunodeficiency Virus
D004279:DNA, Viral; D015683:Gene Products, gag; D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus; D004254:DNA Nucleotidyltransferases; D019426:Integrases