Identification of T cell-signaling pathways that stimulate latent HIV in primary cells.
Eradication of HIV infection depends on the elimination of a small, but stable population of latently infected T cells. After the discontinuation of therapy, activation of latent virus can rekindle infection. To purge this reservoir, it is necessary to define cellular signaling pathways that lead to activation of latent HIV. We used the SCID-hu (Thy/Liv) mouse model of HIV latency to analyze a broad array of T cell-signaling pathways and show in primary, quiescent cells that viral induction depends on the activation of two primary intracellular signaling pathways, protein kinase C or nuclear factor of activated T cells (NF-AT). In contrast, inhibition or activation of other important T cell stimulatory pathways (such as mitogen-activated protein kinase, calcium flux, or histone deacetylation) do not significantly induce virus expression. We found that the activation of NF-kappaB is critical to viral reactivation; however, all pathways that stimulate NF-kappaBdonot reactivate latent virus. Our studies further show that inhibition of NF-kappaB does not prevent activation of HIV by NF-AT, indicating that these pathways can function independently to activate the HIV LTR. Thus, we define several molecular pathways that trigger HIV reactivation from latency and provide evidence that latent HIV infection is maintained by the functional lack of particular transcription factors in quiescent cells.
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California-Los Angeles, 10833 LeConte Avenue, Los Angeles, CA 90095, USA.
David G
DG
Brooks
Philip A
PA
Arlen
Lianying
L
Gao
Christina M R
CM
Kitchen
Jerome A
JA
Zack
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D002453:Cell Cycle / Q000276:immunology; D016332:Fetal Tissue Transplantation / Q000276:immunology; D006678:HIV / Q000502:physiology*; D006801:Humans; D016031:Liver Transplantation; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology; D014775:Virus Activation / Q000276:immunology; D017735:Virus Latency / Q000276:immunology*
D015704:CD4 Antigens