Transcriptional profiles of latent human immunodeficiency virus in infected individuals: effects of Tat on the host and reservoir.
The persistence of human immunodeficiency virus (HIV) in optimally treated infected individuals poses a major therapeutic problem. In latently infected cells, one of the observed phenotypes is absent elongation of viral transcription. Thus, the positive elongation factor b (P-TEFb), which is usually recruited by NF-kappaB or Tat, is not present on the HIV long terminal repeat (LTR). Although most attempts to activate these proviruses centered on NF-kappaB, we investigated effects of Tat. To this end, we generated transgenic mice, which secreted a chimera between Tat and the green fluorescent protein from beta cells of the pancreas. This extracellular Tat distributed widely, entered nuclei of resting cells, and specifically transactivated the HIV LTR. No deleterious side effects of Tat were found. Next, we determined that Tat can activate latent proviruses in optimally treated infected individuals. In their cells, T-cell activation or exogenous Tat could induce viral replication equivalently. Thus, P-TEFb could activate the majority of the latent HIV, in this case by Tat.
Lin
Xin
X
Department of Medicine, San Francisco General Hospital, Center for AIDS Research and Department of Pathology, University of California, San Francisco, USA.
Irwin
Dan
D
Kanazawa
Satoshi
S
Huang
Laurence
L
Romeo
Joseph
J
Yen
T S Benedict
TS
Peterlin
B Matija
BM
D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D002478:Cells, Cultured; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000821:virology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000821:virology; D042925:Positive Transcriptional Elongation Factor B; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014775:Virus Activation; D017735:Virus Latency; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D049452:Green Fluorescent Proteins; D042925:Positive Transcriptional Elongation Factor B; D017346:Protein Serine-Threonine Kinases