Hit-and-run stimulation: a novel concept to reactivate latent HIV-1 infection without cytokine gene induction.
Current antiretroviral therapy (ART) efficiently controls HIV-1 replication but fails to eradicate the virus. Even after years of successful ART, HIV-1 can conceal itself in a latent state in long-lived CD4(+) memory T cells. From this latent reservoir, HIV-1 rebounds during treatment interruptions. Attempts to therapeutically eradicate this viral reservoir have yielded disappointing results. A major problem with previously utilized activating agents is that at the concentrations required for efficient HIV-1 reactivation, these stimuli trigger high-level cytokine gene expression (hypercytokinemia). Therapeutically relevant HIV-1-reactivating agents will have to trigger HIV-1 reactivation without the induction of cytokine expression. We present here a proof-of-principle study showing that this is a possibility. In a high-throughput screening effort, we identified an HIV-1-reactivating protein factor (HRF) secreted by the nonpathogenic bacterium Massilia timonae. In primary T cells and T-cell lines, HRF triggered a high but nonsustained peak of nuclear factor kappa B (NF-kappaB) activity. While this short NF-kappaB peak potently reactivated latent HIV-1 infection, it failed to induce gene expression of several proinflammatory NF-kappaB-dependent cellular genes, such as those for tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8), and gamma interferon (IFN-gamma). Dissociation of cellular and viral gene induction was achievable, as minimum amounts of Tat protein, synthesized following application of a short NF-kappaB pulse, triggered HIV-1 transactivation and subsequent self-perpetuated HIV-1 expression. In the absence of such a positive feedback mechanism, cellular gene expression was not sustained, suggesting that strategies modulating the NF-kappaB activity profile could be used to selectively trigger HIV-1 reactivation.
Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Frank
F
Wolschendorf
Alexandra
A
Duverger
Jennifer
J
Jones
Frederic H
FH
Wagner
Jason
J
Huff
William H
WH
Benjamin
Michael S
MS
Saag
Michael
M
Niederweis
Olaf
O
Kutsch
D001426:Bacterial Proteins / Q000276:immunology / Q000302:isolation & purification / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D042802:Oxalobacteraceae / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000821:virology; D015533:Transcriptional Activation; D014775:Virus Activation; D017735:Virus Latency
D001426:Bacterial Proteins; D016328:NF-kappa B