Picking up on the theme of the last blog posting, a new study in the “in press” section of J. Virology investigates the potential causes of immune activation in HIV infection. The researchers - led by Angela Meier from Marcus Altfeld’s laboratory at Partners AIDS Research Center - carefully document the close parallel between declining viral load levels in response to treatment and declining levels of immune activation markers (CD38 and HLA-DR) on CD8 T cells, concluding that “the dramatic decline of immune activation following the suppression of HIV-1 viremia by HAART strongly suggests a direct causal effect of HIV-1 itself, or components of the virus, on immune activation.”
The study authors explore this question further by examining the ability of HIV to encode single-stranded RNA sequences that can directly activate the immune system via toll-like receptors (TLRs). The authors focus on uridine-rich sequences (uridine is one of the nucleoside components of RNA) because these types of sequences have previously been shown to interact with TLRs. They synthesized nine different uridine-rich sequences from the laboratory HIV strain HXB2 and found that all of them could induce significant amounts of cytokine production by plasmacytoid dendritic cells and monocytes in vitro. The researchers also demonstrate that this activity depends on interactions between the RNA and the TLR7 and TLR8 by using inhibitors of these TLRs and also by using cells from mice lacking MyD88 (an adaptor protein that is essential for signaling through TLR7 and TLR8).
The question of whether these HIV-derived RNA sequences can also activate CD4 and CD8 T cells via their effects on dendritic cells and monocytes is also partially addressed; the researchers report that they can induce upregulation of the activation marker CD69 on CD4 and CD8 T cells but these T cells do not produce cytokines. Data on the activation markers CD38 and HLA-DR is not reported. Notably, other researchers attempting to induce T cell activation using TLR ligands have also reported CD69 upregulation and elevated expression of CD38 after overnight culture, but with little effect on HLA-DR expression, perhaps calling into question the relevance of these data to the immune activation documented in HIV infection (which is associated with elevated CD38 and HLA-DR expression). In order to try and address this issue definitively, several research groups are now planning in vivo studies of TLR inhibitors in SIV and HIV infection.
JVI Accepts, published online ahead of print on 16 May 2007
J. Virol. doi:10.1128/JVI.00421-07
MyD88-dependent Immune Activation mediated by HIV-1-encoded TLR Ligands
Angela Meier, Galit Alter, Nicole Frahm, Harlyn Sidhu, Bin Li, Aranya Bagchi, Nickolas Teigen, Hendrik Streeck, Hans-Juergen Stellbrink, Judith Hellman, Jan van Lunzen, and Marcus Altfeld*
Partners AIDS Research Center, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, MA, USA; Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA, USA; IPM Study Center, Hamburg,Germany; University Medical Center Hamburg-Eppendorf, Infectious Disease Unit, Hamburg, Germany
Immune activation is a major characteristic of HIV-1 infection and a strong prognostic factor for HIV-1 disease progression. The underlying mechanisms leading to immune activation in viremic HIV-1 infection however are not fully understood. Here we show that following initiation of HAART, the immediate decline of immune activation is closely associated with the reduction of HIV-1 viremia, which suggests a direct contribution of HIV-1 itself to immune activation. To propose a mechanism, we demonstrate that the ssRNA of HIV-1 encodes for multiple uridine-rich TLR7/8 ligands that induce strong MyD88-dependent pDC and monocyte activation, as well as accessory cell-dependent T cell activation. HIV-1-encoded TLR ligands may therefore directly contribute to the immune activation observed during viremic HIV-1 infection. These data provide initial rationale for inhibiting the TLR pathway to directly reduce the chronic immune activation induced by HIV-1 and the associated immune pathogenesis.
Comments