Molecular mechanisms of HIV-1 persistence in the monocyte-macrophage lineage

Abstract

The introduction of the highly active antiretroviral therapy (HAART) has greatly improved survival. However, these treatments fail to definitively cure the patients and unveil the presence of quiescent HIV-1 reservoirs like cells from monocyte-macrophage lineage. A purge, or at least a significant reduction of these long lived HIV-1 reservoirs will be needed to raise the hope of the viral eradication. This review focuses on the molecular mechanisms responsible for viral persistence in cells of the monocyte-macrophage lineage. Controversy on latency and/or cryptic chronic replication will be specifically evoked. In addition, since HIV-1 infected monocyte-macrophage cells appear to be more resistant to apoptosis, this obstacle to the viral eradication will be discussed. Understanding the intimate mechanisms of HIV-1 persistence is a prerequisite to devise new and original therapies aiming to achieve viral eradication.

Figure 1

monocyte-macrophage lineage. All cells from the monocyte-macrophage lineage appear to derive from a same progenitor multipotent cell, the hematopoietic stem cell (HSC). The HSC, located in the bone marrow, may differentiate either into a myeloid or a lymphoid precursor, setting up the divergence between the myeloid (blue) and plasmacytoid (green) lineage. The myeloid precursor is then able to migrate into the blood stream and to differentiate into a monocyte. Monocytes migration to specific tissues and their differentiation occur upon a stimulation of a different cytokines, interleukins and/or other factors cocktail. Depending to the location, the monocytes become either interstitial dendritic cells, macrophages or microglial cells. Lymphoid precursor runs parallel with the myeloid one, but can directly differentiate into another type of dendritic cell, the plasmacytoid dendritic cell.

Figure 2

Functions of CTIP2 in the regulation of HIV-1 gene transcription. CTIP2 (COUP-TF Interacting Protein 2), a transcriptional repressor, has been pointed out as an actor of the latency establishment in the macrophage lineage. First, it has been shown that CTIP2 has a direct impact onto the HIV-1 LTR promoter by replacing transcriptional activator, such P300 (top left). CTIP2 interacts with Sp1, which is anchored to the LTR, switching nuc-1 from a transcriptionally active to a repressive state. Following its binding to Sp1, CTIP2 recruits sequentially histone deacetylase (HDAC) 1 and 2, which remove acetylation marks from the nuc-1 nucleosome, and then SUV39H1, which add a tri-methylation mark onto the lysine 9 of the histone protein H3. As for SUV39H1, it interacts with HP1, a protein stabilizing nuc-1 in a transcriptional closed state. Moreover, CTIP2 is also able to indirectly repress HIV-1 gene transcription. Indeed, CTIP2 can counter the action of the viral protein Vpr. One of the roles of Vpr is to induce a cell cycle arrest through activation of the p21 gene. Sp1-mediated recruitement of Vpr to the p21 gene promoter increases the production of the p21 protein, a cell cycle regulator. Consequence of such block in cell cycle is an enhancement of the viral transcription. The binding of CTIP2 to the p21 promoter forces Vpr release, HDACs and SUV39H1 recruitment, HP1 association and p21 gene silencing.

Figure 3

Pharmaceutical approaches of the potential reactivation pathways on latently integrated HIV-1 genome. Multiple ways of reactivation are possible to occur to re-initiate the HIV-1 transcription. Extern signals, such as TNF-α, can trigger the activation of transcriptional activator, like the heterodimer p50/p65. In the mean time, host protein balance may change, leading to higher availability of transcriptional activators. For instance, miRNAs regulates the rate of PCAF, a coactivator produced by the host cell (green arrow - Multiple potential reactivation pathways). There are some critical steps in this process that may be targeted to reactivate or hinder the latency establishment (Red boxes). HDAC inhibitors (HDACi) may prevent the formation of heterochromatin; Prostratin induces the IKK activation, which provokes the activation of transcriptions factors; HMBA increases the pTEFb release from the inactive stock; it is possible to reverse the miRNAs negative impact on the mRNAs of transcriptional activators and/or CycT1 through specific siRNAs.