Nuclear positional control of HIV transcription in 4D

Abstract

Retroviruses integrate their genome into the chromatin of the host cell and are subject to the same control mechanisms governing transcription in the nucleus. There is increasing evidence that the spatial position of a gene within the nucleus in time affects its activity. Therefore it becomes important to study the chromatin environment in space and time of the HIV-1 provirus, particularly in cells where a tight transcriptional control allows the virus to hide away from antiviral treatment and immune response. We recently showed that the HIV-1 provirus is found at the nuclear periphery of latently infected lymphocytes associated in trans with centromeric heterochromatin. After induction of transcription, this association was lost, although the location of the transcribing provirus remained peripheral. Our results reveal a novel mechanism of transcriptional silencing involved in HIV-1 post-transcriptional latency and open wider perspectives for the general organization of chromatin in the nucleus.

Keywords: HIV; chromatin; latency; nucleus; transcription.

Figure 1

(A) A schematic representation of the early steps of HIV-1 integration. The HIV-1 preintegration complex (PIC) travels through the pore of the infected cell's nucleus. The steep chromatin concentration gradient that the PIC encounters restricts the choice of the integration site to a peripheral localization. Integration at the inner nuclear membrane (NM) within the repressive compartment defined by the lamin and the lamin-associated domains (LADs) is disfavored. Integration into active genes and open chromatin is instead favored. (B) HIV-1 integration into LADs is disfavored. The integration sites of (i) cell carrying a proviral vector that is well-expressing (n = 587) and (ii) cells carrying an integrations site that is poorly expressing but inducible (n = 384) derived from Lewinski et al. are compared to random integrations (100 iterations of n = 500) for their association to lamin associated domains (LADs) as defined in Guelen et al.