Fig. 7. Proposed model of HTLV-1 selection in vivo.

In this model, an infected T cell clone whose provirus is integrated in a genomic region that typically lies in a transcriptionally repressive compartment in the nucleus is more likely to survive in vivo in the face of immune-mediated selection, because the frequency of proviral reactivation is lower than that in regions of constitutively accessible chromatin, so the virus is less frequently exposed to the immune response. The radial intranuclear position of the provirus and its proximity to the centromere each influence selective clonal survival independently of the intensity of host transcription flanking the provirus. A clone whose provirus is integrated into constitutive heterochromatin is less likely to persist in vivo, because the clone lacks the proliferative advantage enjoyed by HTLV-1–expressing cells (1). Gene repression at the nuclear periphery and nucleolar periphery is not invariable (61); in addition, certain chromatin regions, facultative LADs, are reversibly associated with the nuclear lamina (62). Thus, facultative heterochromatin may be the optimal site for in vivo survival, minimizing exposure to immune selection while retaining the potential to be reexpressed. Clonal survival of HIV-1 in vivo similarly correlates with the intranuclear and intrachromosomal position of the provirus: These positional effects appear to be stronger than the influence of local host transcription intensity in HIV-1 infection.