Posttranslational modification of histones is known to regulate chromatin 
structure and transcriptional activity, and the nuclear lamina is thought to 
serve as a site for heterochromatin maintenance and transcriptional silencing. 
In this report, we show that the nuclear lamina can also play a role in the 
downregulation of heterochromatin and in gene activation. Herpes simplex virus 
DNA initiates replication in replication compartments near the inner edge of the 
nucleus, and histones are excluded from these structures. To define the role of 
nuclear lamins in HSV replication, we examined HSV infection in wild-type and 
A-type lamin-deficient (Lmna-/-) murine embryonic fibroblasts (MEFs). In Lmna-/- 
cells, viral replication compartments are reduced in size and fail to target to 
the nuclear periphery, as observed in WT cells. Chromatin immunoprecipitation 
and immunofluorescence studies demonstrate that HSV DNA is associated with 
increased heterochromatin in Lmna-/- MEFs. These results argue for a functional 
role for A-type lamins as viral gene expression, DNA replication, and growth are 
reduced in Lmna-/- MEFs, with the greatest effect on viral replication at low 
multiplicity of infection. Thus, lamin A/C is required for targeting of the 
viral genome and the reduction of heterochromatin on viral promoters during 
lytic infection. The nuclear lamina can serve as a molecular scaffold for DNA 
genomes and the protein complexes that regulate both euchromatin and 
heterochromatin histone modifications.