IMMUNOBIOLOGY The host genomic environment of the provirus determines the abundance of HTLV-1–infected T-cell clones

persists by driving clonal proliferation of infected T lymphocytes. A high proviral load predisposes to HTLV-1–associated diseases. Yet the reasons for the varia-tion within and between persons in the abundance of HTLV-1–infected clones remain unknown. We devised a high-throughput protocol to map the genomic location and quantify the abundance of> 91 000 unique insertion sites of the provirus from 61 HTLV-1 persons and> 2100 sites from in vitro infection. We show that a typical HTLV-1–infected host carries between 500 and 5000 unique insertion sites. We demonstrate that nega-tive selection dominates during chronic infection, favoring establishment of provi-ruses integrated in transcriptionally si-lenced DNA: this selection is significantly stronger in asymptomatic carriers. We define a parameter, the oligoclonality index, to quantify clonality. The high proviral load characteristic of HTLV-1– associated inflammatory disease results from a larger number of unique insertion sites than in asymptomatic carriers and not, as previously thought, from a differ-ence in clonality. The abundance of estab-lished HTLV-1 clones is determined by genomic features of the host DNA flank-ing the provirus. HTLV-1 clonal expansion in vivo is favored by orientation of the provi-rus in the same sense as the nearest host gene. (Blood. 2011;117(11):3113-3122