Background
Both HTLV-1 and HIV-1 cause a lifelong incurable infection, but mechanisms of viral persistence may vary. In HIV-1 infection, prior data demonstrated a progressive accumulation of intact proviruses in heterochromatin during long-term ART, likely as a result of immune-mediated selection that promotes viral persistence in repressive chromatin. Whether and how proviral integration site locations influence persistence of HTLV-1-infected cells remains less clear.
Methods
We analyzed DNA from 5 adult people living with HTLV-1, four with long-term asymptomatic infection and one with early-onset Adult T-cell leukemia (ATL). Proviral sequences and corresponding chromosomal locations were identified using adapted protocols of FLIP-Seq and MIP-Seq and compared to data from long-term ART-treated persons with HIV-1 or elite controllers (EC).
Results
Average proviral loads were 111,661 copies/million PBMC among asymptomatic carriers, and 749,554 viral copies in the participant with ATL. DNA analysis yielded 132 proviral sequences and 24 integration sites across all 5 participants. Approximately 77% of HTLV-1 proviruses showed no major structural defects and were likely replication-competent. The proportion of clonally expanded intact sequences was lower in HTLV-1 study participants, averaging only 34% of all intact sequences, compared to greater than 80% in persons long-term ART or EC. Observed integration sites in HTLV-1 study participants were mostly genic, representing 63% of all integration sites. Non-genic sites composed 30% of the remaining reservoir, while proviruses integrated in satellite or centromeric regions were only found in 7% of the reservoir cells. No integration sites were found in ZNF-family genes for HTLV-1, in sharp contrast to HIV-1 infection where ZNF genes represent hotspots for persistence of intact proviruses. There was no evidence for preferential persistence of intact HTLV-1 genomes in oncogenes or proliferation-associated genes in asymptomatic carriers and in the ATL case.
Conclusions
Integration sites of intact HTLV-1 genomes were markedly more diverse than in persons with HIV-1 on long-term ART or EC, and less likely to accumulate in heterochromatin regions. These data suggest that HTLV-1-infected cells are under more limited selection pressure and/or less dependent on the chromatin microenvironment for long-term persistence. Relative to HTLV-1 infection, HIV-1 reservoir cells seem more vulnerable to host immune pressure.
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