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

ABSTRACT: Human T-lymphotropic virus type 1 (HTLV-1) persists by driving clonal proliferation of infected T lymphocytes. A high proviral load predisposes to HTLV-1-associated diseases. Yet the reasons for the variation 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 negative selection dominates during chronic infection, favoring establishment of proviruses integrated in transcriptionally silenced 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 difference in clonality. The abundance of established HTLV-1 clones is determined by genomic features of the host DNA flanking the provirus. HTLV-1 clonal expansion in vivo is favored by orientation of the provirus in the same sense as the nearest host gene.

SUBMITTER: Gillet NA

PROVIDER: S-EPMC3062313 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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

Gillet Nicolas A NA Malani Nirav N Melamed Anat A Gormley Niall N Carter Richard R Bentley David D Berry Charles C Bushman Frederic D FD Taylor Graham P GP Bangham Charles R M CR

Blood 20110112 11

Human T-lymphotropic virus type 1 (HTLV-1) persists by driving clonal proliferation of infected T lymphocytes. A high proviral load predisposes to HTLV-1-associated diseases. Yet the reasons for the variation 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 infe ...[more]

PMID: 21228324

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Project description:BACKGROUND: To address the clinical and virological significance of a high HTLV-1 proviral load (VL) in practical blood samples from asymptomatic and symptomatic carriers, we simultaneously examined VL and clonal expansion status using polymerase chain reaction (PCR) quantification (infected cell % of peripheral mononuclear cells) and Southern blotting hybridization (SBH) methods. RESULTS: The present study disclosed extremely high VL with highly dense smears with or without oligoclonal bands in SBH. A high VL of 10% or more was observed in 16 (43.2%) of a total of 33 samples (one of 13 asymptomatic carriers, 8 of 12 symptomatic carriers, and 7 of 8 patients with lymphoma-type ATL without circulating ATL cells). In particular, an extremely high VL of 50% or more was limited to symptomatic carriers whose band findings always contained at least dense smears derived from polyclonally expanded cells infected with HTLV-1. Sequential samples revealed that the VL value was synchronized with the presence or absence of dense smears, and declined at the same time as disappearing dense smears. Dense smears transiently emerged at the active stage of the underlying disease. After disappearance of the smears, several clonal bands became visible and were persistently retained, explaining the process by which the clonality of HTLV-1-infected cells is established. The cases with only oligoclonal bands tended to maintain a stable VL of around 20% for a long time. Two of such cases developed ATL 4 and 3.5 years later, suggesting that a high VL with oligoclonal bands may be a predisposing risk to ATL. CONCLUSION: The main contributor to extremely high VL seems to be transient emergence of dense smears detected by the sensitivity level of SBH, corresponding to polyclonal expansion of HTLV-1-infected cells including abundant small clones. Major clones retained after disappearance of dense smears stably persist and acquire various malignant characteristics step by step.

Project description:Provirus mutations of human T-lymphotropic virus 1 (HTLV-1), mostly the lack of the 5' long terminal repeat (LTR) genomic region, have been described and associated with severe adult T cell leukemia/lymphoma (ATLL), non-sense point mutations with low proviral load, and Western blotting indeterminate results. Until now, no information concerning provirus mutations of HTLV-2 and its consequences, as well as those of HTLV-1/2 in HIV-coinfected individuals, had been described. Therefore, we searched for these mutations in provirus samples of 44 HIV/HTLV-1- and 25 HIV/HTLV-2-coinfected individuals. Using protocols well established for amplification and sequencing of segments of the LTR, env, and tax regions, we searched for defective type 1 particles that retain LTRs and lack internal sequences and type 2 particles that lack the 5'LTR region. In addition, using as references the prototypes ATK (HTLV-1) and Mo (HTLV-2), we searched for point mutations in the LTR and synonyms and nonsynonymous mutations and non-sense mutations in env and tax regions. Defective HTLV-1 and HTLV-2 provirus type 1 or 2 was detected in 31.8% of HIV/HTLV-1- and 32.0% of HIV/HTLV-2-coinfected individuals. Synonymous and nonsynonymous mutations were identified mostly in HTLV-2 and associated with lower levels of specific antibodies. No non-sense mutations that resulted in premature termination of Env and Tax proteins were detected. On the contrary, mutation in the stop codon of Tax2a produced a long protein characteristic of the HTLV-2c subtype. The clinical significance of these mutations in coinfected individuals remains to be defined, but they confirmed the lower sensitivity of serological and molecular diagnostic tests in HIV/HTLV-1/2 coinfections.IMPORTANCE HTLV-1 and HTLV-2 are endemic to Brazil, and they have different effects in HIV/AIDS disease progression. HIV/HTLV-1 has been described as accelerating the progression to AIDS and death, while HIV/HTLV-2 slows the progression to AIDS. Provirus mutations of HTLV-1 were implicated in severe leukemia development and in problems in the diagnosis of HTLV-1; in contrast, provirus mutations of HTLV-2 had not been confirmed and associated with problems in HTLV-2 diagnosis or disease outcome. Nevertheless, data obtained here allowed us to recognize and understand the false-negative results in serologic and molecular tests applied for HTLV-1 and HTLV-2 diagnosis. Defective proviruses, as well as synonymous and nonsynonymous mutations, were associated with the diagnosis deficiencies. Additionally, since HIV-1 and HTLV-1 infect the same cells (CD4 positive), the production of HIV-1 pseudotypes with HTLV-1 envelope glycoprotein during HIV/HTLV-1 coinfection cannot be excluded. Defective provirus of HTLV-2 and Tax2c is speculated to influence progression to AIDS.

Dataset Information

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

Publications

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

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