Polygenic Control of Human T Lymphotropic Virus Type I (HTLV‐I) Provirus Load and the Risk of HTLV‐I–Associated Myelopathy/Tropical Spastic Paraparesis

Vine, Alison M.; Witkover, Aviva; Lloyd, Alun L.; Jeffery, Katie; Siddiqui, Asna A.; Marshall, Sara E.; Bunce, Mike; Eiraku, Nobutaka; Izumo, Shuji; Usuku, Koichiro; Osame, Mitsuhiro; Bangham, Charles R. M.

doi:10.1086/342953

Cited by 81 publications

(79 citation statements)

References 42 publications

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“…More importantly, various studies have suggested that host genetic polymorphisms play a critical role in determining the efficacy of an individual immune response to HTLV-1 or HTLV-2 (25,46). Consistently, we detected highly variant serological responses in inoculated rabbits, irrespective of the inoculum.…”

Section: Vol 83 2009supporting

confidence: 86%

Human T-Cell Leukemia Virus Type 2 Rex Carboxy Terminus Is an Inhibitory/Stability Domain That Regulates Rex Functional Activity and Viral Replication

Xie

Kesic²,

Yamamoto³

et al. 2009

J Virol

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Human T-cell leukemia virus (HTLV) regulatory protein, Rex, functions to increase the expression of the viral structural and enzymatic gene products. The phosphorylation of two serine residues (S151 and S153) at the C terminus is important for the function of HTLV-2 Rex (Rex-2). The Rex-2 phosphomimetic double mutant (S151D, S153D) is locked in a functionally active conformation. Since rex and tax genes overlap, Rex S151D and S153D mutants were found to alter the Tax oncoprotein coding sequence and transactivation activities. Therefore, additional Rex-2 mutants including P152D, A157D, S151Term, and S158Term were generated and characterized ("Term" indicates termination codon). All Rex-2 mutants and wild-type (wt) Rex-2 localized predominantly to the nucleus/nucleolus, but in contrast to the detection of phosphorylated and unphosphorylated forms of wt Rex-2 (p26 and p24), mutant proteins were detected as a single phosphoprotein species. We found that Rex P152D, A157D, and S158Term mutants are more functionally active than wt Rex-2 and that the Rex-2 C terminus and its specific phosphorylation state are required for stability and optimal expression. In the context of the provirus, the more active Rex mutants (A157D or S158Term) promoted increased viral protein production, increased viral infectious spread, and enhanced HTLV-2-mediated cellular proliferation. Moreover, these Rex mutant viruses replicated and persisted in inoculated rabbits despite higher antiviral antibody responses. Thus, we identified in Rex-2 a novel C-terminal inhibitory domain that regulates functional activity and is positively regulated through phosphorylation. The ability of this domain to modulate viral replication likely plays a key role in the infectious spread of the virus and in virus-induced cellular proliferation.

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Section: Vol 83 2009supporting

confidence: 86%

Human T-Cell Leukemia Virus Type 2 Rex Carboxy Terminus Is an Inhibitory/Stability Domain That Regulates Rex Functional Activity and Viral Replication

Xie

Kesic²,

Yamamoto³

et al. 2009

J Virol

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“…The high proviral load characteristic of HTLV-1 infection is the strongest correlate of the risk of HTLV-1-inflammatory diseases such as HAM/TSP (20,35). However, the factors that determine an individual's set point of proviral load, which can differ between individuals by Ͼ1000-fold, are not yet understood.…”

Section: Discussionmentioning

confidence: 99%

The Role of CTLs in Persistent Viral Infection: Cytolytic Gene Expression in CD8+ Lymphocytes Distinguishes between Individuals with a High or Low Proviral Load of Human T Cell Lymphotropic Virus Type 1

Vine¹,

Heaps²,

Kaftantzi³

et al. 2004

The Journal of Immunology

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The proviral load in human T cell lymphotropic virus type 1 (HTLV-1) infection is typically constant in each infected host, but varies by >1000-fold between hosts and is strongly correlated with the risk of HTLV-1-associated inflammatory disease. However, the factors that determine an individual’s HTLV-1 proviral load remain uncertain. Experimental evidence from studies of host genetics, viral genetics, and lymphocyte function and theoretical considerations suggest that a major determinant of the equilibrium proviral load is the CD8+ T cell response to HTLV-1. In this study, we tested the hypothesis that the gene expression profile in circulating CD8+ and CD4+ lymphocytes distinguishes between individuals with a low proviral load of HTLV-1 and those with a high proviral load. We show that circulating CD8+ lymphocytes from individuals with a low HTLV-1 proviral load overexpressed a core group of nine genes with strong functional coherence: eight of the nine genes encode granzymes or other proteins involved in cell-mediated lysis or Ag recognition. We conclude that successful suppression of the HTLV-1 proviral load is associated with strong cytotoxic CD8+ lymphocyte activity in the peripheral blood.

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“…Thus, in a strong CTL responder the net effect of the CD8 ϩ T-cell response is beneficial, while in a weak CTL responder the same cell population can contribute to inflammation and tissue damage. This theoretical model was later supported by new evidence (Vine et al 2002) (figure 2b), which suggested that TNF-α exerts a harmful effect in HTLV-I infection only in individuals whose proviral load exceeds a threshold value.…”

Section: (B) Correlation Between Cd8mentioning

confidence: 71%

Review. An introduction to lymphocyte and viral dynamics: the power and limitations of mathematical analysis

Asquith

Bangham

2003

Proc. R. Soc. Lond. B

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Mathematics is a useful tool in the analysis and understanding of population dynamic aspects of the immune response. However, the power of mathematical modelling in immunology is frequently limited by the shortage of experimental data. Here, we review the contribution of mathematics to two areas of immunology. We highlight the problem caused by lack of knowledge of the system, which can greatly restrict the use of mathematics and lead to errors caused by model-specific results.

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Polygenic Control of Human T Lymphotropic Virus Type I (HTLV‐I) Provirus Load and the Risk of HTLV‐I–Associated Myelopathy/Tropical Spastic Paraparesis

Cited by 81 publications

References 42 publications

Human T-Cell Leukemia Virus Type 2 Rex Carboxy Terminus Is an Inhibitory/Stability Domain That Regulates Rex Functional Activity and Viral Replication

Human T-Cell Leukemia Virus Type 2 Rex Carboxy Terminus Is an Inhibitory/Stability Domain That Regulates Rex Functional Activity and Viral Replication

The Role of CTLs in Persistent Viral Infection: Cytolytic Gene Expression in CD8+ Lymphocytes Distinguishes between Individuals with a High or Low Proviral Load of Human T Cell Lymphotropic Virus Type 1

Review. An introduction to lymphocyte and viral dynamics: the power and limitations of mathematical analysis

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