WrightFleming Institute, Imperial College London, Norfolk Place, London W2 1PG, UK
Correspondence
Charles Bangham
c.bangham{at}imperial.ac.uk
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ABSTRACT |
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Published ahead of print on 11 September 2003 as DOI 10.1099/vir.0.19334-0.
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INTRODUCTION |
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HTLV-1 |
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The provirus load of HTLV-1 usually reaches a stable equilibrium set point that fluctuates in most cases by no more than 2- to 4-fold over a period of years (Matsuzaki et al., 2001). This provirus load is frequently very high: in a Japanese population, the median provirus load was 5 % PBMCs in patients with HAM/TSP and 0·3 % in asymptomatic HTLV-1 carriers (Nagai et al., 1998
; see below). In contrast with HIV-1, the between-isolate and within-isolate sequence variation of HTLV-1 is very limited (Niewiesk et al., 1994
; Slattery et al., 1999
). However, there are minor variations in sequence between geographical regions (Slattery et al., 1999
), and indeed certain HTLV-1 subgroups, defined by nucleotide sequence, are associated with different risks of HAM/TSP (Furukawa et al., 2000
; see below).
The HTLV-1 provirus is found chiefly in CD4+ T cells in vivo, but up to a quarter of the provirus load may be carried by CD8+ T cells (Hanon et al., 2000a). The cellular tropism of HTLV-1 and the question of whether the virus is latent or persistent are considered below.
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The immune response to HTLV-1 |
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The helper T cell response |
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The dominant HTLV-1 antigen recognized by CD4+ T cells was Env protein, followed by Gag, Pol etc. (Goon et al., 2002). Interestingly, there was evidence of preferential HTLV-1 infection of these virus-specific CD4+ T cells: although most of the provirus was present in cells of other specificities, HTLV-1 was detected consistently at a higher frequency in HTLV-1-specific CD4+ T cells than in human cytomegalovirus-specific CD4+ T cells (Goon et al., 2002
). The question arises whether such preferential infection impairs the immune response to HTLV-1. However, it is not possible to draw simple and robust conclusions on this point because of the complexity of the dynamics of interactions between helper T cells, virus-infected cells and other components of the immune response, notably cytotoxic T cells.
More precise analysis of the functions of HTLV-1-specific helper T cells will be possible when an efficient method is devised to isolate live antigen-specific CD4+ cells directly from fresh PBMCs.
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CD8+ T cell response to HTLV-1 |
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The main features of this unusual CD8+ T cell response (Bangham, 2000, 2002
) are the high frequency of HTLV-1-specific CD8+ T cells and their state of chronic activation. Tax protein dominates as the target antigen of HTLV-1-specific CTLs (Jacobson et al., 1990
; Kannagi et al., 1991
), but CTLs specific to Gag, Pol and Env have also been detected (Jacobson et al., 1990
; Parker et al., 1992
). Pique et al. (2000)
also found CTLs specific to small putative regulatory proteins of HTLV-1, including Tof and Rof, providing strong evidence that these proteins, whose existence and actions have been debated, are indeed produced in vivo. Interestingly, Rex protein does not appear to be a target for CTLs (Smith et al., 1997
): the reason for this is not understood.
In most virus infections, CD8+ T cells play a critical role in limiting virus replication, by killing virus-infected cells and by secreting IFN-. It was therefore natural to propose (Bangham, 1996) that HTLV-1-specific CD8+ T cells played a major part in determining the provirus load at equilibrium, and that individual variation in provirus load was caused by individual variation in the efficiency of this response. This hypothesis was consistent with the observation (Niewiesk et al., 1994
) that the tax gene was subject to stronger positive selection in asymptomatic carriers of HTLV-1, who in general have a lower provirus load, than in patients with HAM/TSP.
The hypothesis has been countered by a suggestion (Jacobson, 2002) that HTLV-1-specific CD8+ T cells cause the tissue damage in HAM/TSP (see Pathogenesis of HAM/TSP below). These two proposals are in fact not mutually exclusive, because there is always a trade-off between the beneficial and the harmful effects of CD8+ T cells. For example, the CD8+ response to lymphocytic choriomeningitis virus in the mouse is responsible both for clearing the infection and (under certain circumstances) for the fatal lymphocytic choriomeningitis (Buchmeier et al., 1980
). But the question remains: is the net effect of CD8+ T cells beneficial or harmful in HTLV-1 infection?
The hypothesis that a strong CD8+ T cell response to HTLV-1 is beneficial faces two main problems. First, the frequency of HTLV-1-specific CD8+ T cells is correlated positively with the provirus load (Kubota et al., 2000), especially in asymptomatic HTLV-1 carriers (Wodarz et al., 2001
), and the frequency is slightly higher in patients with HAM/TSP than in asymptomatic HTLV-1 carriers. We have found that the mean (or median) frequency of such cells in the peripheral blood is 2- to 4-fold higher in patients with HAM/TSP than in asymptomatic carriers, whether the cells are assayed by limiting dilution analysis (Daenke et al., 1996
), class I tetramer binding (Jeffery et al., 1999
) or IFN-
ELISPOT assays (P. Goon and others, unpublished data). Second, until recently there has been no experimental means to quantify the efficiency of the CD8+ T cell response, even though the CTL efficiency parameters were formulated in experimentally measurable terms by Nowak & Bangham (1996)
. These two problems are considered below.
(1) Frequency of anti-HTLV-1 CD8+ T cells
Ogg et al. (1998) observed an inverse correlation between the frequency of HIV-specific CD8+ T cells and the plasma virus load in subjects in the quasi-equilibrium phase of HIV infection. The intuitive interpretation of this observation is that a strong immune response reached equilibrium with a low virus load. But the proliferation rate of virus-specific T cells is stimulated by the antigen (virus) load. Therefore, one can also argue that the frequency of CD8+ T cells should be positively correlated with the virus load. In fact, both experiment (Ogg et al., 1998
; Kubota et al., 2000
; Betts et al., 2001
; Wodarz et al., 2001
; Addo et al., 2003
) and theory (Wodarz & Bangham, 2000
; Wodarz et al., 2001
; Bangham, 2002
) show that variations in experimental protocol or mathematical model can readily produce either a positive, negative or zero correlation between the specific CTL frequency and virus load. The conclusion is clear: when equilibrium is reached between a persistently replicating pathogen and the immune response, the frequency of specific CD8+ T cells is an unreliable index of the efficiency or effectiveness of the T cell response.
(2) Efficiency of the anti-HTLV-1 CTL response
Nowak & Bangham (1996) showed that individual variation in the efficiency of the CTL response to a persistent virus at equilibrium could lead to wide variation in the virus load between individuals whose frequency of specific CTLs was not significantly different. This model made two experimentally testable predictions. Firstly, polymorphisms in genes that influence the efficiency of the CTL response, notably the class I MHC genes, would be associated with individual variation in the provirus load and therefore in the risk of associated diseases such as HAM/TSP. Secondly, CTL efficiency, defined in precise and (in principle) experimentally testable terms, would be greater in subjects with a low provirus load than those with a high provirus load. We have now tested both of these predictions.
In a case control study of candidate gene polymorphisms in an endemically HTLV-1-infected population in Kagoshima, southern Japan, we found that possession of either of the class 1 MHC alleles HLA-A*02 or HLA-Cw*08 was associated with a significant reduction in both HTLV-1 provirus load and the risk of HAM/TSP (Jeffery et al., 1999, 2000
; Vine et al., 2002
; Table 1
). The likely mechanism indeed the only plausible mechanism suggested is that HLA-A*02-restricted or HLA-Cw*08-restricted CTLs are particularly efficient at killing HTLV-1-infected cells. These observations therefore strongly supported the idea that variation in CTL efficiency accounts for variation in provirus load. In further support of this conclusion, individuals who were heterozygous at all three HLA class 1 loci had a significantly lower provirus load than those who were homozygous at one or more loci (Jeffery et al., 2000
). This observation is consistent with the idea that CTL recognition of many epitopes contributes to the efficiency of antiviral surveillance (Weidt et al., 1995
; Carrington et al., 1999
).
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The efficiency of CTLs was embodied in two parameters in the models of Nowak & Bangham (1996): c, the rate of CTL proliferation in response to a given dose of antigen, and p, the rate at which CTLs kill virus-infected cells. We hypothesized that efficient anti-HTLV-1 CTLs would overexpress genes concerned with cell division, or cell-mediated lysis, or both. To test this hypothesis, we used nucleotide microarrays to assay the mRNA expression of 12 000 genes in fresh ex vivo CD4+ cells and CD8+ cells from groups of asymptomatic HTLV-1 carriers with a low provirus load, carriers with a high provirus load, patients with HAM/TSP, and uninfected controls. Cluster analysis of the resulting gene expression profiles (A. M. Vine and others, unpublished data) showed a remarkably clear result in each of three independent experiments. A low provirus load of HTLV-1 was associated with overexpression of a core group of about 12 genes in the CD8+ cells. Of these 12 genes, 10 encode proteins that are directly concerned with the lytic mechanism by which a CTL kills its target cell, including granzymes A, B, M, K, perforin, NKG2D and granulysin. In contrast, there was no distinct pattern of upregulation of cell cycle-related genes in these same cells. Thus, although the frequency of HTLV-1-specific CD8+ cells is lower in subjects with a low provirus load, such individuals express higher total levels of mRNAs of lysis-related genes in their circulating CD8+ cells than do individuals with a high provirus load.
We concluded that a vigorous CD8+ cell response to HTLV-1 reduces the equilibrium provirus load. But how important is this effect? More precisely, what proportion of the observed between-person variation in HTLV-1 provirus load is attributable to variation in the efficiency of their respective CTL response to the virus? In recent experiments we have measured the rate of CD8+ cell-mediated lysis of autologous ex vivo HTLV-1-infected cells (B. Asquith, and others, unpublished data). The results indicate that up to 50 % of the variation in the provirus load observed between asymptomatic carriers is accounted for by variation in the rate of CTL-mediated lysis (see above). Differences in the rate of CTL-mediated lysis appear to account for a lower proportion (around 35 %) of variation in provirus load between patients with HAM/TSP. The reasons for this difference are not yet known.
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Pathogenesis of HAM/TSP: does the immune response contribute? |
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The presence in the CNS of abundant antibody and T cells specific to HTLV-1 raised the questions whether and how they contribute to the tissue damage observed. Direct damage to HTLV-1-infected cells is unlikely to contribute, because few (Lehky et al., 1995) if any (Matsuoka et al., 1998
) resident CNS cells become infected with HTLV-1. It is possible that HTLV-1-specific antibody or T cells also recognize a cell antigen expressed by CNS cells. Recently, Levin et al. (2002)
have obtained intriguing evidence for such a mechanism in HAM/TSP. But although this mechanism might contribute to tissue damage in HAM/TSP, it cannot be the main or the only mechanism, because it is difficult to explain either the initiation or the distribution of inflammatory lesions by this mechanism alone.
Because HAM/TSP occurs only in the human CNS, formal tests of the mechanisms of pathogenesis are impossible and the evidence will therefore remain circumstantial.
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Why do some individuals develop HAM/TSP? |
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The effect of the TNF- promoter polymorphism was particularly interesting because of a strong interaction with provirus load. That is, the -863A allele conferred a 10-fold increased risk of HAM/TSP among people whose HTLV-1 provirus load was greater than 2 copies per 100 PBMCs, but the TNF-
allele had no effect if the provirus load was below this apparent threshold. Asquith & Bangham (2000)
suggested the following explanation for this effect. In a patient with HAM/TSP, abundantly expressed HTLV-1 antigens notably Tax stimulate CD8+ T cells to produce inflammatory cytokines, including TNF-
and IFN-
. In a healthy HTLV-1 carrier, by contrast, even one whose provirus load is as high as a typical patient with HAM/TSP, there is less HTLV-1 antigen expressed, perhaps because of more efficient CTL surveillance. The lower antigen abundance in these healthy carriers falls below the threshold required (Valitutti et al., 1996
) for the CD8+ cells to produce TNF-
and IFN-
, although there is still sufficient antigen to induce CTL-mediated lysis.
The mechanisms responsible for the association of HLA-DRB1*0101 and HLA-B*54 with an increased risk of HAM/TSP remain unexplained. Experiments are now under way to examine the gene and protein expression in DRB1*0101-restricted and B*54-restricted HTLV-1-specific T cells, in an attempt to answer this question.
Further immunogenetic studies in other HTLV-1-infected populations may lead to the identification of other significant host genetic influences in HTLV-1 infection. But there are important caveats here. First, as in other population genetic studies, the studied population must be large, lacking in genetic admixture (in particular genetic stratification; see above). Second, the relative importance of specific host genetic factors in the immune control of HTLV-1 is certain to differ between populations, because of genetic heterogeneity: for example, HLA-B*54, which is associated with a significantly higher load of HTLV-1 in Kagoshima (Jeffery et al., 2000), is common in far-eastern populations but virtually absent elsewhere. However, it seems highly improbable that the fundamental conclusion, that the CD8+ T cell response is a major factor determining the provirus load of HTLV-1 and the risk of HAM/TSP, will differ in other populations.
There are case reports of HAM/TSP developing within a few months of transfusion with HTLV-1-infected blood (Kaplan et al., 1991; Gasmi et al., 1997
), but cases of ATL have not been reported so soon after transfusion. This observation raised the possibility that the route of infection determines the provirus load and the risk of different HTLV-1-associated diseases. It has also been suggested (Hasegawa et al., 2003
) that infection by the oral route might lead to a degree of immunological tolerance of HTLV-1. However, in areas of endemic HTLV-1 infection the great majority of people have been infected by the mucosal route, by breast feeding or sexual contact, and cases of ATL and HAM/TSP both result. Further, the epidemiological evidence suggests that the provirus load (the set point in each individual) is independent of the route of transmission (Nakagawa et al., 1995
; Iga et al., 2002
). A simpler explanation of the apparent association between ATL and HTLV-1 infection in childhood (or by the mucosal route) is that ATL requires the accumulation of several mutations, like other malignancies, and that many years are necessary, on average, for these unlikely events to occur. Since most people who have been infected for many years were infected as children or young adults, most will have been infected by breastfeeding or sexual contact, rather than by transfusion.
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Non-lytic protective effects of CD8+ cells |
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Coevolution of HTLV-1 and the immune response: reciprocal selection between the virus and CD8+ T cells |
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This abundant, chronically activated CD8+ T cell response would be expected to exert significant selection pressure on the virus and evidence of such selection was indeed obtained by Niewiesk et al. (1994). Naturally occurring sequence variants of Tax escape recognition by fresh autologous CTLs (Niewiesk et al., 1995
), consistent with the idea that CTL selection favoured the emergence of these variant Tax sequences. However, recombinant Tax proteins that contained these putative CTL escape mutations were highly defective in their transactivating activity (Niewiesk et al., 1995
). It is therefore likely that negative selection on the virus due to defective Tax function balances the positive selection exerted by anti-Tax CTLs. The inability of Tax to tolerate amino acid changes (Smith & Greene, 1990
; Niewiesk et al., 1995
) may explain the continued effectiveness of CTL-mediated control of HTLV-1 replication: Tax is essential to the infectious cycle of HTLV-1, and is the first HTLV-1 protein to be expressed.
Just as the strong CTL response appears to exert selection on the tax gene, so the persistently expressed Tax protein would be expected to exert selection on the T cells. Specifically, after months or years of continuous antigenic stimulation, one should observe selection of T cell antigenic receptors (TCRs) with a particularly high affinity for HTLV-1 Tax peptides. Such selection has been observed by Saito et al. (2001): in HTLV-1-infected subjects with the HLA-A*02 allele there was a strong predominance of a four-amino-acid motif (Gly-Leu-Ala-Gly) in the hypervariable region (CDR3) of the TCR V
13.1 that makes contact with the A2/Tax1119 antigenic complex. By chance, the first complex of human TCR/MHC/peptide whose X-ray crystallographic structure was determined (Garboczi et al., 1996) also consisted of TCR V
13.1/HLA-A2/Tax1119. Remarkably, the same motif (Gly-Leu-Ala-Gly) was present at the tip of the TCR CDR3 loop in this complex. The crystallographic structure (Fig. 1
) showed that the Leu residue at position 98 in the CDR3 loop made particularly strong hydrophobic interactions with the A2/Tax1119 complex. Substitution of single amino acids in the Tax1119 peptide reduced the affinity of binding of the A2/Tax peptide complex by the TCR of two T cell clones (Hausmann et al., 1999
), strengthening the conclusion that the sequence of Tax1119 appears particularly well suited to binding HLA-A2.
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How much does reverse transcriptase contribute to the maintenance of HTLV-1 provirus load? |
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Theory (Wodarz et al., 1999) indicates that, even if the ratio of the per-cell rates of infectious and mitotic spread of HTLV-1 remains constant throughout infection the most economical hypothesis the net contribution of reverse transcription (infectious spread) may be very small when the system reaches equilibrium. This explanation could reconcile the evidence for persistent replication of HTLV-1 by the infectious pathway with the observed relative sequence constancy of the HTLV-1 provirus.
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Why is HTLV-1 expressed at a low level in peripheral blood? |
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A simpler explanation of the low HTLV-1 protein expression in peripheral blood is as follows. T cells spend the majority of their lives in the lymph and the solid lymphoid organs, not in the blood. The typical transit time of a T cell in the mammalian lymphoid system is of the order of several hours: 5 h in the spleen and 12 to 24 h in peripheral lymph nodes (Ford, 1975
; Westermann et al., 1988
, 1993
; Pabst et al., 1993
). Furthermore, because Tax protein upregulates the expression of several adhesion molecules (Valentin et al., 1997
; Yamamoto et al., 1997
), an HTLV-1-infected T cell may progress abnormally slowly through the lymphoid system. However, the T cell transit time in the blood is only around 30 min (Schick et al., 1975
). A T cell that starts to express Tax during its transit in the lymphoid system is therefore unlikely to re-emerge into the blood, because most will be killed by the abundant activated Tax-specific CTLs before they can do so. Thus the lymph nodes and the spleen may act as a filter that removes HTLV-1-expressing lymphocytes from the circulation. An HTLV-1 provirus-containing cell that emerges into the circulation has only approximately 30 min in the blood during which it can start to express Tax. Therefore, if we make the simplest assumption that the kinetics of Tax expression in vivo are the same as the kinetics in vitro (Hanon et al., 2000a
, b
), it follows that the fraction of provirus-positive cells that express detectable levels of Tax protein in the blood will be very low.
The above discussion relates only to non-malignant HTLV-1 infections. In ATL similarly, HTLV-1 provirus transcription rises spontaneously and rapidly during short-term in vitro incubation of lymphocytes in a proportion of cases. The Tax gene appears to be conserved selectively in ATL. However, HTLV-1 transcription in ATL may be subject to quite different constraints and selection forces (Kannagi et al., 1993), and is beyond the scope of this review: the reader is referred to Uchiyama (1997)
and Yoshida (2001)
for a useful discussion. The immune response to HTLV-1 has not been well-studied in ATL patients. However, it is worth noting that Kannagi et al. (1983
, 1984)
first detected the anti-HTLV-1 CTL response by assaying the lysis of ATL cells, and a CTL response was detected only in patients in remission from ATL. More work is needed on the immune response to HTLV-1 in ATL because of the important possibility of immunotherapy for this serious and refractory illness.
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How is HTLV-1 transmitted? |
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It had been known for many years that cellcell contact is required for efficient transmission of HTLV-1 both in vivo (Okochi & Sato, 1984) and in vitro (Yamamoto et al., 1982
; Popovic et al., 1983
). But the mechanism of cell-to-cell transmission, and therefore the reason why it was so much more efficient than transmission by free virions, was unexplained.
We observed that HTLV-1-specific T cells are themselves infected more frequently with HTLV-1 than are T cells specific to other antigens. This preferential infection was evident in both CD8+ T cells (Hanon et al., 2000a) and in CD4+ T cells (Goon et al., 2002
; P. Goon and C. R. M. Bangham, unpublished data). These observations, together with the requirement for cell-to-cell contact and the poor infectivity of cell-free particles, raised the possibility that HTLV-1 transmission was assisted by the process of T cell antigen recognition. More precisely, HTLV-1 might spread across the immunological synapse (Grakoui et al., 1999
), the specialized area of contact that is formed between a lymphocyte and another cell in which distinct protein microdomains mediate adhesion, antigen recognition and secretion of cytokines or lytic granules.
Confocal microscopy (Fig. 2) of conjugates formed spontaneously between ex vivo CD4+ cells from an HTLV-1-infected person and autologous (or allogeneic) lymphocytes revealed a structure at the cellcell junction which indeed resembles the immunological synapse (Igakura et al., 2003
). Polarization of the adhesion molecule talin and the microtubule organizing centre (MTOC) to the cellcell junction was accompanied by accumulation of the HTLV-1 core protein Gag and the HTLV-1 genome at the cellcell junction (Fig. 2
). After 2 h, both the Gag protein and the HTLV-1 genome were transferred from the infected to the uninfected cell (Igakura et al., 2003
; Fig. 2
).
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We concluded that HTLV-1 has lost the need to release cell-free virions in order to spread from cell to cell. Instead, HTLV-1 uses the mobility of the host cell to spread both within and between hosts. Since HIV-1 also spreads much more efficiently from cell to cell than by release of virus particles, it is possible that HIV-1 uses a mechanism similar to that used by HTLV-1.
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CONCLUSIONS |
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One of the largest single factors that accounts for the variation between individuals in the equilibrium provirus load in healthy carriers of HTLV-1 is individual variation in the efficiency of the CTL response to the virus.
An efficient CTL response, associated with a low provirus load, is characterized by strong mRNA expression of granzymes and other CTL lysis-related genes, and rapid killing of HTLV-1-infected lymphocytes. The molecular basis for this high CTL-responsiveness to HTLV-1 is unknown, although it is associated with certain class 1 HLA alleles (A*02, Cw*08) in southern Japan. The frequency of CD8+ T cells specific to a persistent replicating pathogen at equilibrium is not a useful index of the effectiveness of that CD8+ T cell response.
The median frequency of HTLV-1-specific CD4+ cells is between 10- and 25-fold greater in HAM/TSP patients than in asymptomatic carriers with a similar provirus load. The median frequency of specific CD8+ cells is 2- to 4-fold greater in patients with HAM/TSP than in carriers with an equivalent provirus load. Since CD4+ T cells predominate in early, active lesions in HAM/TSP, the possibility must be considered that CD4+ T cells are primarily responsible for initiating the inflammatory lesions.
Finally, a higher risk of HAM/TSP in southern Japan is associated with the host genotype HLA-A2-, HLA-Cw8-, HLA-DR1+, TNF-863A+, SDF-1+801A- and with infection with HTLV-1 subgroup A. Although the efficiency of the CTL response to HTLV-1 can account for most of the observed variation in provirus load among asymptomatic carriers and for a significant proportion of the variation in patients with HAM/TSP, it is insufficient to explain why some infected people progress to HAM/TSP. The factors responsible for this progression remain to be discovered.
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