The immune control of HTLV-1 infection: selection forces and dynamics

This is a very interesting review article on immune response to human T cell lymphotrophic virus. The review is by Dr. Charles R M Bangham and his colleagues from Imperial College, London. I would like to highlight some major points from the review.

1. Risk of HAM/TSP depends on HTLV-1 proviral load: Studies have shown a strong and reproducible association between a high proviral load and a high risk of HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is a remarkable difference in the stability of proviral load of HTLV-1 in each infected patient over time. There is also variation in the proviral load among patients. As HTLV-1 does not vary much in sequence either within or between hosts, it appears that variation in proviral load among hosts is caused by differences in the host rather in the virus.

2. HTLV-1 proviral load is correlated with the HTLV-1 specific CTL activity: CTL are abundant in the blood of both HAM/TSP patients and asymptomatic carriers. CTLs kill autologous cells that express viral antigens (one of the chief antigens is Tax) and by suppressing viral replications by secreting IFN gamma. Because of very high frequency of infected cells and CTLs in the peripheral blood, it is possible to determine the rate of this autologous CTL mediated lysis in fresh peripheral venous blood. This is done by measuring the effect of varying the frequency of CD8+ cells on the rate of disappearance of HTLV-1-expressing cells. These studies showed that in both HAM/TSP patients and in asymptomatic careers, there was a strong negative correlation between the proportion of HTLV-1 Tax+ cells eliminated per day and the proviral load in vivo. These findings may imply that a high rate of CTL mediated killing suppresses the proviral load in vivo. Based on various other studies it has been hypothesized that positive selection of the virus is caused by the HTLV-1 specific CTL response, these CTLs in turn limit the viral replication in vivo.

3. HTLV-1 infection accelerates the turnover of both CD4+ and CD8+ T cells in vivo- In a recently conducted experiment, the lymphocytes were labeled with denatured glucose administered by intravenous infusion. The results showed that there was a strong increase in the turnover rate of both CD8+ cells and of HTLV-1 infected CD4+ cells. The life span of Tax+ cells as well as HTLV-1 specific CTLs in circulation was decreased. Since this study was conducted in vivo, it provides one of the most direct evidence that HTLV-1 infection is associated with a persistently high rate of lymphocyte proliferation.

4. The rate of HTLV-1 expression varies among hosts and among T cell clones within one host- No association has been observed in the sequence of the virus and either the proviral load or the rate of proviral expression. However, studies have shown significant heterogeneity among HTLV-1 infected hosts in the rate of expression of HTLV-1. Dr. Bangham and others have shown that the level of spontaneous proviral expression in PBMCs ex vivo, is systematically greater in patients with HAM/TSP than in careers, at a given proviral load. It means both groups having same proviral load can have different expression. Studies have also shown that the rate of HTLV-1 virus expression varies among individual T cell clones in a single host. These observations lead to the hypothesis that each provirus containing T cell clone has a characteristic rate of onset of spontaneous proviral expression and this characteristic rate is maintained in the daughter cells of that clone.