Dual Infection of HIV-1 and HTLV-I in South India: A Study on a Patient with AIDS-Related Complex

A dually HIV-and HTLV-infected ARC patient was found by serological studies in South India. These viruses were isolated and molecular study showed that the patient had both HIV-1 and HTLV-I but not HIV-2 and HTLV-II. In addition to this, 9 other dually infected persons which include another full-blown AIDS case have been identified as on July 1993 in South India. Our findings provide an opportunity to clarify geographical distribution of these human retroviruses.     

The myeloneuropathies of Jamaica

This article summarizes the present state of knowledge of TSP/HAM as it is seen in Jamaica. It reviews the historical and clinical aspects of the disease, and shows how the discovery of HTLV-I has generated research in several countries and contributed to a better understanding of the disease. It highlights the need for continued collaboration between basic scientists and clinical neurologists in order that the dilemmas relating to therapy and pathogenicity may be successfully addressed.     

Genetic variability in the extracellular matrix protein as a determinant of risk for developing HTLV-I-associated neurological disease

Aggrecan, which is a well-known proteoglycan in joint cartilage, also exists in the spinal cord and plays an important role in maintaining water content in the extracellular matrix structure. In this study, we first examined the variable number of tandem repeat (VNTR) polymorphism of the aggrecan gene in 227 HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, in 217 HTLV-I-infected healthy carriers (HCs), and in 85 normal controls. The VNTR allele 28 (1,630 bp) was more frequently observed in HAM/TSP patients than in HCs (χ ²=12.02, p=0.0005, odds ratio 1.79, 95% C.I. 1.29–2.50) and in controls (χ ²=13.43, p=0.0002, odds ratio 2.54, 95% C.I. 1.52–4.25), although this allele was not related to disease progression or to HTLV-I provirus load. We also found that the aggrecan concentration in cerebrospinal fluid (CSF) from rapidly progressive HAM/TSP patients was significantly higher than in slowly progressive patients (corrected p=0.0145) but not in infected non-inflammatory neurological other disease controls (OND) (corrected p=0.078). We then analyzed this aggrecan VNTR polymorphism in the different set of patients with HAM/TSP (n=58) and healthy carriers (n=70). This analysis, again, revealed that allele 28 was detected more frequently in HAM/TSP group than in HCs (χ ²=11.03, p=0.0009, odd ratio 3.04, 95% C.I. 1.55–5.97). The reproducibility of our study was regarded as a second- or third-class association by comparing combined p values and the Better Associations for Disease and GEnes (BADGE) system. Our results suggest that aggrecan polymorphism can be a novel genetic risk factor for developing HAM/TSP.Financial support: Grant in Aid for Research on Brain Science of the Ministry of Health, Labor and Welfare, Japan.     

Retroviral proteomics and interactomes: intricate balances of cell survival and viral replication

Overall changes in the host cellular proteome upon retroviral infection intensify from the initial entry of the virus to the incorporation of viral DNA into the host genome, and finally to the consistent latent state of infection. The host cell reacts to both the entry of viral elements and the manipulation of host cellular machinery, resulting in a cascade of signaling events and pathway activation. Cell type- and tissue-specific responses are also characteristic of infection and can be classified based on the differential expression of genes and proteins between normal and disease states. The characterization of differentially expressed proteins upon infection is also critical in identifying potential biomarkers within infected bodily fluids. Biomarkers can be used to monitor the progression of infection, track the effectiveness of specific treatments and characterize the mechanisms of disease pathogenesis. Standard proteomic approaches have been applied to monitor the changes in global protein expression and localization in infected cells, tissues and fluids. Here we report on recent investigations into the characterization of proteomes in response to retroviral infection.     

Overcoming the blockade at the upstream of caspase cascade in Fas-resistant HTLV-I-infected T cells by cycloheximide

In spite of carrying large amount of Fas death receptor on the cell surface, Human T cell lymphotropic virus type-I (HTLV-I)-infected T cell lines are resistant to Fas-mediated cytotoxicity. We investigated the mechanism(s) of HTLV-I-induced Fas resistance. Western blotting and enzymatic activity analyses revealed that the Fas-elicited apoptotic signal in HTLV-I-infected T cells was intervened at the level(s) prior to the activation of caspase-8. Upon stimulation, the clustering of Fas receptors scarcely occurred in HTLV-I-infected cells. Cycloheximide treatment converted the resistant cells to sensitive cells; the presence of short-lived anti-apoptotic molecule(s) that can block the caspase-8 activation within HTLV-I-infected T cells is suggested.     

Dynamics of human T-cell lymphotropic virus I (HTLV-I) infection of CD4+ T-cells

Stilianakis and Seydel (Bull. Math. Biol., 1999) proposed an ODE model that describes the T-cell dynamics of human T-cell lymphotropic virus I (HTLV-I) infection and the development of adult T-cell leukemia (ATL). Their model consists of four components: uninfected healthy CD4+ T-cells, latently infected CD4+ T-cells, actively infected CD4+ T-cells, and ATL cells. Mathematical analysis that completely determines the global dynamics of this model has been done by Wang et al. (Math. Biosci., 2002). In this note, we first modify the parameters of the model to distinguish between contact and infectivity rates. Then we introduce a discrete time delay to the model to describe the time between emission of contagious particles by active CD4+ T-cells and infection of pure cells. Using the results in Culshaw and Ruan (Math. Biosci., 2000) in the analysis of time delay with respect to cell-free viral spread of HIV, we study the effect of time delay on the stability of the endemically infected equilibrium. Numerical simulations are presented to illustrate the results.     

Evolutionary Dynamics of HTLV-I

Using mathematical models to describe the in vivo dynamics of HTLV-I infection, an explanation is offered for the slow rate of evolution of HTLV-I relative to HIV-1. In agreement with experimental findings, it is assumed that cell activation is required for successful replication in T helper cells and that HTLV-I induces a significant degree of bystander activation. It is found that the rate of evolution of HTLV-I is limited by the restricted availability of activated uninfected T cells, both at high and low proviral loads. This limits the within-host sequence diversity of HTLV-I and may therefore account for the slow rate of evolution of the virus in the population. Specific differences in the in vivo dynamics of HTLV-I and HIV-1 are identified which may account for the discrepancy in the rate of evolution of these two retroviruses. Received: 7 September 1999 / Accepted: 6 December 1999     

Visualisation of phenotypically mixed HIV-1 and HTLV-I virus particles by electron microscopy

Virions produced after HIV-1 infection of HTLV-I transformed cells have an expanded tropism that has been attributed to the presence of HTLV-I glycoproteins in the envelope. This report now directly identifies these phenotypically mixed virions by immunogold labelling electron microscopy. Furthermore we estimate there are 2% of these in cell-free supernatant, which represents up to 1 x 10(7) particles/ml from an in vitro infection. HTLV-1 envelope labelling was localised to a single region, suggesting a defined event in packaging of foreign envelope proteins into HIV-1 virus particles.     

Analysis of Tax-Expressing Cell Lines Generated from HTLV-ITax-Transgenic Mice: Correlation between c-mycOverexpression and Neoplastic Potential

Human T-cell leukemia/lymphotropic virus type I (HTLV-I) infection causes a variety of human diseases, including adult T-cell leukemia/lymphoma. The viral transactivator Tax has been implicated as a key factor in the HTLV-I-induced transformation pathway. To investigate the components of this pathway, we derived fibroblast-like cell lines, designated T6 and T9, from tail biopsies oftax-transgenic C57BL/6 mice that do not develop tumors. Phenotypic characterization of T6 and T9 cells and T6-derived subclones revealed that they differ in their abilities to form fociin vitroand tumorsin vivo.The observed differences in the levels of Tax expression did not correlate with their degree of neoplastic potential. However, a control cell line derived from a nontransgenic C57BL/6 mouse did not form fociin vitroor tumorsin vivo,indicating that Tax was required for the transformation process. Results of Northern analyses showed that the T9 cells and the highly malignant derivatives of T6 cells expressed elevated levels of c-mycmRNA. These findings suggest that progression of thetax-transgenic cells toward a more malignant phenotype might involve c-mycderegulation.