Selective alterations in immunoregulatory lymphocyte subsets in early HIV (human T-lymphotropic virus type III/lymphadenopathy-associated virus) infection

In order to characterize the effects of HIV (human T-lymphotropic virus type III/lymphadenopathy-associated virus) on the immune system, Leu8^– and Leu8⁺ subsets of CD4 and CD8 cells were studied in seropositive homosexually active men without acquired immune deficiency syndrome (AIDS). Controls included both heterosexual men and HIV-seronegative homosexually active men. The decrease in CD4 levels, observed in HIV-seropositive men who were asymptomatic, as well as in those who had persistent generalized lymphadenopathy or constitutional symptoms of HIV infection, occurred proportionally in both the Leu8^– and the Leu8⁺ CD4 subsets. This observation, that HIV infection does not selectively diminish either subset of CD4 cells, indicates that the selective loss of T cell-mediated functions which accompanies the development of AIDS is not related to preferential loss of the Leu8⁺ CD4 subset. Among CD8 cells, however, HIV infection resulted in a threefold elevation in the number of Leu8^– CD8 cells, while the number of Leu8⁺ CD8 cells remained constant. The increase in Leu8^– CD8 cells was present in recent seroconverters, persistently seropositive men, and patients with AIDS. We propose that the increase in Leu8^– CD8 cells represents an HIV-specific cytotoxic T-cell response. These cells may operate by killing infected CD4 cells, thereby partially controlling viral infection while simultaneously contributing to the destruction of the immune system.     

Serologic confirmation of simian T-lymphotropic virus type I infection by using immunoassays developed for human T-lymphotropic virus antibody detection.

Serum specimens from diverse species of Old World monkeys, categorized as seropositive (n = 97) or seronegative (n = 23) for human T-lymphotropic virus (HTLV) infection, were tested by using recombinant env-spiked Western immunoblot assays and synthetic peptide assays for simultaneous detection and discrimination of simian T-lymphotropic virus (STLV) infection. Of the 97 seropositive specimens, 93 reacted with the recombinant transmembrane (r21env) protein and 90 reacted with a recombinant, MTA-1, derived from the central region of the external glycoprotein of HTLV-I (rgp46env), thus yielding test sensitivities of 96 and 93%, respectively. While 1 of the 23 negative monkey specimens reacted with r21env, none reacted with rgp46env, for overall specificities of 96 and 100%, respectively. Analysis of synthetic peptide-based immunoassays demonstrated that while 85 of 97 (88%) seropositive specimens reacted with HTLV-I-specific epitope (p19gag), none of the specimens reacted with HTLV-II-specific epitope (gp52env). These results show that recombinant envelope-spiked Western blots provide a simple means for serologic confirmation of STLV-I infection and that type-specific synthetic peptides can be used to confirm the virus type in seropositive monkey specimens.     

Natural history of human T-lymphotropic virus type 1 (HTLV-1) infection

The natural history of human T-lymphotropic virus type-1 (HTLV-1) infection has been difficult to be clarified, because only a small proportion of HTLV-1 carriers develop adult T-cell leukemia(ATL) after a long incubation period. We have performed a long-term follow-up study of HTLV-1 carriers for 17 years. Based on the findings of this study and other studies, the natural history of HTLV-1 carriers is hypothesized as follows. The major routes of infection of this virus are from mother to child, between spouses, and through blood products. The target of HTLV-1 infection is CD4 positive peripheral blood mononuclear cells (PBMCs). The number of infected cells is supposed to be increased just after the infection, then decreased in a year. The number of infected cells does not change thereafter during more than 10 years. In 90% of newly infected people, this level is low or medium ranging from less than 0.05% to 5% of PBMCs infected; however, approximately 10% of newly infected people develop into carriers with many number of infected cells as more than 5% of PBMCs infected. Clonal expansion of infected cells is likely to be contributing to the maintenance of the HTLV-1 infection. Replication of certain clones among many infected cells may be accelerated by the expression of Tax protein and some of them develop to have a phenotype to avoid immune surveillance. Finally, some of these clones, which acquired the accumulation of genomic abnormality, develop the pre-leukemic state. The increased number of certain T-cells due to HTLV-1 infection may also cause imbalance of the immune system, resulting in immune dysfunction or inflammatory diseases like myelopathy and uveitis. Therefore, it seems to be important to find ways to prevent HTLV-1 associated diseases among the carriers especially those with many infected cells.     

Seroepidemiology of human T-lymphotropic virus type I infection among intravenous drug abusers in Taiwan

In order to assess seroprevalence of human T-lymphotropic virus type I (HTLV-I) infection among intravenous drug abusers in Taiwan, serum samples were collected from 858 male study subjects. Antibodies against HTLV-I (anti-HTLV-l) in sera were tested by enzyme-linked immu-nosorbent assay and confirmed by Western blotting. The overall prevalence of anti-HTLV-l (2.3%) in drug abusers was significantly higher than that in the general population in Taiwan with a relative risk of 4.9, but it was only slightly higher than that in prostitutes (1.9%). There was a statistically significant increase in prevalence with age. Drug abusers engaged in prostitution had a significantly higher prevalence (18.2%) than those who were not (2.1%). No significant association with anti-HTLV-l positivity was observed with marital status and educational level. Tattooed abusers had an increased prevalence (2.7%) compared with the untattooed (1.4%). Drug abusers tattooed before 1980 had a significantly higher prevalence (3.5%) than those tattooed after 1980 (0.8%). Anti-HTLV-l prevalence was higher for those who had been blood transfused (4.5%) than untransfused abusers (2.0%). © 1994 Wiley-Liss, Inc.     

Effects of human T-lymphotropic virus type II on human immunodeficiency virus type 1 phenotypic evolution

Summary.  Phenotypic change and broader coreceptor usage by HIV-1 have been associated with disease progression. HIV-1 coreceptor usage by primary isolates obtained from HIV-1-infected and HIV-1/HTLV-II-coinfected individuals was determined. HIV-1 was isolated from 15 of 20 HIV-1-infected and 17 of 24 HIV-1/HTLV-II-coinfected individuals. None of the isolates from either the HIV-1-infected or the coinfected group infected CCR5Δ32 PBMCs, suggesting that they all were R5-tropic. Further, both spontaneous and PHA-stimulated production of MIP-1β and RANTES were similar in HIV-1-infected and coinfected individuals. These data indicate that coinfection with HTLV-II has no effect on HIV-1 coreceptor usage or ex vivo β-chemokine production. Received December 23, 2000/Accepted May 16, 2001     

Seroincidence of human T-lymphotropic virus type I infection and characterization of seroconverters in Jamaican food handlers

In a prospective study of food handlers in Jamaica, we estimated the age- and sex-specific seroincidence of human T-lymphotropic virus type I (HTLV-I) infection. Of 682 sexually active adults (132 males and 550 females) who were initially seronegative, 12 (1 male and 11 females) seroconverted over 8 years of follow-up. The seroincidence was 1.2 per 1,000 person-years for males and 3.2 per 1,000 person-years for females. The age-standardized incidence was 1.8 times higher for females than for males (P = 0.55). Within a median of 4 years after seroconversion, the median HTLV-I provirus load was 500 copies/105 cells, and the median antibody titer was 1:3109. Four of 12 seroconverters developed antibody to the Tax regulatory protein. HTLV-I infection in this population occurred at a rate comparable with that described for a Japanese cohort. Provirus load, titer and appearance of antibody to the Tax regulatory protein were typical of chronic carriers within a few years of seroconversion.     

Cell-mediated immune response to human T-lymphotropic virus type I

Human T-lymphotropic virus type I (HTLV-I) is a retrovirus that causes persistent infection in many populations in tropical and subtropical regions. HTLV-I chronically activates the cell-mediated arm of the host adaptive immune response. There has been much debate about the role of the immune response in determining the outcome of HTLV-I infection: most seropositive individuals remain lifelong asymptomatic carriers of the virus, whereas a small proportion-usually those with higher equilibrium proviral loads-develop an inflammatory disease of the central nervous system known as HAM/TSP. Here we discuss the cell-mediated immune response to HTLV-I infection. We summarize recent data on the HTLV-I-specific CD4(+) cell response and explore its potential role in HAM/TSP pathogenesis. We also explore the controversy surrounding the role of the CD8(+) cell response in controlling HTLV-I infection and/or contributing to HAM/TSP disease, highlighting recent studies of T cell gene expression profiles and a newly developed assay of CD8(+) cell functional efficiency. Finally, we introduce a possible role for cellular innate immune effectors in HTLV-I infection.     

Molecular epidemiology of herpes simplex virus type 1 genital infection in association with clinical manifestations

Summary.  The antigenic types of herpes simplex virus (HSV), HSV-1 and HSV-2 are considered to be the etiology of genital herpes. Symptoms of primary HSV-1 and HSV-2 genital infections are similar, however, recurrence of the infection is less frequent after the HSV-1-related genital infection. We determined genotypes of 79 HSV-1 strains isolated from genital lesions in women (43 from primary and 36 from recurrent infections), by analyzing restriction fragment length polymorphism of the HSV-1 strains. Each proportion of genotypes of F1, F12, and F41 in strains isolated from recurrent genital lesions was higher than the corresponding proportion in strains from primary genital lesions. Genotypes of HSV-1 strains isolated two or more times from recurrent genital lesions of each of three subjects were genotye F1, thereby supporting the hypothesis that the F1 genotype is closely associated with recurrence. While the possibility of a genotype preference at the site of infection was not ruled out, genotypes of more than half the number of HSV-1 strains from genital lesions were the same as those from non-genital (mainly oral-facial) lesions analyzed in our foregoing studies, thus indicating that most HSV-1 genotypes are apparently shared by genital and non-genital lesions. Accepted October 1, 1999     

The epidemiology and disease outcomes of human T-lymphotropic virus type II

Human T-lymphotropic virus type II (HTLV-II) is a human retrovirus which is endemic in Amerindian and pygmy tribes. Molecular subtypes show geographic segregation consistent with an ancient origin of this virus within humans in Africa or South America. More recently, injection drug users in the United States and Europe have become infected with HTLV-II, and secondary sexual transmission has introduced the virus at low levels into the general population and blood donors. HTLV-II has been linked with a spastic paraparesis called HTLV-associated myelopathy / tropical spastic paraparesis (HAM/TSP), and perhaps with other neurological syndromes. It is also associated with an increased incidence of pneumonia and bronchitis, inflammatory conditions such as arthritis, and perhaps with increased mortality. Except for a few cases of cutaneous lymphoma in patients coinfected with HIV, there is no evidence that HTLV-II causes lymphoproliferative disease. HTLV-II and HIV coinfection has not been proven to alter the course of HIV disease, but such patients may have altered levels of CD4+ and CD8+ lymphocytes, and antiretroviral therapy may paradoxically increase HTLV-II proviral load.     

An autopsy case of human T-lymphotropic virus type I-associated myelopathy

This report describes the first autopsy case of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM). The disease mainly affected the spinal cord, particularly the lateral and anterior columns, where loss of myelin and axon was observed. The changes were bilateral and occurred mainly along the tract. Perivascular and parenchymal infiltration with lymphocytes and macrophages, as well as astrocytosis, were observed in the white and grey matters of the spinal cord. Blood vessels in the spinal cord and in the subarachnoid space of the spinal cord showed hyalinoid thickening of media and adventitia associated with infiltration of lymphocytes. These findings are similar to those of tropical spastic paraparesis (TSP).     

Temporal dynamics of human T-lymphotropic virus type I tax mRNA and proviral DNA load in peripheral blood mononuclear cells of human T-lymphotropic virus type I-associated myelopathy patients

Human T-cell lymphotropic virus type I (HTLV-I) is the etiologic agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). High HTLV-I provirus load and tax mRNA level have been suggested as predictors of disease progression in patients with HAM/TSP, but little is known about the temporal variation in patients. To clarify the role of high proviral and tax mRNA loads and their fluctuations in the pathogenesis of HAM/TSP, we measured proviral load and tax mRNA in serially collected peripheral blood mononuclear cells (PBMCs) from nine patients with HAM/TSP during a long-term follow-up, by use of real-time polymerase chain reaction using tax primers. The real-time PCR quantitation revealed a wide range of variation of proviral loads (7.82-97.13 copies per 100 PBMCs) and tax mRNA (0.20-245.30 copies) among HAM/TSP patients. Patients showed three different patterns of HTLV-I tax mRNA loads during the course of the disease. Tax mRNA load showed a separate evolution with respect to the disease. The dynamic patterns of proviral load and mRNA Tax expression suggest that only the permanent presence of a basal level of tax mRNA, rather than the tax mRNA load, is related to the development of HAM/TSP. To our knowledge, this is the first longitudinal study to determine tax mRNA expression at different clinical stages.     

Envelope gene sequences of human T-lymphotropic virus type I in Taiwan

Summary Three major types of HTLV-I had been proposed, the Melanesian type, the Zairian type, and the cosmopolitan type, which was further divided into subtypes A, B and C, according to the phylogenetic tree constructed from LTR sequences of current HLTV-I isolates. In this study, the envelope gene sequences of HTLV-I from 9 Taiwanese were analyzed. Based on the phylogenetic tree constructed by unweighed pair group method and the sequence homology analysis by GCG computer programs, the envelope gene sequences of HTLV-I proviruses from these 9 Taiwanese belonged to subtype A or subtype B of the cosmopolitan type and were closely related to HTLV-I from Japan. Twelve subtype-specific nucleotide variations were deduced from the comparison of complete or partial envelope gene sequences of 16 HTLV-I isolates of known subtypes as well as those of 9 Taiwanese. These data provided the basis for subtyping the cosmopolitan type of HTLV-I by amplification of envelope gene sequences and restriction fragment length polymorphism studies. A more extensive survey based upon this proposal was warranted.     

Autonomous growth of human T-lymphotropic virus type I infected human lymphocytes treated with N-methyl-N'-nitro-N-nitrosoguanidine and ultraviolet rays

Human T-cell cultures infected with human T-lymphotropic virus type I (HTLV-I) and interleukin-2 (IL-2)-dependent for their continuous growth were treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and then maintained in the medium containing phorbol 12-myristate 13-acetate (TPA). Cells achieved independence from IL-2 but became TPA-dependent for continuous growth. Multiple ultraviolet (UV) irradiations of TPA-dependent cells resulted in their autonomous growth. G-band karyotype analysis revealed multiple chromosomal abnormalities that were seen in cells before and after MNNG treatment and UV irradiations, and those that were only seen in autonomously growing cells. Viral expression was found to be transiently enhanced in association with emergence of certain chromosomal changes. Exposure of HTLV-I infected cells to certain mutagens may promote the occurrence of the specific rearrangement of cellular genes responsible for regulation of cellular and viral replication and may lead these cells to neoplastic transformation.     

Interleukin-18 and interferon-gamma polymorphisms are implicated on proviral load and susceptibility to human T-lymphotropic virus type 1 infection

Interleukin-18 (IL-18) and interferon-gamma (IFN-γ) exert important functions in both innate and adaptive immune responses against intracellular pathogens and viruses. Previous studies suggested that host genetic factors, including cytokines gene polymorphisms, could be involved in the pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Thus, we analyzed -137C/G and -607A/C of the IL-18 promoter and +874T/A of the IFN-γ in DNA samples from 98 HTLV-1-infected individuals exhibiting or not clinical symptoms and 150 healthy control individuals. The IL-18 promoter -607CC genotype was significantly lower in HTLV-1 asymptomatic carriers (HAC) and HTLV-1-infected individuals (HAC + HAM/TSP) than healthy control group. In contrast, the -607AC genotype was significantly higher in HAC and HTLV-1-infected individuals group compared to the healthy control group. The -137G/-607A IL-18 haplotype was higher in infected group than healthy control group, and the -137C/-607C IL-18 haplotype was increased in the healthy control group compared to the others. Finally, the IFN-γ polymorphism analysis showed that the HTLV-1-infected individuals with +874AT genotype presented higher proviral load than +874AA genotype. These data indicate that the IL-18-607AC genotype and -137G/-607A haplotype could be a risk factor for HTLV-1 infection, whereas the protective effect could be conferred by -607CC genotype and -137C/-607C haplotype. Also, the IFN-γ could be implicated on the proviral load levels.     

Antiviral activity of bovine type III interferon against foot-and-mouth disease virus

Foot-and-mouth disease (FMD) is one of the most serious threats to the livestock industry. Despite the availability of a vaccine, recent outbreaks in disease-free countries have demonstrated that development of novel FMD control strategies is imperative. Here we report the identification and characterization of bovine (bo) interferon lambda 3 (IFN-λ3), a member of the type III IFN family. Expression of boIFN-λ3 using a replication-defective human adenovirus type 5 vector (Ad5-boIFN-λ3) yielded a glycosylated secreted protein with antiviral activity against FMD virus (FMDV) and vesicular stomatitis virus in bovine cell culture. Inoculation of cattle with Ad5-boIFN-λ3 induced systemic antiviral activity and up-regulation of IFN stimulated gene expression in multiple tissues susceptible to FMDV infection. Our results demonstrate that the type III IFN family is conserved in bovines and boIFN-λ3 has potential for further development as a biotherapeutic candidate to inhibit FMDV or other viruses in cattle.     

福建HTLV-Ⅰ的序列测定和系统树分析

目的　了解福建省HTLV Ⅰ毒株的亚型及进化起源。方法　用PCR的方法扩增出福建 5株样品的Env区及LTR区基因 ,测序后与世界各地的代表株进行比较、分析 ,构建进化树。结果将 5株样品与WHP、MT2、TAC1进行比较 ,其Env区核苷酸变异率在 0 .17%～ 1.2 3% ,LTR区在 0 .2 8%～ 1.2 6 % ,无缺失、插入。结论　获自福建的分离株与日本和我国台湾、汕头的代表株最接近 ,属于HTLV ⅠA亚型 (Cosmopolitan)的Transcontinental亚群 ,它们来源于共同的祖先。     

High prevalence of human T-lymphotropic virus type 1 (HTLV-1) in immigrant male-to-female transsexual sex workers with HIV-1 infection

Human T-lymphotropic virus type 1 and 2 (HTLV-1 and HTLV-2) infections in Europe are limited to intravenous drug users and migrants coming from areas in which they are endemic. A survey was undertaken of HTLV-1 and HTLV-2 infections in 393 recent immigrants: 167 HIV-1 positive subjects (including 52 male-to-female transsexual sex workers) and 226 pregnant HIV-1 negative women. The prevalence of HTLV-1 was 3.6% in the HIV-1 positive group and 0.9% in the HIV-1 negative group. The highest HTLV-1 prevalence in both groups was found in persons from Latin America, particularly those born in Peru (up to 26% in the HIV-1 positive group). All of the HIV-1/HTLV-1 co-infected individuals were male-to-female transsexual sex workers in whom the overall prevalence of HTLV-1 infection was 11.5%. HTLV-2 was only found in the HIV-1 positive group (prevalence 1.2%); all of the infected subjects were transsexual sex workers from Brazil (overall prevalence 6.4%). Phylogenetic analysis showed that all of the HTLV-1 isolates were of the cosmopolitan type, clustering with other strains circulating in the patients' birthplaces; the HTLV-2 isolates were of subtype 2a, and clustered significantly with other Brazilian strains. These results suggest the independent origin of each infection in the patient's birthplace. The data raise concerns about the further spread of HTLV infections mainly through the sexual route.     

Transactivation induced by human T-lymphotropic virus type III (HTLV III) maps to a viral sequence encoding 58 amino acids and lacks tissue specificity

The acquired immune deficiency syndrome (AIDS) retrovirus, HTLV-III/LAV, encodes a transacting factor which directly or indirectly stimulates the expression of genes linked to its LTR. To further dissect this phenomenon, we have cotransfected a biologically active molecular clone of HTLV-III and a recombinant plasmid containing an indicator gene, the bacterial gene for chloramphenicol acetyltransferase (CAT), under the control of the HTLV-III LTR. Amplified CAT activity was detected in both lymphoid cells and fibroblasts from a number of species in the presence of the proviral DNA. Deletion experiments confirm the previous assignment of the gene required for transactivation to a region immediately 5' to the envelope gene, and further narrow down the critical functional domain to a coding sequence of 58 codons.