Human T-cell Lymphotropic Virus Infection Research Articles

Síndrome cerebelar y neuropatía periférica como manifestación de la infección por el virus linfotrópico humano de células T,HTLV-I

Type I human T-cell lymphotropic virus (HTLV-I) is a retrovirus with affinity for CD4 cells. This infection may give rise to a broad spectrum of disorders including T-cell leucemia/lymphoma, the myelopathy/tropical spastic paraparesis complex (M/TSP), and to a lesser extent, uveitis, arthritis, polymyositis and peripheral neuropathy. M/TSP is a progressive, chronic myelopathy characterized by spasticity, hypereflexia, muscle weakness and sphincter disorders. Much less frequently it may precede, or give rise to, a cerebellar syndrome with ataxia and intention tremor. We describe the case of a 13 year old adolescent girl who presented with a neurological syndrome which had started with tremor of the head and limbs, ataxia, dysmetria, frequent falls and sphincter disorders. During the two and a half years that she had had this illness she had developed spastic paraparesis of the legs and had repeated urinary infections. Serology of blood and CSF was positive for HTLV-I using the ELISA technique and confirmed by Western-blot. EMG showed predominantly axonal sensomotor neuropathy. A neurogenic bladder was detected on functional urodynamic studies. On MR there was moderate atrophy of the thoracic spinal cord and slight alterations of the subcortical white matter. The presence of a cerebellar syndrome or neuropathy of uncertain origin, in endemic areas, should lead to the inclusion of HTLV-I infection in the differential diagnosis, even in the absence of pyramidal symptoms or defined M/TSP. Maternal seropositivity supports the hypothesis of mother-daughter transmission during lactation.

Response from Sandstrom and Chapman

Dr Onions and colleagues[1xOnions, D. et al. Trends Microbiol. 1998; 6: 431Abstract | Full Text | Full Text PDF | PubMedSee all References[1]infer, from knowledge about feline leukemia virus (FeLV) and murine leukemia virus (MuLV) infections, what might be expected if porcine endogenous retrovirus (PoERV) infections occur in humans. While the capacity of PoERV to infect humans remains unproven[2xPatience, C. et al. Lancet. 1998; 352: 699–701Abstract | Full Text | Full Text PDF | PubMedSee all References, 3xHeneine, W. et al. Lancet. 1998; 352: 695–699Abstract | Full Text | Full Text PDF | PubMedSee all References], the reasoning of Onions et al. argues for investigation of three hypotheses. First, PoERV infections might be expected to be largely abortive. Exploration of the feasibility and efficacy of transient clinical interventions intended to decrease the likelihood that persistent infection will be established (such as peritransplant prophylactic antiretroviral treatment) might be warranted. Second, it may be possible to prevent PoERV infection in recipients of porcine xenografts through pre-transplant vaccination. Third, the presence of FeLV in the saliva of infected cats indicates that hepatitis B or cytomegalovirus infections might provide more appropriate models than human retroviruses for infection control practices following human exposure to PoERV. Sexual or parenteral blood exposure is necessary for transmission of HIV and human T-cell lymphotropic virus (HTLV) infections, and saliva poses a negligible threat. Dr Takeuchi[4xTakeuchi, Y. Trends Microbiol. 1998; 6: 430Abstract | Full Text | Full Text PDF | PubMedSee all References[4]cautions that the exact behavior of a microorganism when it crosses a species barrier cannot be predicted. Nevertheless, current knowledge supports the exploration of the first two hypotheses and warrants attention to the third hypothesis during the development of infection control guidelines for porcine xenograft recipients.Drs van der Kuyl and Goudsmit[5xvan der Kuyl, A.C. and Goudsmit, J. Trends Microbiol. 1998; 6: 431–432Abstract | Full Text | Full Text PDF | PubMed | Scopus (3)See all References[5]highlight the development of pigs transgenically engineered to circumvent hyperacute rejection (HAR), a modification anticipated to facilitate graft survival but also to compromise lytic complement clearance of PoERV (Refs [1xOnions, D. et al. Trends Microbiol. 1998; 6: 431Abstract | Full Text | Full Text PDF | PubMedSee all References, 6xPatience, C., Takeuchi, Y., and Weiss, R.A. Nat. Med. 1997; 3: 282–286Crossref | PubMed | Scopus (819)See all References]). Recipients of xenografts from nontransgenic pigs, the only population studied to date[2xPatience, C. et al. Lancet. 1998; 352: 699–701Abstract | Full Text | Full Text PDF | PubMedSee all References, 3xHeneine, W. et al. Lancet. 1998; 352: 695–699Abstract | Full Text | Full Text PDF | PubMedSee all References], represent the lowest end of a spectrum of risk for PoERV infection. Risks will need to be independently assessed for alternative xenograft applications, including the use of transgenic pigs.Drs van der Kuyl and Goudsmit[5xvan der Kuyl, A.C. and Goudsmit, J. Trends Microbiol. 1998; 6: 431–432Abstract | Full Text | Full Text PDF | PubMed | Scopus (3)See all References[5]also discuss a study by Allan et al. of human recipients of baboon livers[7xAllan, J.S. et al. AIDS Res. Hum. Retrovir. 1998; 14: 821–824Crossref | PubMedSee all References[7]. The important contribution of this work is recognition of the persistent presence of simian foamy virus (SFV) and baboon endogenous retrovirus (BaEV), constituting potentially ongoing niduses for human infection following receipt of baboon xenografts. Given that humans have been infected with SFV of baboon origin following transient occupational exposures[8xHeneine, W. et al. Nat. Med. 1998; 4: 391–392Crossref | PubMed | Scopus (157)See all References[8], it is highly likely that this more intimate ongoing exposure would result in infection. Furthermore, SFV can infect humans and is not eliminated from persistently microchimeric baboon cells. SFV infection has never been associated with disease in any species, including humans. Nevertheless, in light of this knowledge, intentional or negligent exposure of humans to foamy-virus-infected xenografts would be hard to justify and is unlikely to be allowed by regulatory bodies. These studies also support the need for assessment of BaEV infection among humans exposed to baboons or baboon tissue.The FDA requires all porcine xenograft recipients in the USA to be monitored for PoERV infections, including the recipients of porcine neuronal tissue reported by Deacon and colleagues[9xDeacon, T. et al. Nat. Med. 1997; 3: 350–353Crossref | PubMed | Scopus (347)See all References[9]. These negative results, although unpublished, have been presented in public forums.

Neutralizing human monoclonal antibodies to conformational epitopes of human T-cell lymphotropic virus type 1 and 2 gp46.

Ten human monoclonal antibodies derived from peripheral B cells of a patient with human T-cell lymphotropic virus (HTLV)-associated myelopathy are described. One monoclonal antibody recognized a linear epitope within the carboxy-terminal 43 amino acids of HTLV gp21, and two monoclonal antibodies recognized linear epitopes within HTLV type 1 (HTLV-1) gp46. The remaining seven monoclonal antibodies recognized denaturation-sensitive epitopes within HTLV-1 gp46 that were expressed on the surfaces of infected cells. Two of these antibodies also bound to viable HTLV-2 infected cells and immunoprecipitated HTLV-2 gp46. Virus neutralization was determined by syncytium inhibition assays. Eight monoclonal antibodies, including all seven that recognized denaturation-sensitive epitopes within HTLV-1 gp46, possessed significant virus neutralization activity. By competitive inhibition analysis it was determined that these antibodies recognized at least four distinct conformational epitopes within HTLV-1 gp46. These findings indicate the importance of conformational epitopes within HTLV-1 gp46 in mediating a neutralizing antibody response to HTLV infection.

Significance of indeterminate reactivity to human T-Cell lymphotropic virus in Western blot analysis of individuals at risk

Current tests to confirm human T-cell lymphotropic virus (HTLV) infection in individuals at risk of retroviral infection commonly yield indeterminate results. To assess the significance of HTLV-seroindeterminate reactivities in a high-risk population, 16 at-risk individuals who had this serologic pattern by Western blot were studied using a polymerase chain reaction (PCR) assay. Human T-cell lymphotropic virus type II infection was confirmed by the presence of virus-specific nucleic acid in four patients. However, PCR analysis was negative in the remaining 12 individuals. These results indicate strongly that all specimens from at-risk individuals with nondiagnostic HTLV reactivity by current Western blot assay should continue to be considered inconclusive, requiring further testing by more sensitive tests.

The Risk of Transfusion-Transmitted Viral Infections

Accurate estimates of the risk of transfusion-transmitted infectious disease are essential for monitoring the safety of the blood supply and evaluating the potential effect of new screening tests. We estimated the risk of transmitting the human Immuno-deficiency virus (HIV), the human T-cell lymphotropic virus (HTLV), the hepatitis C virus (HCV), and the hepatitis B virus (HBV) from screened blood units donated during the window period following a recent, undetected infection. Using data on 586,507 persons who each donated blood more than once between 1991 and 1993 at five blood centers (for a total of 2,318,356 allogeneic blood donations), we calculated the incidence rates of seroconversion among those whose donations passed all the screening tests used. We adjusted these rates for the estimated duration of the infectious window period for each virus. We then estimated the further reductions in risk that would result from the use of new and more sensitive viral-antigen or nucleic acid screening tests. Among donors whose units passed all screening tests, the risks of giving blood during an infectious window period were estimated as follows: for HIV, 1 in 493,000 (95 percent confidence interval, 202,000 to 2,778,000); for HTLV, 1 in 641,000 (256,000 to 2,000,000); for HCV, 1 in 103,000 (28,000 to 288,000); and for HBV, 1 in 63,000 (31,000 to 147,000). HBV and HCV accounted for 88 percent of the aggregate risk of 1 in 34,000. New screening tests that shorten the window periods for the four viruses should reduce the risks by 27 to 72 percent. The risk of transmitting HIV, HTLV, HCV, or HBV infection by the transfusion of screened blood is very small, and new screening tests will reduce the risk even further.

Prevalence and Epidemiologic Correlates of Human T Cell Lymphotropic Virus Infection Among Intravenous Drug Users

Intravenous drug users (IVDUs) in Seattle (n = 213) were studied to identify the prevalence and predominant types of and risk factors for human T cell lymphotropic virus (HTLV) infection. Detailed questionnaires, serologic screening, and polymerase chain reaction analysis (for a subset) were used. Evidence of HTLV infection was found in 16.5%, of which 89% were HTLV-II. HTLV infection was significantly associated with nonwhite race, older age, more years of intravenous drug use, prior use of heroin, history of gonorrhea, history of any sexually transmitted disease, hepatitis B virus infection, and antibody to herpes simplex virus type 2 (HSV-2). By stepwise logistic regression analysis, associations persisted with race, age, hepatitis B markers, and HSV-2. Thus, the strong association of HTLV with hepatitis B, a marker for injection behavior, and the independent association with HSV-2 infection, a sexually transmitted pathogen, suggest similarities in the epidemiology of HTLV and human immunodeficiency virus infections in IVDUs.

Cutaneous manifestations of systemic infection in children

The child with rash and fever presents a particular challenge in the course of practice. Despite the development of many new diagnostic laboratory techniques over the past few decades, it is very often the morphology, distribution, and history of skin disease that allow the dermatologist or pediatrician to correctly evaluate and treat these patients. This review article emphasizes clinical clues that may aid in the diagnosis of a variety of bacterial, rickettsial, spirochetal, and viral infections in children. In addition, there have been a number of recent advances in the understanding of the pathogenesis and epidemiology of several childhood illnesses with cutaneous manifestations. New information related to staphylococcal scalded skin syndrome, Lyme disease, fifth disease, human immunodeficiency virus infection, and human T-cell lymphotropic virus infection is therefore included.

Differential diagnosis of HTLV-I and HTLV-II infections by restriction enzyme analysis of ‘nested’ PCR products

A ‘nested’ polymerase chain reaction (PCR) assay is described which is capable of detecting single copies of human T-cell lymphotropic virus (HTLV) in genomic DNA extracted from peripheral blood mononuclear cells (PBMCs). A single set of ‘nested’ oligonucleotide primers, based on the highly conserved tax/rex region of the viral genome, was able to detect both HTLV-I and HTLV-II proviral sequences in clinical samples of diverse geographical origins, from the United States, Great Britain, Japan, the Caribbean, Italy, Greece, Iraq and West Africa. Rapid discrimination between HTLV-I and HTLV-II infections was achieved by restriction enzyme analysis of unpurified second-round PCR products, even in those cases in which serological assays had failed to provide a definitive result. Over a 2-year period, a total of 53 HTLV infections (37 HTLV-I and 16 HTLV-II) were identified by this technique and complete concordance with serological typing, available in 41 cases, was observed.

Evaluation of human T cell lymphotropic virus infection in a cohort of injecting drug users.

The diagnosis and confirmation of human T cell lymphotropic virus (HTLV) type II infection has proven difficult, since most assays depend on antigenic cross-reactivity between HTLV-I antigens and HTLV-II antibodies. Type-specific HTLV infection rates were evaluated in a cohort of 233 injecting drug users screened with an HTLV EIA. Of the 52 EIA-reactive specimens, 48 were indeterminate or negative by standard Western blot. Type-specific HTLV results determined by polymerase chain reaction (PCR) were 0, HTLV-I; 92%, HTLV-II; 6%, type indeterminate; and 2%, negative. Among 42 EIA-reactive, HTLV-II-PCR-positive individuals tested by a p21 envr Western blot, all were positive and 74% had antibodies to the tax protein. This study found a high rate (22.3%) of HTLV reactivity, with HTLV-II usually the sole responsible agent; shortcomings in standard HTLV-I-based diagnostics but usefulness of PCR and p21 envr Western blots for typing and confirmation of HTLV reactivity; and a high prevalence (74%) of anti-tax antibody among HTLV-II-seropositive subjects, suggesting increased potential for infectivity.

Sensitivity and specificity of a recombinant transmembrane glycoprotein (rgp21)-spiked western immunoblot for serological confirmation of human T-cell lymphotropic virus type I and type II infections.

Serum specimens (n = 2,712) obtained from individuals residing in diverse geographic regions and categorized as seropositive (n = 122), seroindeterminate (n = 523), or seronegative (n = 2,067) for human T-cell lymphotropic virus (HTLV) infection in accordance with U.S. Public Health Service guidelines were retested by recombinant transmembrane protein (rgp21)-spiked Western immunoblotting. Of the 122 HTLV-positive specimens, those from 85 of 85 (100%) U.S. blood donors, 2 of 2 (100%) Brazilians, 1 of 2 (50%) Indonesians, 14 of 14 (100%) Solomon Islanders, and 18 of 19 (95%) Papua New Guineans reacted with rgp21, yielding an overall sensitivity of 98% (120 of 122). Specimens from individuals whose infections were confirmed to be HTLV type I or HTLV type II by the polymerase chain reaction assay reacted equally well with rgp21. Of the 523 HTLV-indeterminate specimens, those from 21 of 379 (5.5%) U.S. blood donors, 3 of 6 (50%) Brazilians, 10 of 23 (44%) Ugandans, 8 of 49 (16%) Indonesians, 4 of 36 (11%) Solomon Islanders, and 5 of 30 (17%) Papua New Guineans reacted with rgp21. None of these 51 specimens reacted with native gp46 and/or gp61/68 in a radioimmunoprecipitation assay, suggesting a false-positive reaction (9.75%). Of the 2,067 HTLV-negative specimens, 12 reacted with rgp21, yielding a false-positivity rate of 0.6%. These data indicate that while detection of rgp21 is highly sensitive, it can yield false-positive results. Thus, specimens exhibiting reactivity with rgp21 in the absence of reactivity with native gp46 and/or gp61/68 by Western blot should be tested further by a radioimmunoprecipitation assay to verify HTLV type I or type II infection.

Cutaneous manifestations of systemic infection in children

Abstract The child with rash and fever presents a particular challenge in the course of practice. Despite the development of many new diagnostic laboratory techniques over the past few decades, it is very often the morphology, distribution, and history of skin disease that allow the dermatologist or pediatrician to correctly evaluate and treat these patients. This review article emphasizes clinical clues that may aid in the diagnosis of a variety of bacterial, rickettsial, spirochetal, and viral infections in children. In addition, there have been a number of recent advances in the understanding of the pathogenesis and epidemiology of several childhood illnesses with cutaneous manifestations. New information related to staphylococcal scalded skin syndrome, Lyme disease, fifth disease, human immunodeficiency virus infection, and human T-cell lymphotropic virus infection is therefore included.

Human T-Cell Lymphotropic Virus Infection among Blood Donors in South Florida

Knowledge of the epidemiologic pattern of human T-lymphotropic virus (HTLV) in the United States is being enlarged by blood donor screening. We tested stored sera from 29,937 donations made in South Florida in 1984-1985. Twenty-three donors were confirmed as seropositive, a prevalence of 0.8 per 1,000 donations. Specificity was supported by serologic retesting and virus culture of 11 donors located for follow-up. Sex- and age-specific prevalences did not differ significantly; blacks, however, accounted for 65% of seropositive donations. Within South Florida, one section of Miami had a prevalence of 4.5 per 1,000 donations, significantly above the 0.1 to 1.1 per 1,000 rates for other parts. An epidemiologic association with known HTLV-I endemic areas could account for most infections; all seven typed isolates were characterized as HTLV-I. Exposures, however, were diverse, sometimes multiple, and had no necessary relationship to personal lifestyle. This finding suggests that sources of infection were varied. Seropositive family members emphasize familial clustering of HTLV-I infection.

Type-specific antigens for serological discrimination of HTLV-I and HTLV-II infection

55 HTLV-I (human T-cell lymphotropic virus) and 45 HTLV-II carriers, confirmed by HTLV-type specific polymerase chain reaction (PCR), were distinguished by western blot assays with recombinant HTLV I or II envelope glycoproteins. Recombinant protein (RP) B1 contains aminoacids 166-201 from HTLV-I exterior glycoprotein gp46 and was reactive with HTLV-I samples only. RP-IIB, which contains aminoacids 96-235 from HTLV-II exterior glycoprotein gp52, was reactive with all HTLV-II samples. 39 patients (86·6%) had high reactivity by densitometry. Of 55 HTLV-I samples, 35 (65·5%) had antibody reactivity to RP-IIB, but only 1 (1·8%) had high reactivity by densitometry. RP B1 and IIB western blot assays may replace the PCR test in diagnosis of HTLV infection.

Adult T-cell lymphoma in israeli patients of iranian origin

The clinical and laboratory features of four Israeli patients with adult T-cell lymphoma-leukemia (ATL) are presented. In three of them evidence for human T-cell lymphotropic leukemia virus (HTLV-I) infection was obtained. Interestingly, all of the patients immigrated to Israel from the same regions in Iran. Except for lack of skin involvement, the clinical course was typical for ATL as described worldwide. This is the first report of ATL in an Iranian cohort. This observation suggests that Iranian patients with ATL-like illness should be studied for the presence of HTLV-I infection.

Seroepidemiology of hepatitis a, b, and d viruses and human t‐lymphocyte tropic viruses in japanese drug abusers

To evaluate the prevalence of hepatitis virus markers and human T-cell lymphotropic virus infections among drug abusers in Japan, serum samples were collected from 91 male drug abusers at the Shinshu University Hospital and the rehabilitation facility in Matsumoto and from 519 healthy male blood donors as controls. Sera were tested for antibody to hepatitis A virus (anti-HAV), hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs), antibody to hepatitis B core antigen (anti-HBc), immunoglobulin M anti-HBc (IgM anti-HBc), antibody to hepatitis D virus (anti-HDV), antibody to HTLV type 1 (anti-HTLV 1), and antibody to human immunodeficiency virus (anti-HIV). The prevalence of anti-HAV was 13.2% in drug abusers and 10.8% in controls (not significant). The prevalences of HBsAg, anti-HBs, anti-HBc and exposure rate to hepatitis B virus (HBV) were 4.4%, 24.2%, 31.9%, and 35.2%, respectively, in drug abusers and 0.8%, 6.7%, 9.6%, and 9.6% in controls. The exposure rate to HBV was significantly different (P less than 0.001). IgM anti-HBc and anti-HDV were not detected in any sera. Anti-HTLV I was detected in three drug abusers (3.3%) and in one (0.2%) of the controls (P less than 0.01). All sera were negative for anti-HIV in all subjects. Infection with HBV and HTLV I is more common among drug abusers than in the general population of blood donors in Japan.

Multiple opportunistic infections and neoplasms in the acquired immunodeficiency syndrome

The articles by Fischl et al¹and Burkes et al²that appear elsewhere in this issue nicely illustrate the scope of infectious and neoplastic complications found in the acquired immunodeficiency syndrome (AIDS). Just two patients were reported, but between them they had no fewer than nine different infections and two malignancies, including human T-cell lymphotropic virus (HTLV-III) infection, oral candidiasis,<i>Pneumocystis carinii</i>pneumonia, cytomegalovirus infection, fungal brain infection,<i>Toxoplasma</i>brain abscesses, tuberculosis, cysticercosis, Epstein-Barr virus infection, Kaposi's sarcoma, and non-Hodgkin's lymphoma. Convincing evidence now exists that the cause of AIDS is a retrovirus, HTLV-III, and that this infection may be associated with a profound and progressive cellular immunodeficiency state.³Other data also indicate the possibility of impaired humoral defenses, but in adults, so far, this has led to comparatively few clinical sequelae.⁴Serious opportunistic infections and/or Kaposi's sarcoma dominate what appear to be the later

Multiple Opportunistic Infections and Neoplasms in the Acquired Immunodeficiency Syndrome

The articles by Fischl et al 1 and Burkes et al 2 that appear elsewhere in this issue nicely illustrate the scope of infectious and neoplastic complications found in the acquired immunodeficiency syndrome (AIDS). Just two patients were reported, but between them they had no fewer than nine different infections and two malignancies, including human T-cell lymphotropic virus (HTLV-III) infection, oral candidiasis, Pneumocystis carinii pneumonia, cytomegalovirus infection, fungal brain infection, Toxoplasma brain abscesses, tuberculosis, cysticercosis, Epstein-Barr virus infection, Kaposi's sarcoma, and non-Hodgkin's lymphoma. Convincing evidence now exists that the cause of AIDS is a retrovirus, HTLV-III, and that this infection may be associated with a profound and progressive cellular immunodeficiency state. 3 Other data also indicate the possibility of impaired humoral defenses, but in adults, so far, this has led to comparatively few clinical sequelae. 4 Serious opportunistic infections and/or Kaposi's sarcoma dominate what appear to be the later