Michael D. Lairmore

HTLV‐I—associated myelopathy/tropical spastic paraparesis in the United States

HTLV-I—associated myelopathy/tropical spastic paraparesis (HAM/TSP) is endemic in the Caribbean basin and Japan. Because of the close proximity of the United States to the Caribbean and the presence of HTLV-I-seropositive persons in the United States, we sought reports of patients who were HTLV-I-seropositive and had a slowly progressive myelopathy. Over a 2-year period, there were 25 patients reported, 19 of whom were black and 12 of whom had been born in the United States. All patients except two had become symptomatic while living in the United States. Six patients had no apparent risk factor for acquiring HTLV-I. These data demonstrate that HAM/TSP is occurring in the United States and that the diagnosis of HAM/TSP should be considered in patients with a slowly progressive myelopathy regardless of risk factors for acquiring HTLV-I.

HTLV-I-associated myelopathy associated with blood transfusion in the United States: Epidemiologic and molecular evidence linking donor and recipient

Six months after receiving 58 units of blood components, a 65-year-old white man from New York City, with no other risk factors for human T-lymphotropic virus type I (HTLV-I) infection, developed HTLV-I-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). Investigation of blood donors identified a 25-year-old white Hispanic woman from Florida whose platelets had been given to the patient and who was seropositive for the virus on a serum specimen obtained 2 years after the donation. She was born in Cuba and had had 2 sexual relationships with men who either had been born in or had resided in the Caribbean. Polymerase chain reaction (PCR) studies of peripheral blood mononuclear cells indicated that both donor and recipient were infected with HTLV-I. Molecular studies of a 595-nucleotide sequence in the 5 envelope region of HTLV-I indicated that the viruses from donor and recipient were identical in each of 32 positions in which published HTLV-I sequences demonstrate molecular heterogeneity; the donor and recipient viruses were also identical in 2 additional positions in which they differed from all published sequences. Transfusion-associated HAM/TSP has occurred in the United States, but additional cases should be prevented by screening blood donations for HTLV-I. Molecular studies of HTLV-I may prove useful in defining the genetic heterogeneity of HTLV-I isolates in the United States and in studying transmission of this virus.

HTLV‐I‐associated myelopathy endemic in Texas‐born residents and isolation of virus from CSF cells

We report three Texas-born patients with spastic paraparesis and well-documented infection with HTLV-I. CSF examination showed moderate pleocytosis, protein elevation, and elevated IgG index. Oligoclonal bands were present in two patients. On MRI, one patient had frontal lobe lesions that were low intensity on T1- and high intensity on T2-weighted images. HTLV-I immunoblot studies of serum and CSF revealed reactivity to p19, p24, p53, gp46, or gp68 from all three patients. Titration studies of serum and CSF antibodies on ELISA and immunoblot assays indicated an intrathecal virus-specific response. HTLV-I-specific p19 antigen capture assay and polymerase chain reaction (PCR) demonstrated HTLV-I in lymphocyte cultures derived from each patients peripheral blood mononuclear cells (PBMC) or CSF cells. Using HTLV-I- and HTLV-II-specific pol and gag primers, PCR studies of PBMC cells obtained directly from the patients demonstrated that the patients were infected with HTLV-I and not HTLV-II. These three cases are to our knowledge the only US cases in whom virus isolation from the CSF has been accomplished. Importantly, two patients may be the first US cases of myelopathy arising from endemic infection.

Human T-lymphotropic virus (HTLV I-II) infection among patients in an inner-city emergency department.

OBJECTIVEnTo determine the seroprevalence and epidemiologic features of human T-lymphotropic virus (HTLV I-II) among an emergency department patient population with a high rate of human immunodeficiency virus (HIV-1) infection.nnnDESIGNnProspective survey using identity-unlinked consecutive sampling during a 6-week period in 1988.nnnSETTINGnInner-city teaching hospital.nnnPATIENTSnSequential sample of 2544 adult patients with sufficient excess sera for analysis.nnnMEASUREMENTS AND MAIN RESULTSnTwenty-eight (1.1%) (95% CI, 0.7% to 1.5%) serum samples were seropositive for HTLV I-II whereas 152 (6.0%) (CI, 5.1% to 6.9%) were seropositive for HIV-1. The age distribution of HTLV I-II was similar to the study population while HIV-1 was concentrated among younger (25 to 44 years) age groups (P less than 0.05). Only 16 (57.1%) HTLV I-II infected patients had identified risk factors; 11 were intravenous drug users, 4 received transfusions, and 1 had heterosexual exposure to a high-risk partner. None of 39 identified homosexual men had HTLV I-II antibodies although 29 (74.3%) were HIV-1 seropositive.nnnCONCLUSIONnHTLV I-II infection may be more prevalent among certain segments of the U.S. population than previously realized and appears to have a different demographic distribution than HIV-1 infection. Although HTLV I-II may represent a nosocomial risk to health care providers, the risk of occupational transmission is probably less than for hepatitis B virus and even HIV-1. Adherence to universal precautions should minimize the risk.

Characterization of a B-cell immunodominant epitope of human T-lymphotropic virus type 1 (HTLV-I) envelope gp46

The immune response elicited by a synthetic peptide derived from an immunodominant external envelope region (Env-5, amino acids 242-257) of human T-lymphotropic virus type 1 (HTLV-I) was tested in a rabbit model of HTLV-I infection. The synthetic peptide elicited a strong antibody response to the HTLV-I envelope protein gp46; however, these antibodies failed to inhibit HTLV-I-mediated cell fusion. Immunized rabbits were not protected from HTLV-I infection as determined by seroconversion to viral core proteins by immunoblot, HTLV-I p24 antigen detection in lymphocyte cultures and polymerase chain reaction for the HTLV-I provirus in lymphocyte DNA. Env-5 peptide immunization failed to induce T-cell lymphocyte proliferative responses in rabbits, but induced antibody responses in T-cell deficient Balb c nu/nu mice suggesting that the antigenic determinant represented by the Env-5 peptide is primarily a B-cell epitope. These results further define an immunodominant epitope of the HTLV-I envelope protein and suggest that potential synthetic peptide vaccines against HTLV-I infection must contain multiple antigens that induce both humoral and cellular immune reactivity.

Epidemiologic assessment of screening tests for antibody to human T lymphotropic virus type I (HTLV-I)

We tested 196 sera from a human T lymphotropic virus type I (HTLV-I) risk group (prostitute women) with two commercial research enzyme-linked immunoabsorbent assays (EIA) for HTLV-I antibodies. All tested sera were characterized by HTLV-I Western immunoblots and by HTLV-I radioimmunoprecipitation assays. The estimated sensitivities of the EIA tests were 93.8 percent and 100 percent, and the specificities were 98.8 percent and 95.8 percent, respectively, using recommended criteria for seropositivity (requiring reactivity to both gag p24 and env gp46 or gp61/68). Calculated negative predictive values remained excellent (greater than 99.9 percent and 100 percent, respectively) at lower seroprevalence rates but the positive predictive values were only 7.3 percent and 2.3 percent when calculated for a seroprevalence rate of 0.1 percent. These results emphasize the importance and need for additional HTLV-I supplementary serologic testing when screening populations with low HTLV-I seroprevalence rates.

Concomitant augmentation of CD4+CD29+ helper inducer and diminution of CD4+CD45RA+ suppressor inducer subset in patients infected with human T cell lymphotropic virus types I or II

To examine the immunomodulatory effects of HTLV infection, lymphocyte subset analysis was performed on patients infected with human T cell lymphotropic virus type‐I (HTLV‐I, n= 6) or ‐II (HTLV‐II, n= 12) and on normal blood donors (n= 16). The percentages of total B lymphocytes (CD19), natural killer (NK) cells (CDI6), T lymphocytes and their subsets (CD2, CD3, CD4, CD5, CD7, CDS), and IL‐2R (CD2S) were found to be within the range found in normal donors. However, the expression of CD8+ HLA‐DR+ increased significantly in patients with HTLV‐I or HTLV‐II infection (14.1 ± 3.9% and 9.7 ± 2.4% respectively; P<0.01) when compared with controls (3.2 ± 1.1%). In addition, there was a significantly greater proportion of CD4+ CD29+ T lymphocytes (29.3 ± 6.1% and 31.1 ± 9.0%; P<0.05) with concomitant diminution of CD4+CD45RA+ T lymphocytes (8.3 ± 3.3% and 11.4 ± 1.5%; P<0.01) in patients infected with HTLV‐I or HTLV‐II respectively, when compared with controls. The increased percentage of CD4+CD29+ subpopulations showed a direct correlation (rs=0.86; P<0.001) with HTLV‐specific antibody production. No difference in the CD8 population coexpressing CD29 and S6F1 (an epitope of LFA‐1) were observed in the HTLV‐infcctcd group when compared with normal donors and functional analysis exhibited minimal cytotoxicity against lectin labelled heterologous target cells. Thus, the shift in the suppressor/cytotoxic to helper/inducer‘memory’ CD4+ may be associated with immunoregulatory abnormalities often found in persons infected with HTLV‐I or HTLV‐II.

Other Human Retrovirus Infections: HTLV-I and HTLV-II

The first human retrovirus described, human T-lymphotropic virus type 1 (HTLV-I), is considered the cause of adult T-cell leukemia/lymphoma.1 More recently, the virus has been etiologically associated with tropical spastic paraparesis (TSP).2 This chronic neurodegenerative disorder is clinicopathologically identical to HTLV-I-associated myelopathy (HAM), first described by Osame et al in Japan.3 The list of HTLV-I-associated diseases may not be complete, because more clinical syndromes are being associated with the virus infection, exemplified by the recent descriptions of polymyositis and polyarthritis in HTLV-I-infected subjects.4,5 Less clear are the disease associations, transmission routes, and epidemiologic features of HTLV-II infections. HTLV-II was initially isolated from a patient with hairy cell leukemia6 and has subsequently been isolated only sporadically7; detailed studies of the pathogenesis of HTLV-II infection have not been reported. Recent studies using the polymerase chain reaction (PCR) technique have indicated that a high percentage of HTLV seroreactivity among intravenous (IV) drug users and blood donors in certain regions of the United States may be caused by HTLV-II.8

Atypical human T-cell lymphotropic virus type-I-associated T-cell lymphoma in a low-prevalence Alaska native population: Implications for disease surveillance

An atypical case of adult T‐cell leukemia/lymphoma (ATL) associated with human T‐cell lymphotropic virus type I (HTLV‐I) occurred in a 46‐year‐old Inupiat Eskimo man with no behavioral risk factors for HTLV‐I infection. The case was characterized by lack of atypical circulating lymphocytes, hypercalcemia, and opportunistic infections; and by complete remission of the initial renal parenchymal lymphoma. The lymphoma cells had a helper T‐cell (CD4) immunophenotype. Serum antibodies to HTLV I/II, detected by Western immunoblot, were identified in specimens collected 31 months before the onset of illness, at the time of diagnosis, and up to 37 months later, shortly before the patients death. Polymerase chain reaction was used to identify HTLV‐I DNA in peripheral blood mononuclear cells and in lymphoma in involved skin. Clinicians should be alert to sporadic cases of both atypical and classic ATL, even in populations in which the prevalence of HTLV‐I infection is low.

The relationship and biology of human retroviruses.

other animal retroviruses, including long terminal repeat, group-specific polymerase, envelope, and transactivation genes. Human retroviruses discovered to date have been associated with lymphoproliferative or cytopathic disease states. Human immunodeficiency virus (HIV) shares genomic sequence, structural features, replicative mechanisms, and cytopathic features with other animal lentiviruses. Lentiviruses, such as HIV, share the common biological features of inducing fusion and death of infected host cells. Restricted transcription of viral gene products (in concert with host factors) and antigenic variation (primarily in the envelope gene) allow these viruses