Infectious Diseases

Human T-Cell Lymphotropic Viruses Types I and II

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Human T cell lymphotropic viruses types I and II (human retroviruses tha belong to Retroviridae family)

What is the best treatment?

  • There is no effective treatment against HTLV-I or II infections to date.

    • Adult T-cell lymphoma/leukemia (ATL; treatment is discussed in the chapter on Adult T-cell Lymphoma/Leukemia.

    • HAM/TSP: As stated earlier, there is no effective treatment against HTLV-I infection. Several drugs with immunomodulatory or antiviral properties have been tried in the past decades with inconsistent results.

    • Interferon-α (IFN-α): IFN-α has immunomodulatory and antiviral properties. A double-blind multicentric study observed that 66.7% of HAM/TSP patients treated with 3MU three times a week for 4 weeks had an excellent to good response at the end of therapy, and 61.5% 4 weeks after, but the time of follow-up was too short in this study. In an open, uncontrolled study, five of seven patients treated with 6MU daily for the first 2 weeks and three times a week for the following 22 weeks had an improvement up to 6 months after the end of treatment.

      • IFN-α has been approved for the treatment of HAM/TSP in Japan; however, because of the side effects (i.e., depression, bone marrow suppression, flu-like syndrome, alopecia, rash, irritability), long-term treatment is difficult to tolerate.

      • The cost of treatment is also an important issue in developing countries.

    • Interferon-β 1b: (IFNβ-1b) in a single-center open-label trial, 12 patients received IFNβ-1b up to 60mug twice weekly. There was some improvement of the motor function, but HTLV-I proviral load remained unchanged.

    • Antiretroviral drugs: Zidovudine and lamivudine have been evaluated alone or in combination in HAM/TSP. A randomized, double blind trial of both drugs for 6 months has shown no improvement. Recently, raltegravir has been shown to inhibit HTLV-I infection in vitro.

    • Valproic acid (VPA): VPA is a histone deacetylase inhibitor that potentially can activate viral gene expression and expose virus infected cells to immune system lowering the proviral load. However, in a study with 20 HAM/TSP patients, no significant change in the neurological disability was noticed.

    • Corticosteroids: Corticosteroids have been used for years in HAM/TSP either by oral or intravenous route, especially in the initial phase of the disease (less than 3 years from onset of symptoms) or in patients with rapidly evolving symptoms and signs. Uncontrolled studies have shown temporary improvement or stabilization of neurological picture. We favor the use of monthly intravenous methylprednisolone 1g/day for 3 consecutive days during 6 months or oral prednisone 1 mg/kg/day in a tapering dose over 1-2 months.

    • Others: Small uncontrolled studies have examined the potential of pentoxifylline, danazol, green tea, interferon-β, and methotrexate in the treatment of HAM/TSP, but there is no hard evidence in favor of use of any of these.

    • Support measures: Support measures are an important part of the treatment of HAM/TSP complications, such as spasticity, pain, constipation, urinary dysfunction, and recurrent urinary tract infections (Table I).

  • There are no issues related to anti-infective resistance.

  • There are no issues related to anti-infective resistance.

Table I.

Support Treatment in HAM/TSP
Problem Approach
Spasticity baclofen (10-90mg/d), tizanidine (2-12mg/d), diazepam (5-30mg/d), botulinum toxin injection, physical therapy
Urinary incontinence oxybutynin (5-30mg/d), imipramine (10-75mg/d), doxazosin mesylate (1-6mg/d)
Urinary retention bethanecol (10-50mg/d), intermittent catheterization
Recurrent urinary tract infection nitrofurantoin (100mg/d), cranberry
Constipation fiber-rich diet, psyllium muciloid, mineral oil, lactulose
Neuropathic pain amitriptyline (25-150mg/d), nortriptyline (25-150mg/d), gabapentin (600-2400mg/d), pregabalin (75-300mg/d), carbamazepine (200-1200mg/d)
Xerosis moisturizers
Xerostomia artificial saliva
Xerophthalmia topical carboxymethylcellulose

How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology

    • There are no seasonal differences in the incidence of HTLV-I or II infections.

    • Both viruses are transmitted through breastfeeding, sexual intercourse, and contact with blood cell products either by transfusion or sharing needles and syringes.

      • The risk of vertical HTLV-I transmission is 20% and is associated with proviral load, duration of breastfeeding, and levels of maternal HTLV-I antibodies. The risk for HTLV-II remains unknown.

      • Seroconversion risk is 40-60% after blood transfusion, but only blood cell products are capable of transmitting infection.

      • Are there environmental conditions that predispose to this infection?

    • HTLV-I prevalence is heterogeneous around the world with highly prevalent areas: South and central Americas, southwest Japan, Caribbean islands, Middle East, and sub-Sarahan Africa.

    • HTLV-II is usually observed in intravenous drug users and Native American Indians.

    • In some areas, there is a progressive decrease in the prevalence of HTLV-I infection due to prevention of mother to child transmission. In Okinawa, Japan, the prevalence of infection in residents less than 20 years of age decreased from 4.6% in the 1968-1970 to 0.1% in the 1996-1998.

  • Infection control issues

    • Since infection occurs through contact with blood and other body fluids, the use of the appropriate personal protective equipment and hand washing is necessary when dealing with clinical specimens.

    • Unfortunately, there are no vaccines against HTLV-I and II.

    • Useful measures to decrease HTLV transmission include:

      • Preventing mother to child transmission through prenatal screening and counseling of seropositive mothers about avoiding breastfeeding and supplementation with feeding formula

      • Screening of blood donor candidates

      • Abstaining from needle sharing

      • Emphasizing the use of condoms and avoiding unknown or multiple sexual partners

What host factors protect against this infection?

  • HLA: Host genetic factors play an important role in the susceptibility of infectious diseases. The efficacy of cytotoxic T-cell response against viruses is regulated by genes associated with MHC class I alleles. The presence of HLA class I alleles A*02 and Cw*08 is associated with lower HTLV-I proviral loads and lower risk of developing HAM/TSP. Conversely, the presence of HLA class I allele B*504 and class II allele DRB1*01 increases the risk of myelopathy in HTLV-I infected patients.

  • Seroprevalence increases with age, and higher prevalence rates are observed in women compared to men (2:1), probably because of a more efficient male to female transmission. This will reflect in a higher proportion of female HAM/TSP patients.

  • Pathology findings in HAM/TSP are consistent with a chronic progressive inflammatory myelopathy. There is infiltration of CD8+ and CD4+ T lymphocytes and monocytes in both grey and white matter. Symmetrical anterolateral column degeneration is observed in most cases with variable involvement of posterior columns. This pattern in usually observed in the first years of the disease. Gradually, inflammation subsides and degeneration of the white matter occurs, leading to gliosis.

  • Although inflammatory and degenerative lesions are more evident in the lower thoracic cord, similar findings are also observed in the brain of affected individuals.

  • By polymerase chain reaction (PCR) in situ hybridization, HTLV-I proviral DNA is found in T-cells around perivascular areas, suggesting that a T-cell mediated process targeting infected cells is an important event in pathophysiology of HAM/TSP.

What are the clinical manifestations of infection with this organism?

  • Most HTLV-I infected individuals remain asymptomatic throughout life, but 0.5-5% of patients develop a progressive neurological symptoms, of which the most important is a myelopathy named HTLV-I associated myelopathy/Tropical spastic paraparesis (HAM/TSP). Another 1-5% develop a hematological malignancy named adult T-cell lymphoma/leukemia.

  • HAM/TSP: HAM/TSP is a myelopathy originally described in Japan and Martinique. It is characterized by a progressive spastic paraparesis associated with sensory symptoms (pain and paresthesias), constipation, urinary complaints (urgency, incontinence), and sexual dysfunction. Upper limbs are frequently spared. A sensory level, which is often observed in transverse myelitis, is almost absent in HAM/TSP. The onset is insidious, and the course is slowly progressive in most cases. The time from onset of symptoms to wheelchair was 21 years in a study from Martinique. A similar progression to wheelchair (18 years) was recently observed in a study from United Kingdom. A subacute evolution is rare but has been described in highly endemic areas.

  • Other neurological complications observed in HTLV-I infected patients include: peripheral neuropathy, motor neuron disease, myopathy, and cognitive impairment.

    • Peripheral neuropathy: Peripheral neuropathy have been described as the sole manifestation of HTLV-I infection or in association with HAM/TSP. In a study among 335 HTLV-I infected patients without HAM/TSP, 45 had clinical evidence of peripheral nervous system involvement. Therefore, HTLV-I should be included in the work-up for an unknown peripheral neuropathy. Concerning the co-existence of HAM/TSP and neuropathy, 30% of HAM/TSP patients have evidence of axonal neuropathy.

    • Myopathy: Muscles may be affected in HTLV-I infection, not by direct invasion, but in consequence of an immune mediated process. Both polymyositis (PM) and inclusion body miositis (IBM) have been observed. Clinical aspects are the same in HTLV-I PM and IBM compared to idiopathic forms.

    • Motor neuron disease: Occasionally, HAM/TSP patients may present with fasciculations, cramps, and muscle atrophy similar to what is observed in amyotrophic lateral sclerosis (ALS). In a Brazilian study, the prevalence of motor neuron disease was 1.9% in HTLV-I symptomatic patients. The evolution of disability is slower than in idiopathic ALS.

    • Cognitive impairment: White matter lesions have been described in the brain of HTLV-I infected individuals and is associated with mild cognitive deficits.

    • Autonomic dysfunction: Orthostatic hypotension, lack or excessive sweating, and neurogenic bladder dysfunction can be observed in isolation or associated with HAM/TSP.

  • Non-neurological manifestations: Uveitis, pulmonary alveolitis, Sjogren's syndrome, infective dermatitis, xerosis, and arthropathy may be observed in HTLV-I infected patients.

  • HTLV-II: HTLV-II may rarely be associated with a myelopathy indistinguishable from HAM/TSP. Besides, prominent ataxia has been observed in some patients.

What common complications are associated with infection with this pathogen?

  • Complications usually associated with HTLV-I include:

    • Recurrent urinary tract infection: Recurrent urinary tract infections are probably the most frequent infectious complication observed in HAM/TSP patients and are an important cause of morbidity and mortality in this population. They occur as a consequence of autonomic dysfunction, which leads to neurogenic bladder.

    • Tuberculosis: Impairment of the immune system is observed in HTLV infected patients. In regions endemic for both HTLV-I and Mycobacterium tuberculosis, HTLV-I increases the risk of tuberculosis.

    • Crusted scabies: It is an uncommon, but severe infection by Sarcoptes scabei is usually observed in patients with immunosuppression (malignancy, use of corticosteroids, HIV infection) that has been also observed in HTLV-I infected individuals.

    • Strongyloidiasis: HTLV-I infected individuals have a decreased Th2 response (low levels of IL-4, IL-5, IL-13, IgE), which predisposes to Strongyloides Stercoralis infection, including disseminated disease. It is estimated that the risk of strongyloidiasis is twice as high in HTLV-I infected individuals compared to non-infected ones.

How should I identify the organism?

  • HTLV-I and II infections occur via transfer of infected cells either by sexual intercourse, breast- feeding, or exposure to contaminated cell products. Efficient binding and entry of HTLV-I into the cells are mediated by three surface cell receptors: glucose transporter 1 (GLUT-1), neuropilin 1 (NRP1), and surface heparan sulfate proteoglycans (HSPGs). HTLV-2 binds and enters cells through GLUT-1 and NRP1, but not HSPGs.

  • Both viruses infect T lymphocytes, but B lymphocytes and dendritic cells can also be involved. T-cell tropism is differs between HTLV-I and II. Although HTLV-I preferentially infects activated CD4+ T lymphocytes, HTLV-II infects CD8+ T lymphocytes.

  • Cell free HTLV-I is not detected in serum, and it is believed that infection occurs through direct cell-to-cell contact, polarization of a microtubule organizing center, and formation of a virological synapse that allows the entry of viral protein and genomic RNA into the new T lymphocyte. Alternatively, HTLV-I infects dendritic cells that subsequently can also infect new T CD4+ T-cells.

  • Despite an active immune response, HTLV-I evades and persists indefinitely. One view is that the virus replicates through mitosis of infected cells rather than by replication via infectious route. It is known that viral proteins can stimulate T-cell proliferation continuously. Thus, HTLV-I persistence would rely on an equilibrium between viral infected cell proliferation and an active immune response mediated by cytotoxic T-cell lymphocytes.

  • In HAM/TSP patients, proviral DNA can be obtained from blood and cerebrospinal fluid (CSF).

  • At electron microscopy, HTLV-I is a rounded shaped virus of approximately 100nm diameter. An icosahedral capsid protects the viral RNA and functional integrase, reverse transcriptase, and integrase.

  • Both HTLV-I and II can efficiently infect, immortalize and transform human T lymphocytes cultures in vitro, but this experimental system is not useful for diagnosis.

  • After primary infection, HTLV-I and II integrate into cell DNA being denominated provirus. Contrary to HIV, concentration of cell-free HTLV in plasma is negligible, so the most adequate method for HTLV-I and II molecular diagnosis is the detection of proviraI DNA PCR. Diagnostic kits are commercially available and highly specific, but sensitivity is variable (87.5-100%) depending on the methodology employed. HTLV I and II PCR are particularly useful for:

    • Distinguishing between HTLV-I and II infection using type specific PCR

    • Quantifying the proviral load using real-time PCR

    • Detecting infection in infants of HTLV-I or II infected mothers, since passive transfer of maternal antibodies may result in false positive results

  • Serological reactions are used to diagnose HTLV-I and II infections.

    • Screening tests: Tests such as enzyme-linked immunosorbent assay (EISA) or particle agglutination (PA) assay are used first as screening. They can be performed at serum or cerebrospinal fluid (CSF) but do not differentiate between HTLV-I or II infection. These tests are sensitive, but not specific, giving false-positive results. Once the screening test is positive, it must be repeated and confirmed by a more specific test.

    • Confirmatory tests: Western Blot and Immunofluorescence assay (IFA) are used to confirm infection and differentiate viruses, but occasionally they are inconclusive, in which case PCR is needed.

How does this organism cause disease?

  • HTLV-I proviral load: One of the key elements of development of HAM/TSP is the proviral load. The median proviral load is increased more than ten times in HAM/TSP compared to asymptomatic carriers, and a higher proviral load was associated to an increased risk of developing HAM/TSP. Besides, it was observed that progression of neurological disability is associated with a higher proviral load in HAM/TSP patients.

  • HTLV-I proviral load is determined by the interaction between proliferation of viral infected cells and the cellular immune response mediated by cytotoxic T lymphocytes. Recently, it was shown that CD8+ T-cells specific to the HBZ protein and not the immunodominant Tax protein are the most important in HTLV-I control.

  • HAM/TSP pathogenesis: Although the mechanisms of why HTLV-I causes a chronic myelopathy are not completely understood to date, there are three main hypotheses:

    • Direct toxicity: Infected glial cells would express viral proteins in their surface, being recognized and destroyed by HTLV-I specific cytotoxic T lymphocytes

    • Autoimmunity: By molecular mimicry, glial proteins crossreact with HTLV-I proteins, leading to a misdirected antibody mediated immune response.

    • Bystander damage: By this theory, the presence of HTLV-I infected CD4+ T lymphocytes and their recognition by specific cytotoxic CD8+ T lymphocytes in the central nervous system would induce microglia to secrete cytokines resulting in myelin damage. In accordance with this hypothesis, it was observed that there is a high frequency of HTLV-I Tax specific CD8+ cytotoxic lymphocytes in the CSF of HAM/TSP patients.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

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