Human T-lymphotropic virus

The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma and a demyelinating disease called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLVs belong to a larger group of primate T-lymphotropic viruses (PTLVs). Members of this family that infect humans are called HTLVs, and the ones that infect Old World monkeys are called Simian T-lymphotropic viruses (STLVs). To date, four types of HTLVs (HTLV-1, HTLV-2, HTLV-3, and HTLV-4) and four types of STLVs (STLV-1, STLV-2, STLV-3, and STLV-5) have been identified. HTLV types HTLV-1 and HTLV-2 viruses are the first retroviruses which were discovered. Both belong to the oncovirus subfamily of retroviruses and can transform human lymphocytes so that they are self-sustaining in vitro.[1] The HTLVs are believed to originate from interspecies transmission of STLVs. The HTLV-1 genome is diploid, composed of two copies of a single-stranded RNA virus whose genome is copied into a double-stranded DNA form that integrates into the host cell genome, at which point the virus is referred to as a provirus. A closely related virus is bovine leukemia virus BLV. The original name for HIV, the virus that causes AIDS, was HTLV-3.

Human T-lymphotropic virus
a micrograph showing both Human T-lymphotropic virus 1 and HIV
Scientific classification
(unranked): Virus
Realm: Riboviria
Kingdom: Pararnavirae
Phylum: Artverviricota
Class: Revtraviricetes
Order: Ortervirales
Family: Retroviridae
Subfamily: Orthoretrovirinae
Genus: Deltaretrovirus
Groups included
Cladistically included but traditionally excluded taxa
  • Bovine leukemia virus
  • Simian T-lymphotropic virus 1
  • Simian T-lymphotropic virus 2
  • Simian T-lymphotropic virus 3
  • Simian T-lymphotropic virus 5

HTLV-1
Main article: Human T-lymphotropic virus 1

HTLV-1 is an abbreviation for human T-cell lymphotropic virus type 1, also called human T-cell leukemia type 1, a virus that has been implicated in several kinds of diseases, including tropical spastic paraparesis, and as a virus cancer link for leukemia (see adult T-cell leukemia/lymphoma). HTLV-1 has six reported subtypes (subtypes A to F). The great majority of infections are caused by the cosmopolitan subtype A.[2] HTLV was discovered by Robert Gallo and colleagues in 1980.[3] Between 1 in 20 and 1 in 25 infected people are thought to develop cancer as a result of the virus.[4] HTLV-1 infection is thought to spread only through dividing cells since reverse transcriptase generates proviral DNA from genomic viral RNA, and the provirus is integrated into the host genome by viral integrase after transmission. Therefore, the quantification of provirus reflects the number of HTLV-1-infected cells. So, an increase in numbers of HTLV-1-infected cells using cell division, by actions of accessory viral genes, especially Tax, may provide an enhancement of infectivity. Tax expression induces proliferation, inhibits the apoptosis of HTLV-1-infected cells and, conversely, evokes the host immune response, including cytotoxic T cells, to kill virus-infected cells.[5]

Figure 1. Mycosis fungoides,[6] a skin disease showing nodules and plaques composed of lymphocytes spread across the skin, has been associated with HTLV-II infection.[7]
Figure 2. A phylogeny of the subtypes of HTLV and their relationships between endogenous and exogenous retroviruses in the human genome. HERV = human endogenous retrovirus, SFV = simian foamy virus.[8]

HTLV-2
Main article: Human T-lymphotropic virus 2

A virus closely related to HTLV-1, also discovered by Robert Gallo and colleagues. The family of Human T-lymphotropic virus (Figure 2) can be further categorized into four sub types. The figure also divides the retroviruses into exogenous and endogenous. Retroviruses can exist as two different forms: endogenous which consist of normal genetic components and exogenous which are horizontally transferred genetic components that are usually infectious agents that cause disease i.e. HIV. In (Figure 3) open reading frames (ORF) are shown which can if translated can predict which genes will be present and this can help to better understand human retroviruses. Of the four subtypes, HTLV-2 may be linked to Cutaneous T-cell lymphoma (CTCL).[7] In one study involving cultured lymphocytes from patients with mycosis fungoides (Figure 1), PCR amplification showed gene sequences of HTLV-II.[7] This finding may suggest a possible correlation with HTLV-2 and CTCL. Further research and studies must be conducted to show a positive relationship.

HTLV-3 and HTLV-4

HTLV-3 and HTLV-4 have been used to describe recently characterized viruses.[9][10][11] These viruses were discovered in 2005 in rural Cameroon, and were, it is presumed, transmitted from monkeys to hunters of monkeys through bites and scratches.

  • HTLV-3 is similar to STLV-3 (Simian T-lymphotropic virus 3).[12] Multiple strains have been identified.[13] It expresses gag, pol, and env, among other proteins.[14]
  • HTLV-4 is apparently substantially identical to STLV-4 hosted in gorillas.

It is not yet known how much further transmission has occurred among humans, or whether the viruses can cause disease.

The use of these names can cause some confusion, because the name HTLV-3 was one of the names for HIV in early AIDS literature, but has since fallen out of use.[15] The name HTLV-4 has also been used to describe HIV-2.[16] A large Canadian study documented this confusion among healthcare workers, where >90% of HTLV tests ordered by physicians were actually intended to be HIV tests.[17]

Figure 3. ORF maps of HTLV type retroviruses.[8] Betaretroviruses (such as HERV-K) are found in mice, primates and sheep. Deltaretroviruses include bovine leukemia virus and HTLV-1 and -2. Gammaretroviruses include the murine leukemia virus and the feline leukemia virus but also viruses that infect reptiles and birds. Lentiviruses include HIV. Spumaviruses or foamyviruses include SFV and HERV-L. Abbreviations: LTR = long terminal repeat, consisting of the U3, R and U5 regions in the integrated provirus, gag = group-specific-antigen, du = dUTPase, pro = protease, pol = polymerase (reverse transcriptase and integrase), env = envelope, bel 1-3 (bel 1 is also known as tas;the bel 2 reading frame overlaps with another one named bet), tax, rex, tat, rev, vpu, vif, nef and vprencode small additional proteins. The HERV-K Rec protein is also known as K-Rev. HERV-K rec is found in HERV-K type II proviruses, while np9 is encoded by HERV-K type I proviruses.[18] In spumavirus, either gag-pro or pro-pol are encoded in the same translational reading frame.

Transmission

HTLV-1 and HTLV-2 can be transmitted sexually,[19][20] by blood to blood contact (e.g. by blood transfusion or sharing needles when using drugs)[21][22] and via breast feeding.[23]

Epidemiology

Two HTLVs are well established. HTLV-1 and HTLV-2 are both involved in actively spreading epidemics, affecting 15-20 million people worldwide.[24]

HTLV-1 is the most clinically significant of the two: at least 500,000 of the individuals infected with HTLV-1 eventually develop an often rapidly fatal leukemia, while others will develop a debilitative myelopathy, and yet others will experience uveitis, infectious dermatitis, or another inflammatory disorder. HTLV-2 is associated with milder neurologic disorders and chronic pulmonary infections. In the United States, HTLV-1/2 seroprevalence rates among volunteer blood donors average 0.016 percent.

No specific illnesses have yet been associated with HTLV-3 and HTLV-4.

Vaccination and treatments

While there is no present licensed vaccine, there are many factors which make a vaccine against HTLV-1 feasible. The virus displays relatively low antigenic variability, natural immunity does occur in humans, and experimental vaccination using envelope antigens has been shown to be successful in animal models. Plasmid DNA vaccines elicit potent and protective immune responses in numerous small-animal models of infectious diseases. However, their immunogenicity in primates appears less potent. In the past two decades a large initiative has been put forth to understand the biological and pathogenic properties of the human T-cell lymphotropic virus type 1 (HTLV-1); this has ultimately led to the development of various experimental vaccination and therapeutic strategies to combat HTLV-1 infection. These strategies include the development of envelope glycoprotein derived B-cell epitopes for the induction of neutralizing antibodies, as well as a strategy to generate a multivalent cytotoxic T-lymphocyte (CTL) response against the HTLV-1 Tax antigen. A vaccine candidate that can elicit or boost anti-gp46 neutralizing antibody response may have a potential for prevention and therapy against HTLV-1 infection.[25]

Potential treatments include prosultiamine, a vitamin B-1 derivative, which has been shown to reduce viral load and symptoms;[26] azacytidine, an anti-metabolite, which has been credited with the cure of a patient in Greece;[27] tenofovir disoproxil (TDF), a reverse-transcriptase inhibitor used for HIV; cepharanthine, an alkaloid from stephania cepharantha hayata;[28] and phosphonated carbocyclic 2'-oxa-3'aza nucleosides (PCOANs).[29] A newer formulation of TDF, called tenofovir alafenamide (TAF), also has promise as a treatment with less toxicity.

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References
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