What kind of virus is HTLV

HTLV-2

HTLV-2 appears to have originated in Africa several thousand years ago.16 DNA provirus has been detected in breast milk, and maternal-child transmission, probably due to breastfeeding, is documented. Rare cases of mycosis fungoides and large granular lymphocytic leukemia have been detected in HTLV-2–infected individuals, but causality has not been proved. HTLV-2 does appear to be associated with an HAM/TSP-like neurodegenerative disease and other neurologic disorders.17 Bacterial skin infections have been described in those coinfected with HTLV-2 and HIV-1.

Key Points

Characteristics of Human T-Cell Lymphotropic Viruses

HTLV-2

HTLV-2 appears to have originated in Africa several thousand years ago.16 DNA provirus has been detected in breast milk,17 and maternal–child transmission, probably due to breastfeeding, is documented.18 Rare cases of mycosis fungoides and large granular lymphocytic leukemia have been detected in HTLV-2-infected individuals, but causality has not been proven. HTLV-2 does appear to be associated with an HAM/TSP-like neurodegenerative disease and other neurologic disorders.19 Bacterial skin infections have been described in persons coinfected with HTLV-2 and HIV-1.

Human T-Lymphocyte Leukemia Viruses

Human T-Lymphocyte Leukemia Viruses

Clinical Features of HTLV-2 Infection

HTLV-2 has been found infrequently in the setting of human malignancy. The original isolate of HTLV-2 was obtained from a patient with an atypical T cell variant of HCL, but frank integration of HTLV-2 within leukemic cells in vivo was not demonstrated. Other HTLV-2 isolates were obtained from a patient with AIDS and a hemophiliac without coexistent malignancies. Evidence of HTLV-2 infection was seen in two patients with unusual T cell lymphoproliferative disorders and in asymptomatic IVDA in the US and UK.

Three viral mRNA species have been convincingly identified for HTLV-1 and -2. These include full-length genomic RNA encoding the gag, protease and pol genes, singly spliced env mRNA encoding four envelope proteins, and doubly spliced tax/rex mRNA encoding the sequences from the 3′ X region. Recently, investigators have suggested the existence of additional viral mRNA subspecies by using polymerase chain reaction (PCR) amplification techniques to detect subtle variations of viral mRNAs.

Two unique regulatory genes have been identified within the X region of HTLV-1 and -2. One gene, referred to as tax, encodes a transcriptional regulator of the HTLV LTR. It encodes a 40 kDa nuclear phosphoprotein, p40tax in HTLV-1 and a 37 kDa protein in HTLV-2, p37tax. A second gene, rex, encodes two proteins in HTLV-1, p27XIII and p21XIII, and two protein species in HTLV-2, p26x-b and p24x-b, in an alternate, partially overlapping reading frame.

The gag gene is translated as a polyprotein precursor with an apparent molecular mass of 70 kDa, which is cleaved to form mature Gag polypeptides. Mature Gag protein species, p19, p24 and p15, have been recognized. These represent the matrix, capsid and nucleocapsid proteins, respectively, of HTLV-1 and HTLV-2. The p24 protein, as noted, has high amino acid homology between HTLV-1 and -2, whereas the p19 protein shows a lesser degree of homology. Nevertheless, both p19 and p24 show considerable crossreactivity to intact proteins between HTLV-1- and -2-infected individuals. The p19 protein is thought to be myristoylated at its N-terminus, and this modification may facilitate association of p19 with the cell membrane.

An intact reading frame for a protease gene was first detected in the HTLV-2 sequence and subsequently described in some HTLV-1 clones. Initial noninfectious clones of HTLV-1 that were sequenced demonstrated stop codons within potential protease open reading frames (ORFs). The function of the protease has been examined for HTLV-2, and it has been demonstrated that, as in other retroviruses, the viral protease is necessary for appropriate cleavage and processing of Gag polyprecursor proteins into mature Gag structural proteins. Apparently the protease undergoes self-cleavage to generate a mature protease molecule. As in some other retroviruses, the protease ORF overlaps both Gag- and Pol-coding sequences. Therefore, in HTLV-1 and -2, the translation of the protease precursor likely occurs following ribosomal frameshifting.

The largest ORF in the HTLV genome is encoded in the polymerase region. In the case of HTLV-2, these sequences could encode a 982-amino acid Pol precursor. As in other retroviruses, the pol gene encodes the reverse transcriptase protein, as well as integrase and RNase H functions necessary for completion of the retroviral life cycle. HTLV-1 and -2 share approximately 56% amino acid homology within coding sequences of the pol gene. As previously noted, HTLV-1 and -2 show a lower rate of mutation than HIV-1, suggesting a higher fidelity of HTLV reverse transcriptase than that of HIV-1.

In both HTLV-1 and -2, the env gene begins upstream of the 3′ end of the pol gene and partially overlaps it. In HTLV-2, a high molecular mass glycosylated precursor of approximately 68 kDa is thought to be cleaved into a 46 kDa surface glycoprotein (gp46) and a 21 kDa transmembrane protein (p21). The Env proteins of HTLV-1 and -2 probably interact with similar as yet unidentified cellular receptors to mediate viral entry. The requirement for cocultivation of HTLV-infected cells to obtain efficient infection is unclear. However, the need for cocultivation suggests that HTLV-1 and -2 virions may be unstable in the extracellular milieu, or alternatively, that binding of Env alone to cellular receptors may be insufficient to infect cells. Experiments with both live and heat-inactivated HTLV-1 virions by Duc Dudon and Gazzollo and with HTLV-2 virions by Zack and Chen indicate that the virion coat may act to induce T cell proliferation nonspecifically in culture. This function has been speculatively attributed to Env proteins, although no direct mitogenic effects of Env have been demonstrated.

Human T-Cell Lymphotropic Virus I/II

HTLV types I and II are two closely related RNA viruses that can be transmitted through body fluids. Both viruses infect primary lymphocytes. Individuals infected with either of these viruses usually remain asymptomatic for 20–30 years, after which ~ 2–5% of HTLV-I infected individuals develop adult T-cell leukemia/lymphoma. HTLV-I is also the causative agent of a rare neurologic disorder called HTLV-I-associated myelopathy/tropical spastic paraparesis or HAM/TSP, which is characterized by chronic and progressive weakness, stiff muscles, muscle spasms, sensory disturbance, and sphincter dysfunction. HTLV-II was first described in a patient with hairy cell leukemia, but its association with specific diseases is less clear.

The exact risk of transmission for HTLV is uncertain since the window period for current testing is unknown, and there is no confirmatory test to measure the true positive reactive donors. Based on the analysis of donations performed in 2008 at the American Red Cross, the prevalence among allogenic donations is 1 in 35 313 donations. The estimated residual risk is 1 in 3 394 086 when a window period of 51 days is used.

Testing for HTLV-I and HTLV-II viruses includes the detection of IgG-specific antibodies.

Reservoir and Incidence

Human T-cell leukemia virus subtypes 1–3 (HTLV-1, HTLV-2, and HTLV-3) are believed to have developed following multiple instances of transmission of the oncogenic Deltaretrovirus primate T-lymphotropic virus subtypes 1–3 (PTLV-1, PTLV-2, and PTLV-3) from African nonhuman primates to humans. A simian analog of HTLV-4 has not yet been identified, nor has a human analog been identified for the recently discovered PTLV-5 of macaques. HTLV is a significant disease of humans, infecting approximately 10–20 million people worldwide. PTLV infections have been documented in over 33 species of Old World monkeys and apes in Africa and Asia, with seroprevalence increasing with age. Some subtypes have species specificity in natural infections of wild populations with PTLV-2 currently found only in bonobos (Pan paniscus) and PTLV-3 found only in African nonhuman primates. Infection with multiple PTLV subtypes does occur (Locatelli and Peeters, 2012). Some New World primates are susceptible to experimental infection, but natural infection has not been identified in their wild populations (Murphy et al., 2006).

HTLV-1

Infection with HTLV-1 causes two devastating human diseases: adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).8 The cumulative lifetime risk of developing either of these diseases is approximately 5% in infected individuals.5

ATLL is a clonal malignancy of well-differentiated CD4-positive T lymphocytes, occurring in about 2% to 4% of HTLV-1-infected individuals.9 Whereas both CD4+ and CD8+ T lymphocytes are infected, the leukemic cells are exclusively CD4+.10,11 The HTLV-1 DNA provirus is integrated into the genome of malignant cells. Infection appears to have a long latency period, generally manifesting clinically in persons 40 to 60 years of age, after many years of asymptomatic infection. The disease is typically aggressive and rapidly fatal. It is associated with hypercalcemia and characteristic lytic lesions of bone, which have been ascribed to the ability of virus-encoded trans-activating factor tax to activate genes for parathyroid hormone production.

HAM/TSP is a slowly progressive neurologic disease associated with permanent weakness in the legs, paresthesias, long tract neurologic abnormalities, and urinary incontinence.12 Although these manifestations of infection are evident in fewer than 1% of all persons infected with HTLV-1, they occur in about 20% of those infected by contaminated blood. Antibodies to HTLV-1 are present in the cerebrospinal fluid of patients with this disorder. Treatment with corticosteroid or other immunosuppressive agents is only modestly beneficial. HAM/TSP affects patients of all ethnic groups, but it is most prevalent in geographic regions where HTLV-1 has been endemic for a long time.13

HTLV-1 has also been associated with isolated cases of uveitis, arthritis, polymyositis, and panbronchiolitis. Also, coinfection with HTLV-1 and the human immunodeficiency virus (HIV) may accelerate progression to acquired immunodeficiency syndrome. A syndrome of chronic skin infection with Streptococcus pyogenes and Staphylococcus aureus, known as infective dermatitis, has been described among children.14

HTLV

The human T cell leukemia virus (HTLV) was first identified in humans in the 1980s (HTLV-1) (Poiesz, et al., 1980; Yoshida, Miyoshi, & Hinuma, 1982). Four HTLV viruses have been described (HTLV-1 to -4) with only HTLV-1 and -2 being associated with human disease. Infection with HTLV-3 or -4 is rare and has only been reported in primate hunters and communities from regions in central Africa and therefore infections are not well characterized (Bagossi, Bander, Bozoki, & Tozser, 2009; Calattini, et al., 2005; Mahieux & Gessain, 2009; Wolfe, et al., 2005; Zheng, et al., 2010). There are seven HTLV-1 subtypes and four HTLV-2 subtypes, mostly with high homology with their simian (STLV) counterparts (Casoli, Pilotti, & Bertazzoni, 2007). Accordingly, the spread of HTLV in humans is most certainly the consequence of cross-species transmission from non-human primates. HTLV proliferates by clonal expansion of infected lymphocytes and therefore, in contrast to HIV, genetic variation is limited. HTLV can therefore be transmitted via cell-associated virus in infected lymphocytes vertically, by breastfeeding, by exposure to infected blood or blood products (transfusion or IDU), and through sexual contact. HTLV-1 is the most prevalent HTLV virus infection in humans and is the causative agent of adult T cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis (Poiesz, et al., 1980; Proietti, Carneiro-Proietti, Catalan-Soares, & Murphy, 2005; Verdonck, et al., 2007).

An estimated 15–20 million individuals are said to be infected with HTLV worldwide (de The & Bomford, 1993), (see Figure 1.3) although by and large the lack of quality global data does not permit a reliable estimate of worldwide prevalence (Hlela, Shepperd, Khumalo, & Taylor, 2009). The estimate of infected individuals may be higher as: i) seroprevalence studies in the general population are limited; ii) data from Africa and Asia (excluding Japan) was limited; iii) the global population has increased by approximately 17% since this prediction; and iv) diagnosis of HTLV has improved (Hlela, et al., 2009). HTLV-1 is distributed worldwide; however, prevalence rates vary between geographical regions (Hlela, et al., 2009; Proietti, et al., 2005; Slattery, Franchini, & Gessain, 1999).

Regions of high endemicity include south-western Japan (specifically the islands of Okinawa and Tsushima), intertropical Africa (sub-Saharan countries, Guinea-Bissau, Cameroon, and Benin, up to 5%), the Caribbean, some areas within South America, Melanesia (e.g. Papua New Guinea), and the Middle East, specifically Iran. Ethnic clustering of HTLV in indigenous populations in South America has also been reported (Slattery, et al., 1999; Sonoda, Li, & Tajima, 2011). However, the calculated seroprevalence in the general population versus specific populations varies in each of these regions (Hlela, et al., 2009). In North America and Europe, HTLV-1 seroprevalence rates are low in blood donor populations: Norway, 0.002%; Greece, 0.00556%; and North America/Canada 0.01–0.3% (Proietti, et al., 2005), and infection is generally restricted to select groups such as immigrants from endemic areas, their offspring and sexual contacts, IDU and sex workers; although in IDU populations in North America and Europe, the prevalence of HTLV-2 infection is higher than that for HTLV-1.

Subtype A, the cosmopolitan subtype of the six HTLV-1 subtypes, is distributed globally in HTLV-endemic areas. There is geographic restriction of the remaining subtypes with subtypes B, D, and F being found predominantly in central Africa, subtype E in south and central Africa, and subtype C in Melanesia (Proietti, et al., 2005).

HTLV-2 was originally thought to have a more constricted geographical distribution in comparison to HTLV-1, being localized to indigenous tribes in South America. However, HTLV-2 has been identified in ethnic groups in the Democratic Republic of Congo, Cameroon, the Central African Republic, and Gabon, contradicting this theory. HTLV-2 has also spread to Europe and North America through IDU (Slattery, et al., 1999).

Tax-induced disruption of the G1/S transition in HTLV-1–infected T cells (Fig. 8)