HTLV-2

Human T-lymphotropic virus type 2 (HTLV-2) is the close but far less harmful relative of HTLV-1. It was the second human retrovirus discovered, isolated in 1982 from a patient with a T-cell variant of hairy-cell leukaemia, and it shares about 60 to 65 per cent of its genome, its receptors and its mode of spread with HTLV-1. Despite that similarity it is, for practical purposes, not a cause of human cancer: the malignancy it was first found in was never confirmed as a true association, and large studies have established no link to leukaemia or lymphoma. It causes, at most, a rare and milder myelopathy. Its main clinical significance is therefore as the virus that must be distinguished from HTLV-1 when a screening test is positive, and as an infection found in particular populations: some Amerindian and central African communities, and people who inject drugs in high-income countries. It differs from HTLV-1 mainly in its much lower pathogenicity.

Discovery and historical significance

HTLV-2 was identified in 1982, soon after HTLV-1, from a cell line of a patient with a T-cell form of hairy-cell leukaemia. That index association was never borne out, and the virus has since been studied largely as the non-oncogenic counterpart to HTLV-1, valuable for the light its differences shed on why HTLV-1 causes cancer.

Classification, structure, and genome

HTLV-2 is a retrovirus of the genus Deltaretrovirus, the human type of the ICTV species Primate T-lymphotropic virus 2, and one of the primate T-lymphotropic viruses alongside HTLV-1. Its genome is about 60 to 65 per cent identical to that of HTLV-1, with the same structural, enzymatic and regulatory genes, and the two viruses cross-react serologically. The one regulatory difference that matters is its antisense gene: where HTLV-1 carries HBZ, HTLV-2 carries APH-2, the antisense protein of HTLV-2.

Replication cycle

The replication cycle follows that of HTLV-1: the virus enters using the shared GLUT-1 and neuropilin-1 receptors, reverse-transcribes its genome and integrates a provirus, and then persists and spreads by the same cell-to-cell and clonal mechanisms rather than by releasing free virus. The notable difference is tropism: in the host HTLV-2 resides mainly in CD8 T cells, whereas HTLV-1 resides mainly in CD4 T cells.

Pathogenesis

The central question about HTLV-2 is why it is so much less pathogenic than its near-twin, and the answer lies largely in its antisense protein. HTLV-1 HBZ actively drives the proliferation and survival of the infected T-cell clone; HTLV-2 APH-2, although it likewise represses the viral transactivator, does not promote T-cell proliferation. HTLV-2 can reach a high proviral load without the relentless clonal expansion that underlies adult T-cell leukaemia, and it is this difference, more than any difference in how the viruses infect cells, that is thought to explain why HTLV-2 does not cause leukaemia.

Feature	HTLV-1	HTLV-2
In vivo tropism	CD4 T cells	CD8 T cells
Antisense gene	HBZ (drives proliferation)	APH-2 (does not)
Malignancy	Adult T-cell leukaemia/lymphoma	None established
Neurological disease	HAM/TSP (about 2 per cent)	Rare, milder myelopathy
Main settings	Japan, Caribbean, Africa, South America	Amerindian and African groups; injecting drug users

Epidemiology

HTLV-2 is several-fold less common than HTLV-1 worldwide. It is endemic in some Amerindian populations of North, Central and South America and in central African groups, where it spreads, like HTLV-1, by breastfeeding and sexual contact. In North America and Europe it has been amplified and spread chiefly among people who inject drugs, through shared needles. Its transmission routes are otherwise the same as those of HTLV-1.

Natural history

Infection is lifelong and, in the great majority of those infected, entirely asymptomatic. Unlike HTLV-1 it carries no established risk of malignancy, and only a small, uncertain risk of a mild neurological or inflammatory disease, so most carriers never develop any consequence of the infection.

Clinical presentations and complications

HTLV-2 causes no established malignancy. It has been linked, uncommonly, to a mild myelopathy resembling a less severe HAM/TSP, and to a possible small excess of inflammatory conditions, bronchitis and pneumonia attributed to chronic low-grade immune activation, but these associations are weak and the typical carrier remains well.

Diagnosis

Because HTLV-2 cross-reacts with HTLV-1 on screening enzyme immunoassays, a reactive result is resolved by a Western blot or line immunoassay using type-specific envelope antigens, which discriminates the two viruses, and by PCR, which detects and types the proviral DNA. Distinguishing HTLV-2 from HTLV-1 matters chiefly because their clinical implications differ so greatly.

Management

There is no specific antiviral treatment, and in most people there is no disease to treat. The rare myelopathy is managed symptomatically, as for HTLV-1-associated myelopathy.

Prevention and public health

Surveillance and notification

There is no vaccine. Prevention follows the same measures as for HTLV-1: screening of blood and organ donors, which is where HTLV-2 is most often detected, together with safer injection practices and needle-exchange programmes for the populations in which it circulates, and the general precautions against sexual and mother-to-child transmission.

South African context

HTLV-2 is far less prominent in South Africa than HTLV-1, but it circulates in parts of Africa, and it is screened for alongside HTLV-1 in donated blood. Its practical relevance locally is therefore the same: a positive HTLV screen needs typing to separate the clinically important HTLV-1 from the largely benign HTLV-2.

References and recommended reading

• Bangham CRM, Matsuoka M. Human T-Lymphotropic Viruses (HTLV-1 and HTLV-2). In: Fields Virology, 7th edition, Volume 3, Chapter 16. Wolters Kluwer; 2023. The primary reference for the comparative virology of HTLV-1 and HTLV-2, including APH-2 and the basis of the difference in pathogenicity.
• Bruhn RL, Mahieux R, Murphy EL. Human Lymphotropic Viruses: HTLV-1 and HTLV-2. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. ASM Press; 2016. The clinical account of HTLV-2, its epidemiology in injecting drug users and the limits of its disease associations.