HTLV-1: Questions

A complete answer covers the immune-mediated mechanism, the clinical syndrome, and why the extensor plantar response localises the lesion.

Pathogenesis. HAM/TSP is an immune-mediated inflammatory myelopathy, not a direct cytopathic infection. A high proviral load drives persistent expression of viral antigen in circulating infected T-cell clones, and a vigorous but ineffective cytotoxic T-lymphocyte (CTL) response to these cells provokes chronic inflammation. Cytokine-mediated injury and lymphocytic infiltration fall on the thoracic spinal cord, producing demyelination and axonal loss in the lateral corticospinal tracts.

Clinical presentation. A slowly progressive spastic paraparesis of the lower limbs, with upper motor neuron signs (spasticity, brisk reflexes, clonus), bladder and sphincter dysfunction, sensory disturbance and low back pain. It is commoner in women, is chronic and disabling, and is not malignant.

Significance of the extensor plantar response. A bilateral extensor plantar (positive Babinski sign) is an upper motor neuron sign. It confirms the lesion is in the corticospinal tracts of the cord rather than in the lower motor neurons or peripheral nerves, consistent with a myelopathy, and supports the clinical picture of a spastic rather than flaccid paraparesis.

Adult T-cell leukaemia/lymphoma is marked by circulating multilobulated flower cells and by hypercalcaemia with lytic bone lesions.

Owl-eye inclusions point to cytomegalovirus, koilocytes to human papillomavirus, Reed-Sternberg cells to Hodgkin lymphoma, and heterophile antibodies to Epstein-Barr virus infectious mononucleosis.

HTLV-1 causes adult T-cell leukaemia/lymphoma (an aggressive CD4 T-cell malignancy) and HTLV-1-associated myelopathy / tropical spastic paraparesis (HAM/TSP), a chronic inflammatory disease of the spinal cord.

The other pairs belong to KSHV, the Kaposi sarcoma-associated herpesvirus (Kaposi sarcoma and primary effusion lymphoma), Epstein-Barr virus (Burkitt lymphoma and nasopharyngeal carcinoma), the hepatitis viruses (hepatocellular carcinoma) and human papillomavirus (cervical and anal cancer).

An extensor plantar response (a positive Babinski sign), with hyperreflexia and clonus, is a sign of upper motor neuron damage and localises the lesion to the corticospinal tracts, the lateral funiculi of the thoracic cord that are the core casualty in HAM/TSP.

It separates this myelopathy from a lower motor neuron or peripheral-nerve process, which instead reduces tone and reflexes. The neuromuscular junction, cerebellum and dorsal columns produce different signs and none gives an extensor plantar response.

Because cell-free virus is scarce, HTLV-1 is detected and quantified by PCR of integrated proviral DNA, not by RNA. Serological screening by enzyme immunoassay is confirmed by Western blot or line immunoassay, which also distinguishes HTLV-1 from HTLV-2.

The lifetime risk of adult T-cell leukaemia/lymphoma is about 5%, and of HAM/TSP about 2%; most carriers remain asymptomatic for life. The leukaemia is strongly linked to infection acquired in infancy through breastfeeding.

The proviral load, reflecting the number of infected clones, reaches a stable set point that varies more than a thousandfold between people and is the best predictor of progression to both the leukaemia and the myelopathy.

Breastfeeding is the principal route of vertical transmission, with a risk of around 20 to 30% that rises with prolonged feeding and a high maternal proviral load; avoiding breastfeeding is a key preventive measure.

The cell-mediated immunodeficiency of HTLV-1 infection predisposes to Strongyloides stercoralis hyperinfection (and to tuberculosis); disseminated strongyloidiasis is a classic association and worsens the prognosis of adult T-cell leukaemia/lymphoma.

The other infections listed are the opportunists of HIV-related immunosuppression rather than the characteristic HTLV-1 association.

Once established, HTLV-1 is maintained by the mitotic proliferation of infected T-cell clones rather than by reverse transcription of new virus, so inhibitors of reverse transcriptase and integrase do not reduce the proviral load. They have a role only in post-exposure prophylaxis, before the provirus integrates.

HTLV-1 is an RNA retrovirus rather than a DNA virus, the failure is intrinsic to clonal persistence rather than resistance or dosing, and the virus is lymphotropic, not sequestered in neurons.

A complete answer pairs each route with its preventive measure.

• Breastfeeding, the main route of mother-to-child transmission: prevented by antenatal screening and by avoiding, or shortening, breastfeeding by infected mothers.
• Sexual contact, transmitted more efficiently from male to female: reduced by condom use.
• Cellular blood products, organ transplantation and shared needles: near-eliminated by screening blood and organ donors, and by safe-injection or needle-exchange programmes. Cell-free plasma carries little risk.

There is no licensed vaccine, though one is considered feasible.