Further Evidence That HTLV Protects Against HIV Progression

Human T-cell lymphotropic virus type 1 (HTLV-1), human T-cell lymphotropic virus type 2 (HTLV-2), and HIV-1 were among the first human retroviruses to be identified (in 1979, 1981, and 1982, respectively). To date, debate persists concerning the effects of coinfection with HTLV-1 and HIV-1 or coinfection with HTLV-2 and HIV- 1. This is partially because of the paucity of data that has been published and also because of conflicting results in the reports that do exist. Some evidence suggests that HIV-1/ HTLV-1 coinfection can accelerate the progression of HTLV-1 infection while it has no effect on the progression of HIV-1 infection.¹ Other reports have indicated that coinfection with HTLV-1 may attenuate the progression of HIV-1 infection.² Some studies on HTLV-2/HIV-1 coinfection have reported that the progression of HIV-1 infection to AIDS is neither accelerated³ nor suppressed.⁴ Other studies, however, have reported slowed progression of HIV infection to AIDS in patients coinfected with HTLV-2.^2,5

HTLV-2 infection may be associated with higher rates of neurological abnormalities in patients coinfected with HIV-1.6 HTLV-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) is a disabling disease that occurs in approximately 2% of those with HTLV-1/2 infections.⁷ It has a slow onset, and its characteristic manifestations are lower lumbar pain and spastic paraparesis of the lower extremities, including ankle clonus and positive Babinski sign. Evidence indicates that HAM/TSP may be more likely to develop in patients coinfected with HTLV-1/2 and HIV-1 than in patients infected with HTLV-1/2 alone.⁸ Very few systematic studies have been conducted to clarify any of these associations, however.

Two cases of chronic, nonprogressive HIV infection in women, both of whom were coinfected with HTLV- 1/2 and one of whom had HAM/ TSP, are reported. These cases lend support to the theory that HTLV-1/2 infection may be a protective factor against progression of HIV infection even in patients with co-occurring HAM/TSP.

Case report 1
A 66-year-old African Jamaican woman presented to the emergency department (ED) with leg weakness and a tingling sensation that had persisted for 3 months. The patient's medical history was significant for HIV infection, which was diagnosed 13 years ago; colon cancer, for which colectomy was performed 13 years ago; and hypertension. It was suspected that HIV infection occurred through contact with her husband, who was HIV-positive and had died 7 years earlier of an HIV-related infection. The patient had never received antiretroviral therapy (ART), and the HIV infection was considered to be chronic nonprogressive.

On physical examination, the patient's lower extremities had decreased strength. Movement against gravity was possible only on dorsiflexion and plantar flexion of the foot, with flexion and extension of the leg, and with flexion and extension of the thigh. Patellar, Babinski, and Achilles reflexes were hyperactive. The head and neck displayed choreiform movements, which are signs of HAM/TSP.

MRI of the spine without contrast showed no evidence of cord compression but rather mild cervical and lumbar degenerative changes. MRI of the brain without contrast showed moderate to severe white matter abnormalities involving the cerebral hemisphere and pons. Considering the limited display of thoracic spinal degeneration, characteristic of HAM/ TSP, the inflammatory process affecting the thoracic spine was considered to be in an early phase.

One year before the patient was admitted, a quantitative polymerase chain reaction (PCR) analysis demonstrated an HIV-1 RNA level of 9160 copies/mL. Four months later, another PCR analysis showed an HIV-1 RNA level of 5116 copies/mL, which is a clinically significant decrease. The CD4⁺ cell count 1 year before admission was 486/?L; repeated CD4⁺ cell counts 1 month and 4 months later were 583/?L and 390/?L, respectively. A serum test for HTLV-1/2 antibodies was reactive, supporting the diagnosis of an HTLV infection. Tests for HTLV- 1/2 in cerebral spinal fluid using enzyme- linked immunosorbent assay were also positive, supporting the diagnosis of HAM/TSP.

Because of lack of symptom progression, ART was not started. Since there is no effective treatment thus far for TSP/HAM,⁹ the patient was given baclofen 10 mg PO q24h as a supportive measure. After 35 months of follow- up, the patient's HIV infection continues to be chronic nonprogressive. Highly active antiretroviral therapy was begun because of the possible coexistence of HIV/AIDS myelopathy. To date, the patient has tolerated the treatment well. The CD4⁺ cell count remains high but has not significantly increased since assessments performed 5 months previously. The viral load is undetectable, there is less paresthesia, and the patient's muscular rigidity has subsided.

Case report 2
A 46-year-old African American woman presented to the ED with lower back pain and excessive dry cough of 2 weeks' duration and a 20- to 30-lb weight loss occurring over the course of 2 to 3 months. The lower back pain was in the vicinity of the L2 and L3 vertebrae and was diffuse, moderate to severe in intensity, and unremitting. The patient's past medical history was significant for HIV infection, which was diagnosed 9 years earlier, and latent syphilis and hepatitis C virus infection, both diagnosed 1 year before the current presentation to the ED.

The patient had been a habitual cocaine, injection drug, and alcohol user and smoked a half-pack of cigarettes per day for approximately 24 years. She stated that she was indigent and sexually active. She had never received ART and denied ever experiencing chest pain, fever, night sweats, or hemoptysis.

On physical examination, bibasilar rales and bilateral wheezing were noted in the patient's lungs. Her upper and lower extremities had strength of movement against gravity with some resistance with all motion; reflexes were normal. The patient's lumbar area was tender to palpation; skin was intact and very loose from the excessive weight loss over such a short period. ACT scan of the chest displayed significant mediastinal and retrocrural lymphadenopathy and mild axillary lymphadenopathy. Results of a tuberculin skin (ie, purified protein derivative) test were negative.

A lymphocyte subset panel revealed a CD4⁺ cell count of 583/?L, which is high for a patient who has been HIV-positive for nearly a decade. Results of previous laboratory tests, conducted 2 years earlier, revealed a CD4⁺ cell count of 1008/?L. HTLV-1/2 infection was suspected because of the patient's chronic nonprogressive HIV infection and the excessive mediastinal and retrocrural lymphadenopathy, indicative of possible lymphoma. Results of a serum analysis for HTLV-1/2 antibodies were positive.

ART was not initiated because of a lack of symptom progression. After 3 months' follow-up, HIV infection in this patient continues to be chronic nonprogressive and the patient is not receiving ART.

Discussion HTLV-1 is endemic to distinct geographical areas, including Japan, the Caribbean basin, West Africa, Melanesia, South America, and the Middle East.¹⁰ Whereas HTLV-1 infection is most often diagnosed in patients of African American descent in North America, HTLV-2 infection is mainly diagnosed in American Indians.¹¹ Both HTLV-1 and HTLV-2 infections mostly occur in high-risk groups, such as injection drug users. In the United States, large-scale blood supply screening in the general population has documented rates of HTLV-1/2 infection of 0.043%.¹² In a significant proportion of HTLV-1 infections, the patient either has links to an area where the virus is endemic or has a history of risk-related behaviors, such as injection drug use.

Rates of HTLV-1/2 infection are higher among patients infected with HIV-1 than among the general population. HAM/TSP-associated myelopathy is rarely reported in the United States (ie, less than 20 cases).7 Among HTLV-1- or HTLV-2-infected persons who are HIV-negative, the estimated lifetime risk of HAM/ TSP is less than 2%.⁷ However, as mentioned, it has been suggested that HIV/HTLV coinfection may increase the risk of HAM/TSP development. ⁸ One of the patients had a history of injection drug use. The patient with HAM/TSP also had a link to an area (Jamaica) where HTLV is endemic.

These cases provide clinical support for the hypothesis that HTLV- 1/2 coinfection with HIV-1 may be protective against transition to AIDS. One potential mechanism for attenuation of HIV infection in coinfected patients is the increased up-regulation of inhibitory chemokine, which can alter disease progression by slowing the rate of decrease of CD4⁺ cell counts.¹³

Up-regulation of HTLV-1 expression in patients with HIV-1 and HTLV-1/2 coinfection may be a risk factor for HAM/TSP. It has been reported that both HIV/HTLV-1 coinfection and HIV/HTLV-2 coinfection are associated with higher levels of HTLV-1/2 tax/rex messenger RNA (Figure) and viral antigen expression in peripheral blood mononuclear cells (PBMCs) compared with samples obtained from either HTLV-1 or HTLV-2 monoinfected persons.¹

Figure -

Genomic organization of human T-cell lymphotropic virus (HTLV) type 1, HTLV type 2, and HIV. Adapted from Mandell GL et al, eds

.Principles and Practice of Infectious Diseases. 2005.14)

Case-controlled comparison studies have illustrated that HIV/HTLV coinfection does not appear to be associated with a change in the HIV RNA level.¹ Higher levels of HTLV-1 and HTLV-2 proviral burden in PBMCs are associated with higher CD4⁺ T-cell counts. The vacuolar myelopathy associated with HIV infection of the spinal cord typically presents in patients with advanced immunodeficiency and often in conjunction with low CD4⁺ T-cell counts, dementia, and opportunistic infections.¹

In the 2 cases presented here, the patients had high CD4+ cell counts despite the duration of illness and the fact that they have not been receiving ART. A negative test result for chemokine receptor 5 mutation was a reason why the HIV infection status of the patient described in case 1 was deemed chronic nonprogressive.

Little information is available concerning the benefit of ART for treatment of HAM/TSP. Efforts to treat HAM/TSP and HTLV-1-associated autoimmune diseases using various antiretroviral compounds have been disappointing.

The treatment of HAM/TSP with corticosteroids, cyclophosphamide, and interferon alfa benefit some patients, particularly when given early in the clinical course or when given to patients with rapidly progressing forms of the disease. Treatment with danazol, an androgenic steroid, has reversed urinary and fecal incontinence in some cases but not the spastic limb disease or the underlying neurological deficit. Corticosteroids and immunosuppressive agents, such as azathioprine, may ameliorate disease progression but are unsuitable for long-term use because of adverse effects. Immunotherapy with interferon alfa and interferon beta has had minimal to moderate results, depending on the degree of inflammation and tissue destruction involved. Given these data, early treatment of patients with HIV/ HTLV-1 coinfection who present with HAM/TSP is not recommended.

Conclusion
Whether coinfection with HTLV-1/2 and HIV-1 results in a slower progression to AIDS is controversial. Our cases suggest that a protective element may exist. It is noteworthy that coinfected persons have increased CD4⁺ cell counts but are still at risk for opportunistic infections. Infection with these other retroviruses should routinely be considered in patients with a long history of HIV positive status and high CD4⁺ cell counts who are not receiving ART and whose HIV infection is considered to be chronic nonprogressive. This is especially true if the patient has ties to countries in which HTLV is endemic. Appropriate serological tests should be done if the patient has any combination of neurological signs and symptoms.

Research is needed to understand the mechanisms that underlie chronic nonprogression of HIV infection in these patients with dual diagnoses. Future studies should place emphasis on the microbial differences between uncomplicated HIV infection and HTLV-1/2 infection and HIV/HTLV- 1/2 coinfection in a longitudinal manner. Furthermore, the role of HAM/ TSP should be explored long term to allow for a better understanding of the noticeable differences in progression among these various disease entities.

References:

• Harrison LH, Schechter M. Coinfection with HTLV-I and HIV: increase in HTLV-I-related outcomes but not accelerated HIV disease progression? AIDS Patient Care STDS. 1998;12:619-623.

• Beilke M, Theall K, O’Brien M, et al. Clinical outcomes and disease progression among patients coinfected with HIV and human T lymphotropic virus types 1 and 2. Clin Infect Dis. 2004;39:256-263.

• Rezza G. Determinants of progression to AIDS in HIV-infected individuals: an update from the Italian Seroconversion Study. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;17(suppl 1):S13-S16.

• Roucoux DF, Murphy EL. The epidemiology and outcomes of human T-lymphotropic virus type II. AIDS Rev. 2004;6:144-154.

• Turci M, Pilotti E, Ronzi P, et al. Coinfection with HIV-1 and human T-cell lymphotropic virus type II in intravenous drug users is associated with delayed progression of AIDS. J Acquir Immune Defic Syndr. 2006;41:100-106.

• Zehender G, Colasante C, Santambrogio S, et al. Increased risk of developing peripheral neuropathy in patients coinfected with HIV-1 and HTLV-2. J Acquir Immune Defic Syndr. 2002;31:440-447.

• Beilke MA, Japa S, Moeller-Hadi C, Martin-Schild S. Tropical spastic paraparesis/human T leukemia virus type 1-associated myelopathy in HIV type 1-coinfected patients. Clin Infect Dis. 2005;41:e57-e63.

• Posada-Vergara MP, Montanheiro P, Fukumori LM, et al. Clinical and epidemiological aspects of HTLV-II infection in São Paulo, Brazil: presence of tropical spastic paraparesis/HTLVassociated myelopathy (TSP/HAM) simile diagnosis in HIV-1-co-infected subjects. Rev Inst Med Trop Sao Paulo. 2006;48:207-210.

• Machuca A, Rodés B, Soriano V. The effect of antiretroviral therapy on HTLV infection. Virus Res. 2001;78:93-100.

• Manns A, Hisada M, La Grenade L. Human Tlymphotropic virus type I infection. Lancet. 1999;353:1951-1958.

• Hall WW, Takahashi H, Liu C, et al. Multiple isolates and characteristics of human T-cell leukemia virus type II. J Virol. 1992;66:2456-2463.

• Lee HH, Swanson P, Rosenblatt JD, et al. Relative prevalence and risk factors of HTLV-I and HTLV-II infection in US blood donors. Lancet. 1991;15:1435-1439.

• Kannangara S, DeSimone JA, Pomerantz RJ. Attenuation of HIV-1 infection by other microbial agents. J Infect Dis. 2005;192:1003-1009.

• Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia:Churchill Livingstone; 2005.