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Brogden KA, Guthmiller JM, editors. Polymicrobial Diseases. Washington (DC): ASM Press; 2002.

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Chapter 5Concomitant Infections with Human Immunodeficiency Virus Type 1 and Human T-Lymphotropic Virus Types 1 and 2

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Author Information

,1 ,2 ,3 and 2.

1 Centro de Pesquisa Hospital Evandro Changas, Ministerio da Saude, Av. Brasil, 4365, Manguinhos, Cep., Rio de Janeiro 21045-900, Brazil.
2 Department of Medical Microbiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
3 Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.

Two distinct families of human retroviruses, the human immunodeficiency viruses (HIVs) and human T-lymphotropic viruses (HTLVs), cause significant infections worldwide. The viruses have common modes of transmission, both vertically and horizontally, and share an in vivo tropism for cells of the immune system, and in particular, T lymphocytes. As a result a significant number of individuals worldwide have coinfection. At present, it is unclear if coinfection influences the natural history of infection or alters the pathogenicity of an individual virus and/or if this results in the development of unique clinical features. In this article, we summarize our current understanding of these issues with a specific focus on the influence of the HTLVs on the progression and outcome of HIV type 1 (HIV-1) infection.

Epidemiology and Modes of Transmission

It has now been established that HIV-1 and HIV-2 have arisen from cross-species transmission from chimpanzees and sooty mangabeys, respectively, within the past century (189). HIV-1 and HIV-2 are members of a family of primate lentiviruses and have the characteristic properties of being cytopathic with high levels of replication and cell death at all stages of infection. HIV-2 appears to be less pathogenic than HIV-1 with a much slower progression of disease, and infection is relatively geographically restricted. In contrast, in the 20 years since the first description of AIDS, the HIV-1 pandemic remains unchecked, and it has been estimated that to date the cumulative number of individuals infected may be more than 56 million (147). Sexual transmission, predominantly heterosexual, is clearly the primary mode of infection worldwide. Horizontal transmission through contaminated blood products remains significant, and whereas donor screening in many countries has essentially eliminated transmission by blood transfusion, infection in intravenous drug users (IDUs) remains unabated in many areas of the world. The significance of HIV-2/HTLV coinfections remains poorly understood, and although individual reports have been made (121), these seem to occur much less frequently than with HIV-1. As such, this article primarily focuses on coinfections with HIV-1 and the HTLVs.

HTLV type 1 (HTLV-1) and type 2 (HTLV-2) are closely related members of a family of mammalian retroviruses having a similar genomic organization, sharing 65 to 70% nucleotide homology, and belonging to the HTLV/bovine leukemia virus (BLV) group of the subfamily Oncovirinae (49, 70). In contrast to the cytopathic effects of HIV-1, these viruses are relatively noncytopathic and instead often cause proliferation or expansion of infected cell populations. These viruses preferentially infect mature T lymphocytes, with HTLV-1 having a preferential tropism for CD4+ and HTLV-2 having a preferential tropism for CD8+ T lymphocytes (85, 152). In addition, in settings of high proviral loads, infection has been found to extend to non-T-cell populations, including monocytes and B lymphocytes (28, 85, 102, 152). As discussed in detail below, infection is lifelong; it is transmissible vertically by breast-feeding and horizontally by sexual intercourse and contaminated blood products through transfusion of blood and intravenous drug usage. Despite having similar modes of transmission, the efficiencies of transmission of HTLV-1 and -2 are much less than the efficiencies of HIV-1 transmission, because the former are cell-associated and require transfer of infected cells in contrast to the cell-free nature of HIV-1.

HTLV-1 is endemic in many well-defined geographic areas including Japan, the Caribbean, sub-Saharan Africa, South and North America, and Melanesia (49, 70); at present, approximately 20 million individuals are infected worldwide. Most infected individuals are clinically asymptomatic (asymptomatic carriers) but remain infectious throughout their lifetimes. HTLV-2 infection has been prevalent in blood donors and can be considered epidemic among IDUs in the United States, Europe, South America, and Asia (10, 18, 28, 4042, 45, 47, 52, 53, 69, 71, 72, 97, 98, 105107, 113, 114, 129, 153, 158, 159, 181, 198). Infection rates vary widely in different geographic areas ranging from less than 1% in certain European countries to as high as 60% in parts of Vietnam. In many countries HTLV-2 infection is more prevalent in IDUs with HIV-1 infection than in those who are not infected (40). The virus has also been endemic in numerous native American Indian groups (1, 11, 12, 14, 22, 31, 39, 42, 48, 51, 62, 83, 86, 87, 100, 110, 111, 113, 118, 122, 144, 146, 176). At present, no estimates are available for the global number of HTLV-2 infections. Molecular analysis of HTLV-2 isolates from both IDUs and the endemically infected populations noted above have shown the existence of three distinct subtypes, 2a, 2b, and 2c, which can be differentiated on the basis of a combination of genetic and phenotypic analyses (42, 72, 113). At present, there is no evidence that there are differences in the pathogenic properties of these subtypes. HTLV-2a is the predominant infection in urban areas and particularly in IDUs in North America (38, 72). HTLV-2b infection also occurs in IDUs both in North America and Southern Europe and is also the predominant infection in native Amerindian groups in the Americas with the exception of Brazil (38, 42, 72, 113). HTLV-2c is unique, because to date it has been found exclusively in Brazil both in native Amerindian groups and in urban areas, particularly in IDUs (42, 113). HTLV-2 infection in the African continent, specifically among African pygmies, has also been reported (32, 33, 50, 57, 64, 65, 180), and an African origin of HTLV-2 is suggested by the discovery of a fourth and quite divergent HTLV-2d subtype in Efe pygmies and of related simian viruses isolated from African bonobos (Pan paniscus) (66, 185). The origin of HTLV-2 among native Amerindians is unclear, but it is likely that this virus was introduced to the American continent some 15,000 to 35,000 years ago during migrations across the Bering land bridge of HTLV-2-infected Asian groups, which were the ancestors of present-day American Indians. The spread of HTLV-2 among IDUs is almost certainly a recent occurrence, and it is most probable that American IDUs initially acquired the infection from native American Indians. After this introduction, which probably occurred within the past 50 years (159), the virus has successively spread among IDUs through sharing of needles and other drug paraphernalia. Finally, there may have been at least two separate introductions of HTLV-2 into European IDUs from the United States, perhaps at different times, at least one for the 2b subtype in Southern Europe and a second for the 2a subtype in Northern Europe (40). The introduction of HTLV-2 to Southeast Asia almost certainly originated from U.S. military personnel during the Vietnam War, probably through drug use and contaminated blood products (52).

HTLV-1-related simian viruses, termed simian T-lymphotropic virus type 1 (STLV-1), have been discovered in many nonhuman primates in Africa and in Asia (84, 172, 187). HTLV-1 and STLV-1 cannot be separated into distinct phylogenetic groups according to their species of origin but instead are related or grouped on the basis of geographic origin (183), suggesting frequent interspecies transmission (160, 161). As noted above, a simian relative of HTLV-2, termed STLV-2, has been identified in P. paniscus in Africa (60, 115, 184). STLV-2 clusters distinctly from HTLV-2 in phylogenetic analysis, indicating that either there has been ancient interspecies transmission in Africa, or possibly that there has been a co-evolution of STLV-2 and HTLV-2 within their respective hosts (182, 185).

As noted above, HIV-1 and HTLV-1 and -2 have common modes of transmission. With HTLV-1 and -2, horizontal infection via contaminated cellular blood products is an important route of transmission (35, 82, 140, 175). As for HIV-1, the introduction of donor screening in many countries has markedly reduced transmission by blood transfusion but this remains a major mode of transmission in IDUs. Whereas HTLV-2 transmission in IDUs occurs worldwide, HTLV-1 transmission in this population is essentially restricted to a small number areas of endemic HTLV-1 infection and notably Brazil (19, 69). It seems certain that the high rates of infection of HTLV-2 in IDUs are caused by the exchange of contaminated blood in shared syringes and other drug-using equipment. However, it remains unclear why the prevalence of HTLV-2 infection in IDUs in the majority of countries is so much higher than that of HTLV-1.

Sexual transmission also seems to be an important means of HTLV-1 and HTLV-2 infection (81, 92, 95). Studies in areas where HTLV-1 is endemic have shown that heterosexual transmission seems to be more efficient from male to female, and the chance of transmission of HTLV-1 to wives of infected men is approximately 60% (92). In contrast transmission from seropositive women to their uninfected husbands is 0.4%, and this adequately accounts for the much higher seropositivity rates in older women in areas in which HTLV-1 is endemic (16). A similar increase in the prevalence of antibodies to HTLV-2 in women compared with men has also been observed in several of the South American Indian groups (87). This with the extremely high infection rates, which have been reported in elderly women in these populations, supports the importance of sexual transmission of the virus. Indirect support for heterosexual transmission comes also from the observation that among female blood donors who have been shown to have HTLV-2 infection, the most important documented risk factor was sexual contact with an IDU.

Vertical transmission also appears to be extremely important in the maintenance of infection in areas of endemicity. In areas where HTLV-1 is endemic, mother-to-child transmission occurs primarily through breast-feeding (79, 99, 174), and as many as 25% of breast-fed infants become infected. Perinatal infection occurs much less frequently with less than 5% of children born to infected mothers who did not breast-feed becoming infected. A study of Kayapo Indian groups in Brazil, where HTLV-2 infection is endemic, provided strong evidence that vertical transmission is extremely important, with high rates of seropositivity (in some instances, over 20% in children under the age of 9). In addition, familial studies demonstrated that the chance of infection in a child born to an infected mother could be as high as 50% (87). Although the routes of vertical transmission are unknown, these and other studies (101) have suggested that vertical transmission occurs primarily through breast-feeding. It is unclear if HTLV-2 infection may also occur in utero. However, one study has reported that of 20 children born to 19 HTLV-2-infected mothers who did not breast-feed, none became infected, suggesting that this route may be of much less importance (94).

HTLV-1 Clinical Features and Influence of HIV-1 Infection

The spectrum of HTLV-1-related illness ranges from lymphoproliferative malignancies to several inflammatory disorders. The former, adult T-cell leukemia/lymphoma (ATLL), is a group of CD4+ T-cell malignancies with distinct clinical subtypes (178). ATLL generally occurs in individuals infected early in life, often shortly after birth, which suggests that infection of an immature or developing immune system may be important in pathogenesis. ATLL develops after some 20 to 50 years, and the lifetime risk in asymptomatic carriers is between 1 and 5%. The distinct clinical subtypes include the acute, smoldering, chronic, and lymphomatous forms of disease (169). The acute and lymphomatotus forms are clinically the most aggressive and present with extensive lymphadenopathy, hepatosplenomegaly, lytic bone lesions with an associated hypercalcemia, and visceral involvement with skin, gastrointestinal tract, and lung infiltration (178). In addition, these patients are functionally immunocompromised and may develop a variety of opportunistic infections similar to that observed in HIV-1 infection and AIDS. Acute ATLL is characterized by an aggressive CD4+ T-cell leukemia, whereas in the lymphomatous form less than 1% of leukemic cells are present in peripheral blood. Both forms of ATLL have an extremely poor prognosis, with a median survival of approximately 6 and 10 months, respectively. Smoldering ATLL is characterized by skin or lung infiltration without any other visceral involvement, and an absence or only a low number of leukemic cells in peripheral blood. In chronic ATLL, a higher leukocyte count is observed, and this is associated with a lymphadenopathy and hepatosplenomegaly. However, in both of these forms there is no hypercalcemia and no visceral involvement.

The pathogenetic mechanisms involved in the development of ATLL are incompletely understood, but the viral regulatory protein Tax is believed to play a central role. This is related specifically to the ability of Tax to deregulate several normal cellular processes including intracellular protein signalling, transcription of genes involved in cellular proliferation, cell cycle control, and apoptosis (49, 193).

HTLV-1 Tax is a potent transcriptional transactivator not only of viral genes but also of cellular gene expression (49, 193). Tax does not bind DNA directly but physically interacts with many cellular transcription factors that include cyclic AMP (cAMP) response element/activating transcription factor (CREB/ATF) family members, components of the NF-κB/Rel signalling complex, and serum response factors. In many cases this results in the upregulation of a range of cellular genes involved in cell proliferation. These include the genes for interleukin-2 (IL-2) and the IL-2 receptor. The activities of such gene products are believed to contribute to the expansion of infected and possibly transformed cell populations. Although upregulation of these cellular genes may be important in the transformation process, this is also certainly related to the ability of Tax to also disrupt cell-cycle control and apoptosis. Tax upregulates cyclic D2 expression and stimulates G1-to-S-phase transition through upregulated CD4/C4 and CDK6 activities (162, 164). Tax also directly binds and affects the activity of several cell-cycle regulatory proteins, including p15, p16, and cyclin D3 (117, 138).

In addition to disruption of normal G1-to-S-phase transition, Tax interacts with an Mphase regulator HsMADI (91), the human homologue of the yeast mitotic checkpoint MADI protein. Overexpression of Tax and HsMADI results in multinucleated cells, which could explain the karyotypic abnormalities seen in ATLL. The tumor suppressor protein p53 plays a key role in cell cycle control, and Tax has also been shown to disrupt the normal function of this protein. In the presence of Tax, p53 is unable to maintain G1 arrest in response to DNA damage and is also unable to trigger apoptosis when overexpressed. Several recent studies have shown that wild-type p53 protein is stabilized and functionally impaired in HTLV-1-transformed cultured cells, resulting in reduced induction of p53-responsive genes (25, 148, 149). However, HTLV-1 Tax does not seem to interact directly with p53 but instead is thought to alter posttranslational modification of the protein, thus abrogating its function.

It has also been reported (17, 162) that Tax expression induces IL-2-independent proliferation and resistance to apoptosis in IL-2-dependent cutaneous T-cell leukemia/lymphoma type 2 (CTLL-2) cells. In addition, a number of other in vitro studies have shown that Tax alone can induce bcl-2 and bcl-XL expression and apoptosis resistance (68, 139); it is believed that the poor responses of ATLL to conventional chemotherapeutic regimens (169, 178) may be caused by Tax-related apoptosis resistance.

At present, effective treatment of the aggressive forms of ATLL remains poor, and standard combination chemotherapy regimens as used in other lymphoid malignancies have been largely unsuccessful. Survival is directly related to the subtype of ATLL. In a large study of ATLL in Japan (169), the median survival time of ATLL and the projected 4-year survival rate were 6.2 months and 5%, respectively, for the acute type; 10.2 months and 5.7%, respectively, for the lymphomatous type; and 24.3 months and 26.9%, respectively, for the chronic type. In the smoldering type, the median survival was not reached after a median follow-up of 13.3 months, but the projected 4-year survival rate was only about 60%. Recently, there have been reports of the treatment of ATLL with a combination of the reverse transcriptase (RT) inhibitor zidovudine (AZT) and alpha interferon (IFN-α) with good response rates and little toxicity (59, 77, 125). The success of directed antiretroviral therapy in the treatment of ATLL suggests that active virus replication in vivo exists; it also indicates that the use of higher doses of AZT possibly with other antiretroviral agents combined with IFN-α and/or other immune modulators might also prove effective (4). Other agents which also might have a role include biological mediators such as retinoic acid, which induces apoptosis of ATL cells in vitro (4, 43). The recent demonstration that the combination of arsenic trioxide and IFN-α induces specific degradation of the viral transactivator Tax in HTLV-1-transformed cells in vitro, followed by cell cycle arrest and apoptosis of HTLV-1-positive cells, indicates that this could also be effective in vivo (4).

It is unclear if HIV-1 coinfection can influence the development of ATLL or its response to treatment. Although individual cases of the development of ATLL (168) in the setting of HTLV-1 and HIV-1 coinfection have been reported, these have not been of sufficient number to investigate this in detail.

Inflammatory diseases associated with HTLV-1 include the neurological disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (56, 142). The onset of HAM/TSP generally occurs in the 3rd and 4th decades of life, although it has been described to occur in children as young as 6 years. HAM/TSP occurs more frequently in women than in men, and the onset is usually subacute and insidious. Initial symptoms generally include stiffness, with weakness of the lower extremities, and urgency and frequency of urination. Physical findings are weakness of the legs with spasticity, hyperreflexia, and extensor plantar responses. Although strength in the arms is usually preserved, deep tendon reflexes tend to be brisk in the upper extremities, and sensory findings are usually minimal. The lifetime risk of developing HAM/TSP is similar to that of ATLL, and although the pathogenesis is understood incompletely, this disorder is associated with high HTLV-1 proviral loads ranging from 10- to 100-fold greater than that seen in asymptomatic carriers (136). Similarly, high levels of specific antiviral cytotoxic T-cell responses, which correlate with high viral loads, seem to be important, and the frequency of such responses is also significantly higher in individuals with HAM/TSP than in asymptomatic carriers (135). HAM is characterized by a perivascular lymphocytic infiltration in the central nervous system, notably in the thoracic region of the spinal cord and mainly in the early phases of the disease. Investigations in the pathogenesis of HAM have focused on the potential role of HTLV-1 Tax-specific CD8+ cytotoxic T lymphocytes (CTL), and it has been suggested that during cytotoxic T-cell killing, cytokines and lymphokines released may produce local parenchymal damage (9). It is unclear why certain individuals develop HAM/TSP and others develop ATLL; however, genetic factors seem to be important (89, 90, 192), and in relation to HAM/TSP, several have been identified that seem either to be protective or to predispose to the development of this disorder (89, 90). It is unclear if concomitant HIV-1 infection might influence the development of HAM/TSP or if HTLV-1 might influence the development of HIV-1-associated neurological disease (6). In this regard one report from Brazil compared the development of myelopathy in individuals coinfected versus those infected with HIV-1 alone. A statistically significant higher proportion of coinfected individuals developed not only myelopathy but also peripheral neuropathy (75). However, the relative contribution of each virus to the development of myelopathy could not be determined. In addition, it is unclear if all patients who developed myelopathy would fully satisfy the clinical criteria for HAM/TSP.

To date, no consistently effective treatments for HAM/TSP have been reported. Interventions with corticosteroids, plasmapheresis, interferon, and, more recently, with antiretroviral drugs have been attempted, but with mixed and generally poor results. Early reports on the use of AZT produced conflicting results (67, 166).

Recently, virological improvement has been reported for HAM/TSP patients receiving the RT inhibitor lamivudine (3TC). Specifically, treatment resulted in a 10-fold reduction in levels of proviral DNA in five patients with HAM/TSP, and in one of these there was a concomitant fall in the frequency of HTLV-1-specific CTL responses (179). This also suggests that active RT activity and virus replication are important in HTLV-1 infection and in patients with HAM/TSP. The observation that lamivudine can reduce HTLV-1 proviral loads in vivo contrasts with in vitro susceptibility studies of RT inhibitors. Garcia-Lerma and coworkers (54) studied five HTLV-1 isolates and found that, although they were susceptible to AZT, dideoxycytosine, dideoxyinosine, and stavudine, all had inherent high-level resistance to 3TC, suggesting that the latter may not be useful in treatment of HTLV-1 infections. The development of resistance apparently is not a problem at present, because no mutations developed in the RT region of the HTLV-1 provirus, whereas resistance was present in HIV-1 in five HIV-1/HTLV-1-coinfected patients who had been treated with AZT (55). More recently, a study of two TSP/HAM patients treated with AZT plus 3TC showed that whereas one patient had a 2-log-unit decrease in HTLV-1 proviral load, an increase of 1 log unit was observed in the second after several months of treatment (120). The reasons for these conflicting data are unclear, but it is possible that the RT inhibitors used may have other effects perhaps involving normal cellular processes in addition to inhibition of reverse transcription. Little experience has taken place in the use of protease inhibitors in treating HTLV-1 infections. However, a comparison of the substrate specificities of HTLV-1 and HIV-1 suggests that the substrate binding site of the HTLV-1 protease is more extended than that of the HIV-1. It remains unclear, however, if these differences will be reflected in vivo both in terms of susceptibility to protease inhibitors and of the range of inhibitors available for effective treatment.

Other inflammatory processes associated with HTLV-1 include uveitis, arthritis, thyroiditis, alveolitis, and in children an infective dermatitis (49). The pathogenesis of these disorders remains unknown, but their development also seems to be associated with high proviral loads. At present, it is unclear if concomitant HIV-1 infection may alter the natural history or development of these disorders.

HTLV-2 Clinical Features and Influence of HIV-1 Infection

In contrast to HTLV-1, the role of HTLV-2 in human disease remains poorly defined; however, increasing evidence shows that the infection may also be associated with rare lymphoproliferative and a spectrum of neurological disorders (70). In addition, several epidemiological studies have suggested that underlying HTLV-2 infection may predispose to the development of a wide range of bacterial infections. The major limitations of many these studies are that they have often been based on individual case reports and that many patients have also had concomitant HIV-1 infection. As a result, in some instances it has been difficult to accurately assess the exact role of HTLV-2 and to confidently define and establish contributing factors that might have arisen from HIV-1 coinfection. Moreover, because numerous HTLV-2-infected patients have a history of intravenous drug use, it is unclear if this activity or related activities could also have confounded the analysis and interpretation of the clinical studies. In this section the clinical disorders that have been associated with HTLV-2 infection are summarized, and where possible the role and impact of HIV-1 coinfection is discussed.

Lymphoproliferative Disorders

The first two isolations of HTLV-2 were from cultures of peripheral blood lymphocytes of patients with hairy cell leukemia (93, 155). Although subsequent studies using both serological and molecular methods have failed to support the involvement of HTLV-2 in this disorder, reevaluation of one of these patients showed that, in addition to hairy cell leukemia, a coexisting CD8+ T-lymphoproliferative process occurred (154). Molecular studies showed integration of the HTLV-2 provirus in the CD8+ T lymphocytes but not in the malignant hairy cell population (154). This was the first direct demonstration of the potential of HTLV-2 to cause lymphoproliferative disorders, and in contrast to HTLV-1, this involved CD8+ T lymphocytes. Subsequently, several reports described HTLV-2 infection in patients with disorders of large granular lymphocytes (116, 123). Specifically, two patients with large granular lymphocytic leukemia and one with a large granular lymphocytosis were shown to have HTLV-2 infection. However, as noted in the patient with hairy cell leukemia, it could be shown that in the latter patient the provirus was not present in the abnormal large granular lymphocytes but instead was found primarily in the CD8+ T-lymphocyte population. In addition, serological evaluation of numerous additional patients did not support a role for HTLV-2 infection in disorders involving large granular lymphocytes. It is thus unclear if infection of CD8+ T lymphocytes in these patients was merely coincidental or if it contributed in any way to the development of their lymphoproliferative disorders. The observation that HTLV-2 had infected CD8+ T lymphocytes in two such diverse clinical conditions is consistent with the direct studies of Ijichi and colleagues (85), who demonstrated that the virus has a preferential in vivo tropism for this lymphocyte population in both HTLV-2-infected and HTLV-2/HIV-coinfected individuals.

In the setting of HIV-1 and HTLV-2 coinfection we observed the development of a syndrome of severe exfoliative erythroderma with prominent dermal infiltration with CD8+ T lymphocytes, lymphadenopathy, and eosinophilia in two IDUs (96). Although this disorder clinically resembled a cutaneous T-cell leukemia/lymphoma, no attempts were made to determine whether the infiltrating CD8+ T-cell populations were clonal or represented a malignant expansion. However, subsequently Poiesz et al. (150) described a patient also infected with HIV-1 and HTLV-2 with a closely similar if not identical clinical presentation in whom a clonal CD3+ CD8+ CD4 cutaneous T-cell lymphoma was diagnosed. Taken together, these studies have clearly demonstrated that HTLV-2 infection can result in proliferation of infected CD8+ T-lymphocyte populations, which seem in most instances to be clinically benign. However, in the setting of HIV-1 infection it seems possible that malignant CD8+ T-lymphoproliferative disorders can develop. It remains unclear if HIV-1 infection directly contributes to the development of these disorders or if this may be secondary to a state of generalized immunosuppression. Because an intact immune system would be essential in controlling the expansion of HTLV-2-infected T lymphocytes, HIV-1 coinfection could alter this and, as a result, coinfected individuals might be expected to develop a higher incidence of HTLV-2-associated T-cell malignant disorders. It is also possible that after HTLV-2 infection alone, additional intracellular events could occur which could also lead to transformation as in ATLL.

Neurological Disorders

By analogy with HTLV-1, HTLV-2 infection might also be expected to be associated with neurological disorders. The first descriptions of such disorders were from two patients who were dually infected with HIV-1 and HTLV-2 and who presented with a myelopathy indistinguishable from HAM/TSP (7, 156). Subsequently, a report (80) described two sisters only infected with HTLV-2, who had developed a chronic neurodegenerative process characterized by spasticity, paraparesis, and prominent ataxia. Overall, the clinical features were suggestive of a syndrome of the olivopontocerebellar atrophy variant of multiple system atrophy. Although these two patients had spasticity as a prominent component of their illness, this disorder did not remotely resemble HAM/TSP. The association of HTLV-2 with spastic ataxia was supported by two studies in Miami, which described two and four females, respectively (73, 167), with a distinctive picture of ataxia, spasticity, and variable alterations in mental status. Although it is unclear if these two studies may have included some of the same patients, these reports strongly support an association of HTLV-2 and neurological disorders where ataxia is a prominent feature. Subsequently, at least five other reports (13, 88, 109, 131, 132) described patients with single HTLV-2 infection who presented with symptoms identical with classical HAM/TSP. In addition to myelopathy, a single report told of the development of a spinocerebellar syndrome in a HTLV-2-infected Guaymi Indian from Panama (23). Similar syndromes have been described in several patients with HTLV-1 infection, and it has been suggested that this may represent a unique neurological manifestation of either HTLV-1 or HTLV-2 infection (23). In a recent study of a cohort of HIV-1-coinfected individuals, the prevalence of antibodies to HTLV-2 was significantly higher in those with a predominantly sensory polyneuropathy (PSP) than in asymptomatic controls (196). Moreover, patients with PSP have higher proviral loads than those without PSP (197), which is similar to that in individuals with HAM/TSP compared with asymptomatic carriers (136). To date, all cases of neurological disease, with only one exception that was singly infected with HTLV-2, were female, which is similar to HTLV-1 where females have also been found to be more likely to develop HAM/TSP. In addition to specific disease entities epidemiological studies have suggested that HTLV-2 may cause a form of generalized neurological dysfunction. In a cohort of IDUs, HTLV-2 infection was independently associated with the development of global neurological disability (36).

Thus, although support is now increasing for the existence of HTLV-2-associated neurological syndromes, the real frequency of each of these syndromes is unknown. As already noted, confounding elements exist, which often make it difficult to definitely attribute infection to the clinical outcome. HIV-1 can cause a variety of neurological disorders, and this may have played a role in some of the disorders described above. Moreover, because many HTLV-2-infected individuals may be involved in drug usage, the effect of these compounds or adulterants used in their preparation may also confound any study involving such individuals (21, 137).

Prospective studies of endemically infected Amerindian groups, which would be relatively free of confounders such as HIV and intravenous drug usage, will help elucidate the exact role of HTLV-2 in neurological disease. However, it is possible that these studies might be confounded by other factors such as nutritional deficiencies. Similarly, it might be expected that unique neurological disorders or perhaps other related diseases (173) will present only in the setting of HIV-1 and HTLV-2 coinfection, and long-term prospective studies in this population will help to resolve this.

HTLV-2 and Infectious Disease

Murphy and coworkers in the Retrovirus Epidemiology Donor Study (REDS) have conducted prospective studies of HTLV-1- and HTLV-2-infected and seronegative individuals in five U.S. cities to determine whether HTLV-2 is associated with an increased incidence of infectious diseases. At the time of enrollment initial observations suggested that HTLV-2 infection was associated with a history of pneumonia and with urogenital and soft tissue infections within the previous 5 years (133, 134, 165, 188). Follow-up evaluation approximately 2 years after enrollment supported the view that HTLV-2 infection seemed to be associated with an increased incidence of bronchitis, bladder or kidney infection, and oral herpes infection, with the overall conclusion that there is an increased incidence of infectious diseases among otherwise healthy HTLV-2-infected individuals (133, 134). An independent study of HTLV-2-infected IDUs (126) also demonstrated the existence of an increased risk for the development of bacterial pneumonia, soft tissue abscess formation, and lymphadenopathy compared with noninfected IDUs. However, these findings were not confirmed by Safaeian and coworkers (157), who failed to demonstrate an association of HTLV-2 infection with the development of bacterial pneumonia, infective endocarditis, and soft tissue abscess formation. Moreover, Murphy et al. (130), in a more detailed study of IDUs, failed to confirm their earlier findings that HTLV-2 infection was associated with abscess formation. The reasons for the conflicting findings are unclear, but confounding factors including race, sex, and frequency of intravenous drug use may have played a role. Recently, an investigation into cause-specific mortality in a large population of IDUs with HIV and HTLV-2 infections failed to demonstrate that HTLV-2 infection was significantly associated with mortality from any cause, and it was suggested that the virus was not a significant pathogen even in the setting of concomitant HIV infection (61).

To date, experience in the treatment of HTLV-2 infections has been extremely limited. Machucha et al. (120) evaluated the responses in two HTLV-2/HIV-1-coinfected patients receiving triple antiretroviral drug combinations including lamivudine and a protease inhibitor. The two HTLV-2/HIV-1-coinfected patients showed an initial increase in HTLV-2 proviral load after beginning treatment, followed by a slight decline several months later. As expected, plasma HIV-1 RNA declined to <50 copies/ml in both patients during therapy. Thus, it is unclear if antiretroviral therapy will prove to be of benefit. However, in the setting of increased viral loads with myelopathy or another neurological disorder, empiric treatment might be warranted and might prove beneficial.

Influence of HTLV-1 and HTLV-2 Infection on HIV-1 Infection

Concomitant infections with HIV-1 and HTLV-2 are common in urban areas worldwide primarily as a result of intravenous drug use. In contrast, infections with HTLV-1 and HIV-1 are relatively restricted to geographical regions endemic for HTLV-1. Coinfection with HTLV-1 and HIV-1 infection in IDUs is comparatively rare, although recent reports have suggested that it may be as significant as that involving HTLV-2 in certain urban areas of Brazil. Information on the influence of HTLV-1 and HTLV-2 infections on the progression of HIV-1 infection is conflicting. Although many have suggested an acceleration of HIV-1 infection (3, 44, 58, 63, 76, 108, 143, 163), others showed little or no influence (78, 186) and one study even suggested the possibility of a slowing of HIV-1 progression (190). Unfortunately, most of these studies have been limited by small numbers of patients, by the inability to determine exactly the relationship between the origins and relative timing of the HIV-1 and HTLV-1/2 infections, and in some cases, by the fact that in several studies no attempts were made to differentiate between HTLV-1 and -2 (108, 143). One exception was an international study specifically designed to determine whether HTLV-2 infection may influence the progression of HIV-1 infection (78). In all, a total of 370 IDUs from three urban areas in the United States and one in Italy, all of whom had seroconverted to HIV-1 positivity within 2 years, were enrolled. Of these, 61 (16%) were coinfected with HTLV-2 and patient follow-up times ranged from 5 to 10 years. With use of the development of an AIDS-defining illness and death as end points, it could be clearly shown that HTLV-2 coinfection was associated neither with progression to AIDS nor with mortality. Analysis of CD4+ T-lymphocyte levels also showed similar declines over time in both groups. Whereas there appeared to be a more rapid fall in the percentage of CD4 cells in the first year in the HTLV-2-infected individuals after seroconversion, this difference was not found to be significant in regression analysis, and overall the study demonstrated that HTLV-2 infection did not affect this immunological marker of HIV-1 progression. In contrast, Brites et al. in a Brazilian study (20) evaluated 895 HIV-1-infected individuals, of whom 16.3% were coinfected with either HTLV-1 or HTLV-2 and although this study was not as strictly controlled, it was reported that women coinfected with HTLV-1 or HTLV-2 had a higher risk of developing AIDS than those infected with HIV-1 alone.

A cross-sectional study (163) suggested that persons with HTLV-1 infection were more likely to be in late clinical stages of HIV infection than those with HIV alone. It could also be shown that coinfected individuals had higher levels of CD4+ lymphocytes (46), suggesting that HTLV-1 infection may produce proliferation of CD4 lymphocytes. Similarly, a study of CD4+ and CD8+ T-lymphocyte counts in HIV and HTLV-1 coinfected patients also showed that these were both higher in the setting of coinfection (8). In the former study it was not possible to determine whether HTLV-1 infection actually contributed to the development of their presenting clinical conditions. Sobesky et al. (171), in a study of a cohort of adults in French Guiana, of whom about 12% were coinfected with HIV-1 and HTLV-1, reported that coinfection could be strongly correlated with decreased survival and also noted an increase in CD4+ T-lymphocyte levels.

In a comparative analysis of virus loads, a study of 23 patients with HIV-1/HTLV-1 coinfection and 92 with single HIV-1 infection in Brazil reported no significant differences in HIV-1 viral load (74). Moreover, these results were not influenced by AZT treatment or adjustment of CD4 levels. Although this study did not report on the influence of HIV-1 on HTLV-1 proviral loads, a subsequent report (26) compared HTLV-1 proviral loads in asymptomatic HTLV-1-infected individuals, singly infected patients with HAM/TSP, and 25 HIV-1/HTLV-1-coinfected patients from Martinique. Whereas proviral loads were higher in HAM/TSP patients, there was no significant difference in HTLV-1 and HTLV-1/HIV-1 coinfections. In contrast to previous studies, this study showed no differences in CD4 counts between singly infected and coinfected individuals. In view of reports that the development of neurological and inflammatory disorders is associated with higher HTLV-1 proviral loads, this would suggest indirectly that HIV-1 coinfection would not be expected to influence or accelerate the development of such processes. Similarly, Woods et al. (191) found no influence of HIV-1 on HTLV-2 proviral loads.

Although the influence of HTLV-1 and HTLV-2 infection on HIV-1 progression remains unclear, and is limited by factors alluded to above, numerous in vitro studies have provided compelling evidence for potential interactions, both direct and indirect, between the viruses and have established a theoretical basis for how the former may influence the progression of HIV-1 infection. Specifically, several studies have demonstrated that both HTLV-1 virions and envelope proteins are mitogenic and can activate CD4+ T cells and upregulate HIV-1 replication (127, 170, 194, 197). The two viruses can activate each other in vitro (34), and there is increased antigen production in peripheral blood mononuclear cell (PBMC) cultures and higher levels of expression of HTLV-1 mRNA-expressing cells in peripheral blood after HIV-1 coinfection (5). Coinfection of cultured macrophages by T-cell-tropic HIV-1 and HTLV-1 enhances HIV-1 replication, whereas coinfection with macrophage-tropic (M-tropic) HIV-1 and HTLV-1 upregulates HTLV-1 infection (177). It has also been proposed that coinfection might lead to the development of "pseudoviruses" that might have an extended in vivo tropism and as a result an increase in pathogenicity (104, 119, 151). The HTLV-1 regulatory protein Tax can influence HIV-1 replication in many ways. Tax has been shown to increase HIV transcription by activation of the HIV-1 long terminal repeat (15). Although this seems inherently weak, this effect can be enhanced dramatically by the presence of low levels of HIV-1 Tat and is apparently mediated through cooperation of Tat and NF-κB (27). In addition one study demonstrated that HTLV-1 Tax can interact with the p21 cyclin-dependent kinase to activate HIV-1 replication, and it has also been reported that soluble Tax can increase the susceptibility of CD4 T cells to both M- and T-tropic HIV by an as yet unknown mechanism (128).

More recently, several studies have provided evidence for important indirect effects of HTLV-1 and HTLV-2 on HIV-1 replication via the production of CC-chemokines. Studies conducted several years ago showed that HTLV-1 and HTLV-2 infections are associated with the spontaneous proliferation of PBMCs in vitro, and this has been associated with the production of a range of cytokines and lymphokines (103, 124). More recently, investigations with infected cell lines or PBMC cultures have shown that HTLV-1 infection was associated with the production of the CC-chemokines MIP-1α, MIP-1β, and RANTES and that these in turn could influence HIV-1 replication (2, 29, 30, 37, 127, 141). The CC-chemokines are the natural ligands for the coreceptors required for HIV-1 entry, and it could be shown that these could suppress in vitro infection by M-tropic HIV-1 strains and enhance infection by T-cell-tropic HIV-1 strains (127). Moreover, it has also been suggested that overproduction of CC-chemokines may actually protect individuals from infection by M-tropic HIV-1 strains, on the basis of observations that individuals who have been repeatedly exposed to HIV-1 yet remain uninfected produce high levels of CC-chemokines (145, 195).

These observations have been supported by two studies (24, 112) that investigated CC-chemokine production in cell lines from HTLV-2- and HIV-1-coinfected individuals. Casoli et al. (24) demonstrated that cultured PBMCs from coinfected individuals produced high levels of these CC-chemokines and that the kinetics of production and concentrations were inversely related to those of HIV-1 replication. With cocultures of PBMCs or isolated CD8+ T lymphocytes from singly infected HTLV-2 individuals, and with CD4+ T lymphocytes from singly infected HIV-1 individuals separated by a semipermeable membrane, it could be demonstrated directly that CC-chemokines produced by the former could inhibit HIV-1, and that MIP-1α played the predominant inhibitory role. These studies were supported and extended in an independent study (112) by using short-term cultures of PBMCs from HTLV-2-infected and HIV-1-coinfected individuals where it could be demonstrated that there was spontaneous production of significant levels of MIP-1α and -1β and, to a lesser extent, RANTES. In contrast, spontaneous CC-chemokine production was not observed in PBMCs from uninfected or HIV-1-infected individuals. Although HTLV-2 preferentially infects CD8+ lymphocytes in vivo, it was also shown that whereas RANTES was produced exclusively by the CD8+-enriched population, MIP-1α and MIP-1β were produced by both the CD8+-enriched and CD8+-depleted populations of HTLV-2-infected PBMCs. RT-PCR demonstrated active expression of the HTLV-2 regulatory protein Tax in the infected CD8+ T-lymphocyte population, and it was also shown that Tax could transactivate the promoters of MIP-1β and RANTES. Therefore, it seems that HTLV-2 stimulates the production of CC-chemokines both directly at a transcriptional level via the viral transactivator Tax and also indirectly from noninfected CD4+ T cells. These findings suggest that HTLV-2, via chemokine production, would be expected to alter the progression of HIV-1 infection in coinfected individuals, and specifically it could be anticipated that, depending on the time course and dynamics of coinfection, HTLV-2 infection could potentially inhibit or enhance the progression of HIV-1 infection. Specifically, it might be expected that, if HTLV-2 infection preceded that of HIV-1, inhibition of M-tropic HIV-1 by CC-chemokines early in infection could delay or prevent the progression of HIV-1 infection. In contrast, if infection occurred after or late in HIV-1 infection this could possibly enhance the pathogenicity of T-tropic strains. Moreover, it is possible these different influences may well account for the differences noted in the clinical outcomes in coinfected individuals.

Conclusions

HIV-1 and HTLV-2 coinfections are epidemic in many urban areas of the world where they are maintained primarily through practices associated with IDU. HIV-1 and HTLV-1 coinfections primarily occur in areas endemic for HTLV-1. Although IDU is important in maintaining coinfections in certain of these areas, it is not as significant as that involving HTLV-2. At present, no evidence suggests that HIV-1 may influence the natural history of HTLV-1 infection. However, several studies have suggested the possibility that HIV-1 may contribute to the development of HTLV-2 malignant lymphoproliferative processes. Whether HTLV-1 and HTLV-2 infection may influence the progression of HIV-1 infection is also unclear. However, compelling evidence shows that HTLV-2 may certainly influence this through CC-chemokine production, and this may have either a negative or positive influence depending on the temporal relationship of infection by the two viruses. Prospective clinical, immunological, and virological analyses will allow a clearer understanding of the interactions of these viruses in coinfected individuals, which in turn will allow the development of optimal therapeutic interventions.

Acknowledgments

These studies were supported by the Japanese Foundation for AIDS Prevention (W.W.H.) and the Brazilian Research Council (CNPq) (A.A.).

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