Human T-lymphotropic virus type II (HTLV-II), discovered shortly after HTLV-I, has an interesting epidemiology and a controversial role as a pathogen. Long considered an innocuous infection detected mainly as a by-product of serologic testing aimed at HTLV-I, HTLV-II has received comparatively less investigation than the prototype virus. This brief review attempts to give a picture of current knowledge on the epidemiology of the virus among Amerindians and among intravenous drug users (IVDU), its modes of transmission, and the recent association of HTLV-II with neurologic syndromes and perhaps other conditions.
Amerindians. The past 5 years has revealed that HTLV-II is endemic among a number of Amerindian tribes in South, Central, and North America. A full description of HTLV-II epidemiology in these groups is beyond the scope of this paper, but Hall et al. (1) have contributed an excellent review. Like the uneven microepidemiology of HTLV-I in southern Japan, HTLV-II has a wide range of crude prevalence in different tribes, from a high of >30% among the Kayapo of Brasil to 2-3% in the Navajo and Pueblo of the United States (2,3). Since HTLV-II has been postulated to have been brought with ancestors of these tribes in their migrations from Asia over 10,000 years ago, it is unclear whether the different prevalence levels reflect different historical prevalence levels or are the result of subsequent mixing with nonendemic peoples.
Inferences on the intratribal epidemiology of HTLV-II are limited by the small size and nonrandom sampling of many studies on this subject. Nevertheless, most studies show an increase in prevalence with age, and some also show the higher prevalence among females that is characteristic of HTLV-I (2). These data suggest that HTLV-II is maintained within these relatively isolated populations by means of mother-to-child and sexual transmission, as appears to be the case for HTLV-I. The discovery of HTLV-II in two groups of Pygmies and in a small number of non-Pygmies in central Africa is interesting in that it suggests a possible African origin for the virus (4,5). One Pygmy isolate has been completely sequenced, and it is an HTLV-II subtype B similar to isolates from Pueblo and Seminole Indians in the United States (6).
IVDU. Levels of HTLV-II seroprevalence of up to 20% have been reported among IVDU in the United States, Spain, Italy, and Scandinavia. Once again, the distribution of the virus is not uniform; there is substantial variation in HTLV-II seroprevalence among IVDU in various U.S. cities (7), the prevalence is higher among Black and Hispanic than among White IVDU in the United States (8), and there is little or no HTLV-II among French IVDU despite the close proximity to Italy and Spain (A. Gessain, personal communication). Prevalence increases with age among IVDU, although in this case age appears to be a surrogate variable for the duration of drug injection. After adjustment for age, seroprevalence is higher in female IVDU than in male IVDU, suggesting that sexual, in addition to parenteral, transmission is responsible (8,9).
The high HTLV-II prevalence in certain subgroups of IVDU suggests that the virus may be easily transmitted by needle sharing, although probably less efficiently than hepatitis B and C. However, the uneven demographic and geographic distribution of HTLV-II suggests either that there is limited mixing between HTLV-II-infected subgroups of IVDU or that the virus has been introduced into one or more of these subgroups within the last few decades. The finding of a higher HTLV-II seroprevalence in Black than in Amerindian U.S. IVDU is interesting, given the dominant hypothesis that HTLV-II was introduced from Amerindians into IVDU (7).
Blood Donors. Routine serologic screening of U.S. blood donors for HTLV-I was instituted in 1988, and the enzyme immunoassays utilized also detect HTLV-II antibody, albeit with a slightly lower sensitivity. The confirmed HTLV-I/II seroprevalence is currently ≈1 to 2 per 10,000 blood donations, and HTLV-II accounts for at least half of the HTLV-I/II-seropositive blood donors after typing is performed. Risk factors for HTLV-I/II infection among blood donors segregate according to virus type (10). For HTLV-II, having had an IVDU as a sexual partner, having a history of IVDU, and previous blood transfusions are the predominant risks. For HTLV-I, sexual or familial contact with persons from endemic areas and previous blood transfusions are the main risk factors.
Modes of Transmission. Less epidemiologic investigation has been directed at HTLV-II transmission than for HTLV-I, but the available information suggests that parenteral, sexual, and mother-to-child transmission are also the predominant modes of transmission for the type II virus. In addition to the demographic factors mentioned above, HTLV-II infection is associated with the duration of heroin injection and with the injection of drugs in a “shooting gallery” among IVDU (8). Surprisingly, there was little association with the intensity of cocaine injection, despite the association between human immunodeficiency virus (HIV) seropositivity and cocaine injection. Again, this supports the concept that parenteral transmission by needle sharing among IVDU was relatively restricted to members of the same sociodemographic and drug milieu, in this case Black and Hispanic heroin injectors in the 30- to 60-year age cohort.
Sexual transmission is clearly important given the number of HTLV-II-seropositive female blood donors whose only risk factor for infection is sexual contact with an IVDU (10) and the increased prevalence among patients at clinics for sexually transmitted disease and among persons accepting money or drugs for sex (7). From the higher female than male HTLV-II seroprevalence in most studies of Amerindian tribes, it may also be inferred that male-to-female sexual transmission is more efficient than the converse, as for HTLV-I. Data from the Retrovirus Epidemiology Donor Study (REDS) suggest that the likelihood of HTLV-II transmission to long-term female sexual partners is related both to the duration of the relationship and to the level of HTLV-II proviral DNA in the blood of the infected man (11). Preliminary data from the same study also show that an increased number of lifetime sexual partners is a risk factor for HTLV-II seropositivity in both men and women.
There are few data on mother-to-child transmission of HTLV-II. However, one well-documented case (12), together with the 1 and 8% HTLV-II seroprevalence among children younger than 15 in the Guaymi (13) and Kayapo (2) tribes, respectively, suggests that vertical transmission does occur. It has been established that HTLV-I vertical transmission occurs predominantly via the ingestion by the infant of infected lymphocytes contained in breast milk. Among IVDU, one study suggested that infants of HTLV-II-seropositive mothers who were not breast-fed were at low risk of acquiring HTLV-II (14). The author has estimated that there are ≈140,000 HTLV-II seropositives in the United States alone. If half of these are female, then there is ample potential for the prevention of vertical transmission in the United States, and among endemic peoples elsewhere in the world.
Research into the disease associations of HTLV-II is notable for several initial reports that have not been substantiated upon further investigation. Among the list of false leads must be included hairy-cell leukemia, chronic fatigue syndrome, and most recently, large granular lymphocytic leukemia. The danger of inferring association on the basis of a very small sample of disease cases and the possibility of confounding by coexisting risk factors for HTLV-II have been amply demonstrated.
Neurologic Disease. The best-documented disease association of HTLV-II is HTLV-associated myelopathy (HAM). This syndrome is characterized by spastic paraparesis of the legs, hyperreflexia, and spastic bladder similar to that observed in HAM in three case reports of HAM-like disease in HTLV-II carriers (15,16). An additional one case [prevalence 0.25%; 95% confidence interval (CI), 0.0%-0.6%] was diagnosed from prospective neurologic examination of a cohort of 404 HTLV-II carriers (17). In the same study, 4 (2.4%; 95% CI, 0.7-6.1%) of 166 HTLV-I subjects had a similar myelopathy, suggesting that the rate of HAM may be lower among HTLV-II carriers.
In contrast, two cases of spinocerebellar atrophy reported in Native American Indian sisters infected with HTLV-II (18) and four cases of ataxia and cognitive disorder reported in patients with HTLV-II antibody and proviral DNA (19) have features inconsistent with the HTLV-I HAM syndrome. It is conceivable that the manifestations of neurologic disease may differ because of genetic variation in the immunologic response to HTLV-II or because of coexisting pathology.
HTLV-II HAM cases have laboratory findings different from those of HTLV-I HAM cases. Although all reports of HTLV-II-related neurologic disease have not reported polymerase chain reaction (PCR) results on cerebrospinal fluid (CSF), detection of proviral DNA in the CSF is often negative, and CSF HTLV-II antibody titers are low or nondetectable, presumably due to the low HTLV-II proviral copy number in the CSF (17). In contrast, HTLV-I HAM cases have both high antibody titers and a high viral load, and HTLV-I provirus has been detected in the CSF by both PCR and viral culture (20). These findings suggest that HTLV-II HAM cases have levels of virus that may not be very different from those found in healthy HTLV-II carriers, who in turn may have lower levels of HTLV-II proviral DNA than their HTLV-I counterparts (11). The few cases of HTLV-II HAM with viral subtype data have all been HTLV-IIa, but given the preponderance of HTLV-IIa in the United States, it is premature to infer that HTLV-IIb is less neuropathologic.
CD8 Lymphocytic Proliferation. The fact that HTLV-II is tropic for CD8+ lymphocytes suggests that it may have hematologic effects different from those of HTLV-I, which infects primarily CD4+ lymphocytes. No clear alterations in the percentage of various lymphocyte subsets have been demonstrated in healthy HTLV-I or -II carriers. However, data from the REDS study presented at the 1995 HTLV meeting show small but significant increases in absolute lymphocyte count in HTLV-II carriers compared to age-, sex-, and race-matched seronegative controls. HTLV-II has not been proven to cause any hematologic malignancy despite case reports of hairy-cell leukemia, large granular lymphocytic leukemia, and CD8+ lymphocytic infiltration of the skin occurring in HTLV-II-infected patients.
Patients coinfected with both HTLV-II and HIV may demonstrate increased levels of CD8+ lymphocytes in the blood; however, this may also be seen in early HIV infection without HTLV-I or -II, and there may be no clinical significance to the phenomenon besides an alteration of the CD4/CD8 ratio. The capacity for HTLV-II (or HTLV-I) to accelerate the progression to disease among persons infected with HIV is also controversial, with studies both supporting and refuting this hypothesis.
Skin and Soft Tissue Infections. The first report of HTLV-II infection among IVDU also mentioned that subjects with soft tissue infections had a higher seroprevalence than did IVDU without such infections, although the finding could have been confounded by an excess of Black subjects in the former group. More recently, our group has found that persons with both HTLV-II seropositivity and IVDU may be at increased risk for bacterial pneumonia, abscess, and lymphadenopathy compared to patients with neither risk factors (21). Demographic and other relevant confounders, including HIV disease, were controlled for either by matching or by inclusion in the logistic regression model. Although an etiologic role for HTLV-II in these conditions is biologically plausible due to CD8+ lymphocytosis and increased immunoglobulin in infected persons, unmeasured confounding by other characteristics of IVDU behavior may account for some of the associations observed.
DIRECTIONS FOR FUTURE RESEARCH
Much has been learned about the epidemiology of HTLV-II in the past 5 years compared to the comparable period after its discovery, when the virus was merely a footnote to the more widely studied HTLV-I. Nevertheless, several questions remain. Are there endemic HTLV-II populations other than Amerindian tribes in South, Central, and North America and two Pygmy tribes in Africa? What are the rates of sexual and mother-to-child transmission, and are they sufficient to maintain prevalence above the threshold for propagation within these isolated tribes? From which endemic focus, and by what means, was HTLV-II transmitted to IVDU? Can the uneven geographic and demographic distribution of HTLV-II among IVDU be explained with additional data on patterns of needle sharing within and across demographic subgroups of IVDU?
Additional studies on the transmission of HTLV-II are also necessary to determine whether the efficiency of parenteral, sexual, and mother-to-child transmission is similar to that of HTLV-I, as is assumed currently. As evidence mounts that HTLV-II may cause disease, such epidemiologic data will be important to public health efforts to limit its transmission, particularly among the children and sexual partners of IVDU in the United States, Italy, and Spain and, potentially, among endemic populations.
Additional studies of the pathologic effects of HTLV-II are also needed. Systematic studies of neurologic disease among IVDU-associated and endemic HTLV-II cohorts should help to define better the prevalence and clinical spectrum of HTLV-II HAM, particularly in resolving whether it includes ataxia and other findings not associated with HTLV-I. Diagnosed cases of HTLV-II HAM should be studied to determine if HTLV-IIb as well as HTLV-IIa may be isolated, and the level of viral replication and immunologic response should be measured and compared to that in HTLV-I HAM. Regular hematologic surveillance of healthy HTLV-II seropositives is probably not indicated from a clinical standpoint, although in the context of a study, it could determine whether mild CD8+ lymphocytosis leads to other more serious conditions. Finally, preliminary findings that HTLV-II predisposes to bacterial pneumonia, soft tissue abscess, and lymphadenopathy among IVDU need to be replicated by other studies.
Acknowledgment: Dr. Murphy is a Fulbright Scholar and a Fogarty Senior International Fellow. This work was also partially supported by National Heart, Lung and Blood Institute Research Contracts HB-47114 and HB-57121.
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Proceedings of the VIIth International Conference on Human Retrovirology: HTLV