Virus markers associated with vertical transmission of human T lymphotropic virus type 1 in Jamaica.

In a prospective study involving 150 mothers and their offspring in Jamaica, we examined maternal viral factors associated with the risk of transmission of human T lymphotropic virus type 1 (HTLV-1). Overall, the incidence of HTLV-1 infection among children was 8.3 occurrences per 1000 person-months. A higher maternal provirus level (odds ratio [OR], 1.9 per quartile) and a higher HTLV-1 antibody titer (OR, 2.2 per quartile) were independently associated with transmission to children, whereas the presence of anti-Tax antibody was not. Higher maternal antibody titers also were associated with older age at infection among children who were breast-fed for

Chemokine receptor gene polymorphisms and risk of human T lymphotropic virus type I infection in Jamaica.

Polymorphisms of some chemokine receptor genes and their ligands are associated with susceptibility and progression of human immunodeficiency virus infection. This study assessed whether these variants are also responsible for susceptibility to infection with human T lymphotropic virus (HTLV) type I. Frequencies of CCR5-Delta 32, CCR2-64I, and SDF-1-3'A genotype among 116 HTLV-I-positive and 126 HTLV-I-negative persons of African descent in Jamaica were 1.0%, 14.9%, and 5.4%, respectively. The association of HTLV-I infection with the most common variant, CCR2-64I, was examined in 532 subjects. Thirteen (5.4%) of 241 HTLV-I-negative subjects were homozygous for CCR2-64I, versus 3 (1.0%) of 291 HTLV-I-positive subjects (P=.005). Among HTLV-I carriers, provirus load and antibody titer were not significantly different in persons with CCR2-+/64I or CCR2-+/+. These findings suggest that CCR2-64I, or alleles in linkage disequilibrium with it, may affect the risk of HTLV-I infection in a recessive manner.

Estimating the time of HTLV-I infection following mother-to-child transmission in a breast-feeding population in Jamaica

Mother-to-child transmission of human T-cell lymphotrophic virus type 1 (HTLV-I) is primarily due to prolonged breast-feeding (>6 months) in the post-natal period. Most infant infections are not identifiable until 12-18 months of age by available whole virus Western blot serologic tests because of their inability to distinguish passively transferred maternal antibody from infant antibody. We investigated two methods to assess more accurately the time of infant infection. In prospectively collected serial biospecimens, HTLV-I-specific immunoglobulin (Ig) isotypes of IgM and IgA were determined by Western blot and HTLV-I proviral DNA was detected by polymerase chain reaction (PCR). IgA and IgG reactivity was assessed in periodic serum samples from 16 HTLV-I-seropositive children while IgM reactivity was observed in 100 percent of children at 24 months of age and 73 percent of children at 6-12 months of age; however, this could represent maternal and not infant antibody. Both IgA and IgM reactivity were insensitive indicators of infection, with only 50 percent of children showing reactivity at 24 months of age. PCR testing was performed in biospecimens obtained from 11 of these children. An estimated median time of infection of 11.9 months was determined by PCR, which was similar to the median time to infection determined by whole virus Western blot (12.4 months; P=0.72). PCR Tests support a median time to infection that is similar to that estimated by whole virus Western blot. (AU)

Seroprevalence of human herpesvirus-8 (HHV-8) in countries of Southeast Asia compared to the USA, the Caribbean and Africa

Seroprevalence of HHV-8 has been studied in Malaysia, India, Sri Lanka, Thailand, Trinidad, Jamaica and the USA, in both healthy individuals and those infected with HIV. Seroprevalence was found to be low in these countries. In contrast, the African countries of Ghana, Uganda and Zambia showed high seroprevalences in both healthy and HIV-infected populations. This suggests that human herpes virus-8 (HHV-8) may be either a recently introduced virus or one that has extremely low infectivity. Nasopharyngeal and oral carcinoma patients from Malaysia, Hong Kong and Sri Lanka who have very high EBV titres to show that only 3/82 (3.7 percent) have antibody to HHV-8, demonstrating that there is little, if any, cross-relativity between antibodies to these two gamma viruses. (AU)

Adeno-associated virus and development of cervical neoplasia

Evidence from several sources has suggested that adeno-associated virus (AAV) infection might protect against cervical cancer, in part, by interfering with human papillomavirus (HPV)-induced tumorigenesis. Detection of AAV type 2 (AAV-2) DNA in cervical tissues has been reported. However, there have been few in vivo studies of women with cervical HPV infection or neoplasia, and these have reported inconsistent results. Therefore, we used polymerase chain reaction (PCR) assays targeted to the AAV-2 rep and cap genes to test tissue specimens from women in an epidemiological study of cervical neoplasia in Jamaica. We tested 105 women with low-grade cervical intraepithelial neoplasia (CIN-1), 92 women with CIN-3/carcinoma in situ or invasive cancer (CIN-3/CA), and 94 normal subjects. PCR amplification of human beta-globin DNA was found in almost all cervical specimens, indicating that these materials were adequate for PCR testing. The prevalence of HPV DNA, determined by HPV L1 consensus primer PCR was, as expected, strongly associated with presence and grade of neoplasia. Each of the AAV PCR assays detected as few as 10 copies of the virus genome. However, none of the 291 cervical specimens from Jamaican subjects tested positive for AAV DNA. Negative AAV PCR results were also obtained in tests of cervical samples from 79 university students in the United States. Exposure to AAV was assessed further by serology. Using a whole virus AAV-2 sandwich enzyme-linked immunosorbent assay, we found no relationship between AAV antibodies and presence or grade of neoplasia in either the Jamaican study subjects or women enrolled in a U.S. cervical cancer case (n = 74) - control (n = 77) study. Overall, the data provide no evidence that AAV infection plays a role in cervical tumorigenesis or that AAV commonly infects cervical epithelial cells.(Au)

HDV 16 antibody prevalence in Jamaica and the United States reflects differences in cervical cancer rates

Human papillomavirus (HPV) is widely accepted as the primary etiologic agent in the development of cervical cancer. DNA of a particular HPV type, HPV 16, is found in about half of tumors tested. Inconsistent with this causal relationship, however, population-based studies of HPV DNA prevalence have often failed to find high rates of anogenital HPV infection in countries with high cervical cancer rates. To examine this issue, we used serology to compare HPV 16 exposure in healthy volunteer blood donors in the United States (n = 278) and similar subjects from a country with 3-fold higher cervical cancer rates, Jamaica (n = 257). Jamaican sexually transmitted disease (STD) patients (n = 831) were also studied to examine in detail the relation of HPV 16 antibodies with sexual history. Serology was conducted using an ELISA employing HPV 16 virus-like particles (VLPs). Age-adjusted seroprevalence rates were greatest among male (29 percent) and female (42 percent) STD patients, intermediate in male (19 percent) and female (24 percent) Jamaican blood donors and lowest among male (3 percent) and female (12 percent) U.S. blood donors. The higher seroprevalence in women was significant, and prevalence tended to increase with age. In multivariate logistic regression, controlling for age and gender, Jamaican blood donors were 4.2-fold (95 percent CI 2.4 - 7.2) and STD patients 8.1-fold (95 percent CI 5.0 - 13.2) more likely to have HPV 16 VLP antibodies than U.S. blood donors. Among STD patients, HPV 16 antibodies were associated with lifetime number of sex partners and years of sexual activity, as well as other factors. Our data suggest that HPV 16 VLP antibodies are strongly associated with sexual behavior. Moreover, exposure to HPV 16 appears to be much greater in Jamaica than in the United States, consistent with the high rate of cervical cancer in Jamaica (Au)

Clinical, pathologic, and immunologic features of human T-lymphotropic virus type I- associated infective dermatitis in children

Objectives: To define the clinical and laboratory features associated with infective dermatitis (ID) and confirm its association with human T-lymphotropic virus type 1 (HTLV-I). Design: A case series of patients with ID were compared with patients with atopic dermatitis (AD) which is an important disease in the differential diagnosis of ID. Setting: Patients were recruited from dermatology and pediatric clinics at the University Hospital of the West Indies and the Bustamante Children's Hospital, Kingston, Jamaica. Main Outcome Measures: Clinical and laboratory features of patients with AD were compared with those of patients with ID. Patients: Consecutive patients older than 1« years diagnosed as having ID (n=50) and AD (n=35) were enrolled based on clinical findings. Results: The mean age of patients with ID and AD were 6.9 and 7.8 years, respectively. Histologically, both disease were predominantly chronic dermatitis... Conclusion: Infective dermatitis is a distinct clinical entity associated with HTLV-I, which plays a role in the pathogenesis and immune perturbations observed.(AU)

Human leukocyte antigen class II alleles associated with human T cell lymphotropic virus type I infection and adult T-vell leukemia/lymphoma in a black population

BACKGROUND: Human T-cell lymphotropic virus type I (HTLV-I) is linked to adult T-cell luekemia/lymphoma (ATL) and HTLV-I associated myelopathy (HAM; also known as tropical spastic paraparesis [TSP]), a chronic neurodegenerative disorder. Worldwide, several million HTLV-I carriers are at risk for disease, with an estimated lifetime cumulative risk of 1 percent-5 percent. However, the determinants of disease progression are relatively unknown. We studied human leukocyte antigens (HLA class II) that have been implicated in the pathogenesis of HTLV-I related diseases. METHODS: We analyzed HLA class II alleles among asymptomatic HTLV-I carriers (n = 45), patients with ATL (n = 49) or HAM/TSP (n = 54), and HTLV-I seronegative control subjects (n = 51). All participants were of African descent and were enrolled in epidemiologic studies conducted at the University of the West Indies, Kingston, Jamaica. We used standard microlymphocytotoxicity assays for HLA antigen serotyping and polymerase chain reaction-based methods to examine HLA class II DRB1 and DQB1 alleles. RESULTS: Two antigens determined by serotyping DR15 and DQ1, occurred at significantly increased frequency among HTLV-I carriers compared with seronegative control subjects (42 percent versus 22 percent for DR15 [odds ratio [OR] = 2.7; 95 percent confidence interval [CI] - 1.0-7.2] and 78 percent versus 53 percent for DQ1 [OR = 3.1; 95 percent CI= 1.2-8.5]). Asymptomatic carriers were shown to have and HLA class II allele distribution similar to that of patients with ATL, and the frequencies of the alleles DRB1*1501, DRB1*1101, and DQB1*0602 were significantly increased among patients with ATL compared with patients with HAM/TSP. CONCLUSIONS: These data suggest that host genetic background is an important factor in determining weather HTLV-I carriers develop either ATL or HAM/TSP.(AU)

Incidence of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Jamaica and Trinidad

HTLV-I is sexually transmitted more efficiently from men to women than vice versa, and the majority of HTLV-I endemic areas report a female preponderance of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) cases. The objective of this study was to estimate the gender and age specific incidence rates of HAM/TSP in the general population as well as in the HTLV-I-infected population in Jamaica and Trinidad and Tobago. Incidence rates for HAM/TSP were computed based on all reported incident cases in both countries between 1990 and 1994. Population cenus reports for 1990 were used to calculate the population at risk. The age-standardized HAM/TSP incidence rate (mean +/- standard error of the mean) in Jamaica was 1.8 +/- 0.2/100,000 person years (PY). Among individuals of African descent in Trinidad and Tobago, the rate was 1.7 +/- 0.4/100,000 PY. As in HTLV-I seroprevalence, the incidence rate of HAM/TSP increased with age through the fifth decade of life and was three time as high in women than in men. The HAM/TSP incidence rate, calculated as a function of the number of HTLV-I infection persons in each age stratum, is higher in women (24.7/100,000 PY) than in men 17.3/100,000 PY). With HTLV-I infection, the lifetime risk of developing HAM/TSP was estimated to be 1.9 percent overall and is slightly higher in women (1.8 percent) than in men (1.3 percent). Thus, the higher prevalence of HTLV-I in women in endemic areas does not fully explain the preponderance of female HAM/TSP, suggesting that other cofactors must be present. The higher incidence rate in women between the ages of 40 and 59 years, as well as the increase in HAM/TSP incidence rates with age, are indicative of the importance of adult-acquired HTLV-I infection, presumably through sexual transmission(AU)

Differential patterns of serum biomarkers of immune activation in human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis, and adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) and human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are associated with differing patterns of immune dysfunction. Biomarkers of immune activation may correlate with perturbations of immune function associated with these diseases. We conducted a pilot cross-sectionalstudy to assess four candidate biomarkers of immune activation, beta 2-microglobulin, neopterin, tryptophan, and kynurenine levels were assayed in storedsera from asymptomatic, human T-cell leukemia virus type I (HTL V-I) seronegative (HTLV-I-) and HTLV-I-seropositive (HTLV-I+) individuals, and ATL and HAM/TSP patients previously enrolled in seroepidemiological studies in Jamaica. Mean levels of beta 2-microglobulin, neopterin, and kynurenine were significantly elevated among ATL patients compared to the other study groups. Mean tryptophan levels were signigicantly lower among ATL and HAM/TSP patients than HTLV-I- and HTLV-I+ groups. No significant differences in biomarkers were found between HTLV-I- and HTLV-I+ groups. Among HAM/TSP patients, a significant association was found between elevated neopterin levels and symptoms of less than 4 years duration. In Cox proportional hazards regression modeling, neopterin and tryptophan were found to be independent predictors of survival among ATL patients. This study demonstrates a differential pattern of biomarkers of immune activation among ATL and HAM/TSP patients compared to HTLV-I- amd HTLV-I+ individuals. Neopterin and tryptophan may be useful clinical indicators of disease severity and prognosis among HAM/TSP and ATL patients. (AU)

Type-specific prevalence of human papillomavirus DNA among Jamaican colposcopy patients

Human papillomavirus (HPV) types differ in their associations with cervical cancer. Therefore, the types of HPV in precancerous lesions are important. In many regions with high cancer incidence, the HPV types in precancerous lesions have not been well studied. In Jamaica, a country that has high cervical cancer incidence, 174 colposcopy patients were tested for HPV DNA using polymerase chain reaction. HPV DNA detection was strongly related to presence and grade of cervical neoplasia (P<.001). Furthermore, severe neoplastic change was most highly associated with HPV DNA types also considered high-risk for severe neoplassia in other populations. HPV-45 DNA, a high-risk type uncommon in most previously tested countries, was detected in 12 percent of patients who had neoplasia. Thus, cervical neoplasia in Jamaica, as elsewhere, is linked to HPV. The high prevalence of HPV-45 DNA was notable, and its relation to high cervical cancer incidence in Jamaica must be assessed. (AU)

HLA DRBI *DQB1* haplotype in HTLV-I-associated familial infective dermatitis may predict development of HTLV-I-associated myelopathy/tropical spastic paraparesis

A possible causal association between infective dematitis and HTLV-I infection was reported familial infective dematitis (ID) occurring in a 26-year-old mother and her 9-year-old son. The mother was first diagnosed with ID in 1969 at the age of 2 years in the Dermatology Unit at the University Hospital of the West indies (U.H.W.I.) in Jamaica. The elder of her 2 sons was diagnosed with ID at the age of 3 years, also at U.H.W.I. Both mother and son are HTLV-I-seropositive. A second, younger son, currently age 2 years, is also HTLV-I-seropositive, but without clinical evidence of ID. Major hitocompatibility complex (MHC), class II, human leucocyte antigen (HLA) genotyping documented a shared class II haplotype, DRB*DQBI* (1101-0301), in the mother and her 2 sons. This same haplotype has been described among Japanese patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and has been associated with a possible pathologically heightened immune repsonse to HTLV-I infection. The presence of this haplotype in these familial ID cases with clinical signs of HAM/TSP may have contributed to their risk for development of HAM/TSP. The unaffected, HTLV-I seropositive younger son requires close clinical follow-up. (AU)

Radioimmunotherapy of interleukin-2R - expressing adult T-cell leukemia with yttrium-90-labeled anti-tac

Adult T-cell leukemia (ATL) is a malignancy of mature lumphocytes caused by the retrovirus human T-cell lymphotropic virus-I. It is an aggressive leukemia with a median survival time of 9 months: no chemotherapy regimen appears successful inducing long-term disease-free survival. The scientific basis of the present study is the ATL cells express high-affinity interleukin-2 receptors identified by the anti-Tac monoclonal antibody, whereas normal resting cells do not. To exploit this differnce, we administered anti-Tac armed with Yttrium-90 (Y) to 18 patients with ATL initially (first 9 patients) in a phase I dose-escalation trial and subsequently (second group of 9 patients) in a phase II trial involving a uniform 10-mCi dose of Y-labeled anti-Tac. Patients undergoing a remission were permitted to receive up to eight additional doses. At the 5-to 15-mCi doses used, 9 of 16 evaluable patients responded to Y anti-Tac with a partial (7 patients) or complete (2 patients) remission. The responses observed represent improved efficacy in terms of length of remission when compared with previous results with unmodified anti-Tac. Clinically meaningful (> grade 3) toxicity was largely limited to the hematopoietic system. In conclusion, radioimmunotherapy with Y anti-Tac directed toward the IL-2R expressed on ATL cells may provide a useful approach for treatment of this aggressive malignancy.(AU)

Risk factors and cofactors for human T-cell lymphotropic virus type 1 (HTLV-1) - associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Jamaica

Human T-cell lymphotrophic virus type 1 (HTLV-1) has been etiologically associated with a neurologic syndrome called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as with adult T-cell leukemia/lymphoma. The authors sought to quantify the risk in Jamaica of HAM/TSP associated with HTLV-1 infection and cofactors associated with this disease among infected individuals. Between 1988 and 1989, prevalent and incident HAM/TSP patients and controls with other neurologic diseases were enrolled in a retrospective study. A second control group was composed of HTLV-1-seropositive, asymptomatic carriers in Jamaica, ascertained in a separate study conducted in 1988. Although HTLV-1 seropositivity was not a component of the case definition for HAM/TSP, all 43 HAM/TSP patients were HTLV-1 seropsitive compared with two (4.0 percent) of the controls with other neurologic diseases. Given HTLV-1 seropositivity, one cofactor associated with the risk of HAM/TSP was young age at initial heterosexual intercourse (odds ratio = 4.00, 95 percent confidence interval 1.29-12.46 for individuals aged ó15; odds ratio = 4.26, 95 percent confidence interval 1.41-12.90 for individuals aged 16-17 years at initial intercourse). Among individuals who reported this early age at initial sexual intercourse, an increased risk of HAM/TSP was associated with having reported more than five lifetime sexual partners (odds ratio = 2.88, 95 percent confidence interval 0.90-8.70). Neither an early age at initial sexual intercourse nor the number of lifetime sexual partners was a risk factor for adult T-cell leukemia/lymphoma. These data support the hypothesis that HAM/TSP is associated with sexually acquired HTLV-1 infection, whereas adult T-cell leukemia/lymphoma is not. (AU)

Comparison of HHV-6 antibody titers in West Africa and the Caribbean

Human herpesvirus-6 (HHV-6) infections seems to be ubiquitous early in life, but antibody responses vary by geographic area. We compared HHV-6 antibody titer in 123 West African and 122 Caribbean serum samples. A quantitative immunofluorescence assay (IFA) using antigens derived from an HSB-2 cell line was used to test for IgG HHV-6 (GS strain) antibodies. The prevalence of HHV-6 antibodies was high (98 percent) in both sites. African samples had a significantly higher geometric mean titer (GMT: 697) than did Caribbean samples (GMT: 99). There was no difference between males (GMT: 260) and females (GMT: 270) overall. Children up to and including 9 years old had significantly higher titers (GMT: 483) than did all others (GMT: 237), and female children tended to have higher titers than did male children. In both areas there was a trend towards highest titer at younger age, followed by a decrease in titer in the oldest age group. Environmental and host factors may explain these geographic differences in antibody responses between two groups of African origin. (AU)

Patterns of HTLV-1 infection among family members of patients with adult T-cell leukemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraparesis - abstract

Human T-cell lymphotropic virus type 1 (HTLV-1) is strongly associated with both ATL and HAM/TSP. Only a small proportion of HTLV-1 infected individuals develop either of these diseases with lifelong risk estimates between 1 percent and 5 percent. ATL is believed to be related to early childhood infection via mother to child and HAM/TSP is thought to result from sexually or parenterally acquired infection in adulthood. Through the evaluation of HTLV-1 seroprevalence among family members of ATL and HAM/TSP patients we provide data that early life exposure is important for later development of ATL. Cases of ATV and HAM/TSP and their first degree relatives were enrolled in the study at the UWI, Jamaica, HTLV-1 seroprevalence rates were compared. We enrolled 25 ATL and 31 HAM/TSP families. All cases were HTLV-1 positive. Females accounted for 56 percent of ATL cases and 80 percent of HAM/TSP cases with mean ages of 43 and 49 respectively. The seroprevalence of HTLV-1 among mothers of ATL patients was 100 percent compared to 27 percent among mothers of HAM/TSP patients (p=0.0003). Among fathers of ATL subjects the seroprevalence was 80 percent vs 0 percent for HAM/TSP (p=0.05). The seroprevalence among all family members was 49 percent for ATL and 20 percent for HAM/TSP (p=0.0003). In contrast spouses ofHAM/TSP cases had a 86 percent seroprevalence compared to 57 percent among spouses of ATL cases. ATL and HAM/TSP evolve from distinct pathogenic pathways supported by differences in epidemiologic association. This premise is strongly supported by our observation that family members of ATL patients, particularly mothers have a significantly higher prevalence of HTLV-1 infection (AU)