Polymorphisms in CCR5 chemokine receptor gene in Japan.

Mutations in the human CC chemokine receptor 5 (CCR5) gene may alter the expression or function of the protein product, thereby altering chemokine binding/signalling or human immunodeficiency virus type 1 (HIV-1) infection of the cells that normally express CCR5 protein. We performed a systematic survey of natural sequence variations in an 8.1-kb region of the entire CCR5 gene as well as CCR2V64I in 50 Japanese subjects and evaluated the effects of those variations on CCR5 promoter activity. We also analysed CCR5 promoters and CCR2V64I in 80 more Japanese and 186 Thais. There was no 32-bp deletion observed in Caucasians, but two types of non-synonymous substitutions were found in CCR5 genes of Japanese. Our results showed several novel characteristics of the CCR2-CCR5 haplotype structure that were not reported from studies on Caucasians and African-Americans. Specifically, we were able to show that the G allele at position -2852 from the CCR5 open reading frame in Japanese and Thais is the representative of the CCR5 promoter haplotype that was reported to be associated with rapid progression to acquired immune deficiency syndrome (AIDS) in HIV-1-infected individuals. Furthermore, nearly all non-synonymous polymorphisms in Japanese CCR5 occurred in haplotypes with elevated promoter activity. We thus hypothesized that there was a certain selective pressure favouring low levels of CCR5 expression during human evolution.

A three-base-deletion polymorphism in the upstream non-coding region of human interleukin 7 (IL-7) gene could enhance levels of IL-7 expression.

Interleukin 7 (IL-7) is a key factor in the survival, development and proliferation of B and T lymphocytes. Elevation of plasma IL-7 has been reported in several lymphopenia cases such as HIV-1 patients. After patients started to receive antiretroviral drugs and their CD4(+) cell counts had recovered, IL-7 in plasma decreased to normal levels. There are considerable variations in the levels of plasma IL-7 as well as the rate of CD4(+) T-cell restoration. Although pre-treatment plasma IL-7 levels have been shown to be prognostic for the rate of post-treatment CD4(+) T-cell restoration, the mechanisms responsible for the variations in plasma IL-7 and rate of CD4(+) T-cell restoration are still completely unknown. In the study here, we searched for genetic polymorphisms that might affect levels of IL-7 gene expression. For this purpose, we used 1658-bp PCR-amplified fragments of the IL-7 gene containing 1470 bp of the upstream non-coding region obtained from 151 Japanese and 234 Thai subjects. We found two novel human genetic polymorphisms in the upstream non-coding region of the IL-7 gene. The luciferase reporter assay demonstrated that one of those polymorphisms could increase the gene expression of IL-7. We speculate that this polymorphism, a three base ATC deletion just upstream of an out-of-frame ATG codon in the upstream non-coding region of the IL-7 gene, reduces the efficiency of translation from the upstream, out-of-frame ATG, resulting in increased translation efficiency from the authentic ATG of IL-7. Although the frequency of this allele is very low, it would be interesting to analyse this polymorphism in HIV-1-infected individuals with different rates of immune reconstitution after treatment with a highly active antiretroviral therapy.

Clinical disease associated with HIV-1 subtype B' and E infection among 2104 patients in Thailand.

BACKGROUND: Two HIV-1 envelope subtypes have accounted for virtually all infections in Thailand: subtype B' (Thai B), found mainly in injection drug users (IDU), and subtype E, found in over 90% of sexually infected persons and an increasing proportion of IDU in recent years. It remains unclear whether there are differences in pathogenesis associated with these HIV-1 subtypes. METHODS: From November 1993 to June 1996, demographic, risk, clinical, and laboratory data were collected by enhanced surveillance from HIV-infected inpatients (> or =14 years) at an infectious disease hospital near Bangkok. HIV-1 subtype was determined by V3-loop peptide enzyme immunoassay (EIA). Because of confounding, multivariate analyses were stratified by risk category and controlled for sex and age. RESULTS: The infecting HIV-1 subtype was determined for 2104 (94.9%) of 2217 HIV-infected patients with complete data: 284 (13.5%) were subtype B', 1820 (86.5%) were E. Specimens from 113 (5.1%) patients were non-reactive or dually reactive on peptide EIA and were excluded. Among IDU, 199 (67.2%) had subtype B', and 97 (32.7%) had E. IDU accounted for 70.1% (199/284) of patients with subtype B' and 5.3% (97/1820) of those with E. Patients infected with HIV-1 subtypes B' or E had similar spectrums of opportunistic infections (OI), levels of immunosuppression, and in-hospital mortality rates. Of patients who did not inject drugs, more patients infected with subtype E had extrapulmonary cryptococcosis than those with subtype B' (adjusted odds ratio, 2.6; 95% confidence interval, 1.28-5.37). CONCLUSION: HIV-1 subtypes B' and E seem to be associated with similar degrees of immunosuppression and, with one exception, with similar OI patterns. These data do not suggest an association between HIV-1 subtype and differences in pathogenicity.

Role of maternal humoral immunity in vertical transmission of HIV-1 subtype E in Thailand.

The significance of the maternal humoral immune response in relation to vertical transmission of HIV-1 was investigated in 123 mothers infected with subtype E from Thailand. Antibody binding titers to HIV-1 env domains (monomeric gp120, the CD4/gp120 binding site [BS], V3 loop, and gp41) and antibody-mediated neutralization of primary and T-cell line-adapted (TCLA) subtypes B and E HIV-1 isolates were investigated. No correlation between maternal anti HIV-1 antibodies at delivery and vertical transmission of HIV-1 subtype E was found. However, a trend to higher titer antibody-mediated cross-neutralization of a heterologous subtype B TCLA isolate, HIV-1MN, was observed in nontransmitting mothers postpartum. The HIV-1-specific antibody titers in these infected mothers increased significantly from delivery to 6 months postpartum (p < .05), but this was only partially attributable to hemodilution and an additional factor or factors appear to affect humoral immunity to HIV-1 during late pregnancy.

Clinical presentation of hospitalized adult patients with HIV infection and AIDS in Bangkok, Thailand.

OBJECTIVE: To characterize the clinical spectrum of disease and immune status of adult HIV-1-infected patients in Bangkok. DESIGN: Cross-sectional survey of hospital admissions. METHODS: From November 1993 through June 1996, demographic, clinical, and laboratory data were collected from HIV-infected inpatients (> or =14 years old) at an infectious diseases hospital. RESULTS: Of 16,717 persons admitted, 3112 (18.6%) were HIV-seropositive, 2261 of whom were admitted for the first time. Of 2261, 1926 (85.2%) were male, 1942 (85.9%) had been infected heterosexually or by means not related to drug use, 319 (14.1%) were injection drug users (IDUs), and 1553 (68.7%) had AIDS. The most common AIDS-defining conditions were extrapulmonary cryptococcosis (EPC; 38.4%), tuberculosis (TB; 37.4%), and wasting syndrome (WS; 8.1%). IDUs were more likely (p < .05) to have TB or WS but less likely (p < .05) to have EPC or Pneumocystis carinii pneumonia than patients with no history of injection drug use. Lymphocyte counts were measured for 2047 (90.5%) patients; 81.8% had < or =1500 lymphocytes/microl. CONCLUSION: These HIV-infected patients were admitted with severe immunosuppression. Cryptococcosis and TB are major problems and differ in prevalence among IDUs and persons infected sexually. Clinical and immunologic information is critical in improving the lives of HIV-infected persons in Asia through prevention, treatment, and prophylaxis.

Characterization of sera from subjects infected with HIV-1 subtypes B and E in Thailand by antibody binding and neutralization.

The range and specificity of the humoral immune response to HIV-1 subtypes B and E was investigated in Thai samples. Sera from HIV-1-positive subjects, consisting of subtypes B (n = 24) and E (n = 138), were characterized in relation to the neutralization of primary isolates and T-cell line-adapted (TCLA) strains and binding to monomeric gp120, the CD4/gp120 binding site (BS), and V3 peptides. A subtype-specific pattern of antibody binding was observed with the exception of the CD4/gp 120MN BS. Neutralization of TCLA strains (n = 4) was strongly type-specific (p = .002); however, neutralization of primary isolates (n = 8) was weak and group specific. Thus, the subtype specificity of B and E sera in the neutralization of TCLA strains, but not primary isolates, supports the dominance of the V3 region in TCLA virus neutralization but does not support the distinction of subtypes B and E as discrete neutralization serotypes in Thailand.

PIP: The range and specificity of the humoral immune response to HIV-1 subtypes B and E were investigated in sera and plasma collected from 168 infected patients from Thailand in 1990-94. Specifically, samples were examined for the presence of binding antibody to env regions within monomeric gp120, the CD4/gp120 binding site, and the V3 domain as well as neutralizing antibodies to T-cell line-adapted (TCLA) and primary HIV-1 isolates from subtypes B and E. A subtype-specific pattern of antibody binding was observed with the exception of the CD4/gp120MN binding site. Although neutralization of TCLA strains was highly type-specific, neutralization of primary isolates was weak and group-specific. This finding supports the dominance of the V3 region in TCLA virus neutralization but fails to confirm the distinction of subtypes B and E as discrete neutralization serotypes in Thailand.

The reference range of CD4+ and CD8+ T-lymphocytes in healthy non-infected infants born to HIV-1 seropositive mothers; a preliminary study at Siriraj Hospital.

The results of CD4+, CD8+ T-lymphocyte values as percentage, number, and ratio were studied in infants aged 1 to 29 months. The 283 subsequent blood samples from 89 infants born to HIV-1 seropositive mothers were investigated. From 208 sequential samples of 70 healthy non-infected infants, the reference values of CD4+ and CD8+ T-lymphocytes have been established and compared to Caucasian reference values. The results were analysed in 4 difference age groups (1-5, 6-11, 12-17 and > or = 18 months). At age 12 months, CD4 number and percentage declined significantly while CD8 percent increased. At age 6 months CD4/CD8 ratio decreased. Of 19 infected infants CD4+ percentage and number as well as CD4/CD8 ratio declined at age 6 months and showed significant differences from uninfected infants. A significantly elevated CD8 percentage was demonstrated in infected infants at age of 12 months. In 9 infants who showed symptoms at age 6-18 months, the CD4 and CD8 values were different from the reference range and 6 of 9 patients showed lower CD4 percentage, CD4 number and reversed CD4/CD8 ratio before the symptoms appeared. In 10 infants who were asymptomatic at age 18 months, there was no evidence of immunosuppression at age 6 months or before. After age 6 months, lymphocyte subset values of some asymptomatic infected children were beyond the reference range. These preliminary findings should be very useful for monitoring children born to HIV infected mothers. The results of CD4+ and CD8+ T-lymphocytes in uninfected infants could be used as reference values for the Thai and other Southeast Asian pediatric populations.

Nontyphoidal Salmonella diarrhea in Thai children: a study at Bamrasnaradura Hospital, Nonthaburi, Thailand.

From July 1, 1994 to June 30, 1996, 394 children with Nontyphoidal Salmonella diarrhea were studied at Bamrasnaradura Infectious Disease Hospital in Thailand. The ages ranged from 1 month to 12 years (mean, 1.4 years). Eighty-seven per cent of patients were in the first 2 years of life. Diarrhea, mostly acute with watery stool and fever were the most common presenting symptoms. The duration of diarrhea ranged from 1 to 20 days (mean, 5.2 days). Salmonella group B was the most common serogroup (56.1%). Most isolates were multiresistant strains, however, they were all sensitive to norfloxacin. Four (1%) patients were HIV-infected. Pneumonia found in 2 patients (0.5%) and septicemia in 1 patient (0.3%). None of the patients died. We conclude that nontyphoidal Salmonella diarrhea in children is still endemic in Thailand, especially among infants and high multidrug resistance occurs.

Seroprevalence of human herpesvirus 6 and 7 infections in the Thai population.

Seroprevalence of human herpesvirus 6 (HHV-6) and 7 (HHV-7) was estimated in the Thai population using indirect immunofluorescence assay to determine serum antibodies to HHV-6 and HHV-7. A total of 333 serum samples obtained from umbilical cord blood and venous blood of healthy persons at Siriraj Hospital and Krabi Hospital during 1990-1993 were investigated. Of 73 infants aged 0-1 month, 73% and 78% were found tob e positive for HHV-6 and HHV-7 antibodies, respectively. Antibody to HHV-6 was detected in age groups 2-3 months (38%), 4-5 months (14%), 6 months (44%), 7-11 months (66%), 1-2 year (84%), 3-4 years (82%), 5-9 years (83%), 10-19 years (83%), 20-29 years (80%), 30-39 years (67%), and over 40 years (58%), respectively. This positive rates of HHV-7 antibody in age groups 2-3 months, 4-5 months, 6 months, 7-11 months, 1-2 years, 3-4 years, 5-9 years, 10-19 years, 21-29 years, 30-39 years, and over 40 years were 50%, 21%, 10%, 37%, 47%, 82%, 75%, 72%, 72%, 67%, and 67%, respectively. At 6 months of age as the starting time of infections, 34% (14/41) and 9% (3/41) of infants had presumed primary infections of HHV-6 and HHV-7, respectively. In the follow-up study, 53% (20/38) of children were infected with HHV-6 prior to HHV-7 and only 5% vice versa. Eighty-four percent of children had acquired antibody to HHV-6 by 1-2 years old while 82% of children had acquired antibody to HHV-7 by 3-4 years old. These results suggest that HHV-6 and HHV-7 are prevalent viruses in the Thai population. The infections of both viruses begin at 6 months of age. However, infection of HHV-7 in most children begins later. The data also provided evidence that antigenic distinction between HHV-6 and HHV-7 existed with a limited cross-reactivity in an antibody test. The antibody responses to HHV-6 and HHV-7 occurred independently.

Group C rotavirus infections in patients with diarrhea in Thailand, Nepal, and England.

Atypical rotavirus obtained from fecal specimens of six patients with diarrhea from Thailand, Nepal, and England were characterized by using polyacrylamide gel electrophoresis and immune electron microscopy. The electropherotypes were characteristic of the porcine reference group C rotavirus strain but demonstrated considerable strain-to-strain variation. Human convalescent group C sera had a high titer (1:320) when tested against the human isolates and a low titer (1:40) when tested against a porcine reference strain (Cowden). When porcine antiserum (Cowden) was tested against the human isolates, the titers ranged from 1:40 to 1:320, indicating significant antigenic diversity between strains. Group C rotavirus appears to have a worldwide distribution as an agent associated with diarrhea in children and adults.