Human leucocyte antigen supertypes and immune susceptibility to HIV-1, implications for vaccine design.

T cell responses against HIV-1 have been identified in a number of exposed uninfected populations. We hypothesized that the ability to mount an effective T cell response is partly determined by the human leucocyte antigens (HLA) phenotype of the individual. We examined whether certain HLA supertypes were associated with differential HIV-1 susceptibility in sexually exposed adults and in the setting of mother to child HIV-1 transmission. By multivariate analysis, decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related class I HLA alleles (A2/6802 supertype) in sexually exposed adults (Hazard ratio=0.42, 95% confidence intervals (CI): 0.22-0.81, P=0.009) and perinatally exposed infants (Odds ratio=0.12, 95% CI: 0.03-0.54, P=0.006). The alleles in this HLA supertype are known in some cases, to present the same peptide epitopes (termed 'supertopes'), for T cell recognition. The identification of HIV-1 supertopes, which are associated with protection from HIV-1 infection, has important implications for the application of epitope-based HIV-l vaccines in a variety of racial groups.

The HLA A2/6802 supertype is associated with reduced risk of perinatal human immunodeficiency virus type 1 transmission.

Certain HLAs may, in part, account for differences in human immunodeficiency virus type 1 (HIV-1) susceptibility by presenting conserved immunogenic epitopes for T cell recognition. The HLA supertype A2/6802 is associated with decreased susceptibility to HIV-1 among sex workers. The alleles in this supertype present the same HIV-1 peptide epitopes for T cell recognition in some cases. This study sought to determine whether the HLA A2/6802 supertype influenced HIV-1 transmission in a prospective cohort of HIV-1-infected mothers and children in Kenya. Decreased perinatal HIV-1 infection risk was strongly associated with possession of a functional cluster of related HLA alleles, called the A2/6802 supertype (odds ratio, 0.12; 95% confidence interval, 0.03-0.54; P=.006). This effect was independent of the protective effect of maternal-child HLA discordance. These data provide further evidence that HLA supertypes are associated with differential susceptibility to HIV-1 transmission.

Sociodemographic characteristics, care, feeding practices, and growth of cohorts of children born to HIV-1 seropositive and seronegative mothers in Nairobi, Kenya.

UNLABELLED: OBJECTIVES To compare sociodemographic profiles, child care, child feeding practices and growth indices of children born to HIV-1 seropositive and seronegative mothers. METHODS: A cohort study of 234 children (seropositive and seronegative) born to HIV-1 seropositive mothers and 139 children born to seronegative mothers in Pumwani Maternity Hospital which serves a low-income population in Nairobi, Kenya from December 1991 and January 1994. RESULTS: With few exceptions, at the time of their birth children in all three cohorts had parents with similar characteristics, lived in similar housing in similar geographical areas, had their mothers as their primary care givers, had similar feeding practices and similar growth status and patterns. However, the HIV-1 seropositive mothers were slightly younger (23.8 years vs. 25.0 years, P < 0.01), if married they were less likely to be their husband's first wife (79% vs. 91%, P = 0.02) and more likely to have a one-room house (75% vs. 63%, P = 0.04). All three cohorts had mean Z-scores in length-for-age and in weight-for-height within the normal range (>/= 2.0 Z-scores) from birth to 21 months with the exception of the length-for-age of the seropositive children at the 18-month visit. In all cohorts length-for-age became more compromised than weight-for-length, dropping to about -1.45 Z-score by 21 months; in contrast, weight-for-length dropped to about -0.5 Z-score by this age. The only statistically significant differences in growth indices among the three cohorts were between the two cohorts of seronegative children: those with seronegative mothers were less compromised in length-for-age at 1.5 months (mean Z-score = -0.19 vs. -0.48, P < 0.05) and more compromised in weight-for-length at 6 months (mean Z-score = 0.10 vs. 0.45, P < 0.05) and at 18 months (mean Z-score = -0.73 vs. -0.16, P < 0.05). 27-34% were exclusively breastfed at 1.5 months; 52-61% consumed solid foods in addition to breast milk by 2.5 months. CONCLUSIONS: Low-income HIV-1 seropositive- and seronegative-born children were from families with similar characteristics and similar housing environments. Similar growth patterns in the cohorts suggest that the challenging environment and the choice of weaning foods had an impact on all three cohorts. The aggressive care given the children with HIV-1 seropositive mothers and their children may have reduced the progression and impact of HIV-1 disease on the growth of the seropositive children. Further research is needed to corroborate our findings to be certain that our results are not affected by loss to follow-up bias: we lost the same proportion in all three cohorts but cannot verify that the children we lost had the same growth patterns as those who remained in the study.

Effect of human immunodeficiency virus (HIV) type 1 viral genotype on mother-to-child transmission of HIV-1.

The objective of this study was to determine whether the maternal infecting human immunodeficiency virus (HIV) type 1 clade affects mother-to-child transmission frequency. Mothers in the mother-to-child HIV-1 transmission study in Nairobi, Kenya, were grouped by HIV-1 status of their first enrolled child: uninfected, perinatally infected, or postnatally infected. Restriction fragment length polymorphism (RFLP) analysis was used to determine HIV-1 viral clades of nested polymerase chain reaction products from HIV-1 protease or p24 genes. When inconclusive, sequencing determined the clade. Clade distributions within the groups were compared. The 3 groups displayed a uniform clade distribution. The predominant clades were A (59%) and D (20%). Clades B, C, F, mixed, and recombinant infections comprised the remainder (21%). No significant association was seen between clades A and D and either frequency or mode of vertical transmission. RFLP analysis revealed 2 clade B infections, 9 mixed, and 5 p24/protease recombinant infections in the study population.

Risk factors for postnatal mother-child transmission of HIV-1.

OBJECTIVE: To identify factors affecting HIV-1 breastfeeding transmission. DESIGN: Longitudinal observational cohort study. METHODS: HIV-1 seropositive pregnant women and seronegative controls were enrolled at a maternity hospital in Nairobi. Women and their children were followed from birth, and data on HIV-1 transmission, breastfeeding, clinical illness, and growth were collected. Specimens for HIV-1 serology and/or polymerase chain reaction were obtained at birth, 2, 6, and 14 weeks, 6, 9, 12, and 18 months, and every 6 months thereafter. Children were classified as HIV-1 uninfected, perinatally, or postnatally infected. Potentially breastfeeding transmission related risk factors were compared between postnatally infected and uninfected children. RESULTS: Among children born to seropositive or seroconverting mothers, 317 were uninfected, 51 infected perinatally and 42 infected postnatally. Identified risk factors for postnatal transmission were maternal nipple lesions (OR = 2.3, CI 95% 1.1-5.0), mastitis (OR = 2.7, CI 95% 1.1-6.7), maternal CD4 cell count < 400 mm3 (OR = 4.4, CI 95% 1.9-9.9), maternal seroconversion while breastfeeding (OR = 6.0, CI 95% 1.8-19.8), infant oral thrush at < 6 months of age (OR = 2.8, CI 95% 1.3-6.2) and breastfeeding longer than 15 months (OR = 2.4, CI 95% 1.2-5.1). All factors, except maternal seroconversion due to its rarity, were independently associated with an increased postnatal transmission risk by multivariate logistic regression analysis. CONCLUSION: In addition perinatal antiretroviral therapies, public health strategies should address: (i) prevention of maternal nipple lesions, mastitis and infant thrush; (ii) reduction of breastfeeding duration by all HIV-1-infected mothers; (iii) absolute avoidance of breastfeeding by those at high risk, and (iv) prevention of HIV-1 transmission to breastfeeding mothers.

Anti-HLA alloantibody is found in children but does not correlate with a lack of HIV type 1 transmission from infected mothers.

Searching for mechanisms of natural resistance to HIV infection with which to guide HIV vaccine design, we have examined antibody responses to HLA class I antigens in children of HIV-1-infected mothers. Anti-HLA antibodies are known to block HIV infectivity in vitro and can be protective against SIV challenge in macaques immunized with purified class I HLA. It was hypothesized that alloantibody to maternal HLA in children might contribute to the prevention of mother-to-child transmission of HIV-1. In fact, a surprisingly high proportion of the children examined, 22%, were found to have antibody against class I alloantigens. This alloantibody, however, did not correlate with the HIV status of the children and was found in a similar proportion of children of HIV-negative mothers. The HLA specificity of the antibody was not correlated with noninherited maternal HLA alleles and occurred with a higher frequency in older children. This result suggests environmental factors, rather than exposure to maternal cells, are involved in the formation of the alloantibody. The finding that anti-allo-class I HLA antibodies are not associated with a decreased risk of mother-to-child transmission indicates that this humoral immune response is unlikely to be the natural mechanism that accounts for the lack of transmission observed in many births. This result, however, does not preclude the further investigation of cellular alloimmune responses, or the use of alloimmunization as an artificial HIV immunization strategy.

Nasopharyngeal pneumococcal colonization among Kenyan children: antibiotic resistance, strain types and associations with human immunodeficiency virus type 1 infection.

OBJECTIVES: To compare pneumococcal nasopharyngeal colonization rates among HIV-1-infected children with those of uninfected children born to seropositive mothers and those of seronegative controls. To determine the predominant serotypes and antimicrobial susceptibility among pneumococcal isolates in Kenya. METHODS: Nasopharyngeal pneumococcal colonization was examined in 207 children recruited from the Perinatal HIV-1 Transmission Study conducted in Nairobi, Kenya. Colonization was compared among HIV-1-infected children, uninfected children born to seropositive mothers and control seronegative children. Isolates were serotyped and tested for antibiotic susceptibility to penicillin, tetracycline, erythromycin, chloramphenicol, clindamycin and rifampin. RESULTS: Colonization was higher among HIV-1-infected and uninfected children than among controls only when associated with respiratory illnesses (86% of 7 and 60% of 20 vs. 29% of 31, P = 0.004). No differences were observed when children were asymptomatic (20% of 35, 35% of 94 and 22% of 101). Intermediate penicillin resistance was found in 60% of 94 isolates, 28% were resistant to tetracycline and all isolates were susceptible to the other antibiotics tested. Sixteen serotypes were identified, with 13, 15, 14, 6B and 19F comprising 73% of isolates. Serotype 13 was found in 31% of colonized children. This serotype and 2 others isolated are not found in the current 23-valent polysaccharide vaccine. Overall 41% of colonized children harbored nonvaccine strains. CONCLUSIONS: Although nasopharyngeal pneumococcal colonization was high among children with respiratory illness born to HIV-1-seropositive mothers, increased asymptomatic colonization did not explain the increased risk of invasive pneumococcal disease associated with HIV-1 infection. Intermediate penicillin resistance was common but high level penicillin and multiple antibiotic resistance were not seen. The prevalence of the unique strains circulating in this region will need to be considered in the design of effective pneumococcal vaccines for use in East Africa.

Analysis of neonatal T cell and antigen presenting cell functions.

Neonates are more susceptible to infection than adults and exhibit more intense or prolonged clinical symptoms. The extent to which deficiencies in T cell or antigen presenting cell (APC) function underlie hyporesponsiveness is incompletely understood. Here, immune function of cord blood mononuclear cells (CBMC), from healthy, full-term neonates was compared with adult PBMC. As widely reported, polyclonally-stimulated T cell proliferation was found to be equivalent, while IFN gamma responses were markedly lower amongst neonates. Reasoning that such stimuli may elicit responses qualitatively different from those that would be obtained following MHC-dependent, cognate T cell activation, alloantigen-specific responses were evaluated. Strikingly, neonates exhibited IFN gamma, IL-4 and IL-10 production equal to adults in short term primary culture. Both the frequency (Fisher's p < 0.0004) and intensity (< 7.5 vs 36.5 pg/ml; Wilcoxon P = 0.005) of alloantigen stimulated IL-5 responses were elevated among neonates, a finding equally evident using irradiated adult or neonatal cells as stimulators. Finally, the relative capacity of neonatal APC as stimulators of cytokine synthesis was assessed by a novel approach using CBMC as both responders and stimulators in MLR. Irradiated neonatal cells consistently stimulated similar proliferative but substantially lower IFN gamma responses than did adult APC, independent of responder origin. The data argue; (i) T cells are largely immunocompetent at birth, (ii) accessory cell function is not fully mature, and (iii) the widely observed hyporesponsiveness to pathogenes may be primarily due to immaturity of APC function or costimulator molecule expression.

Romanian adoption. The Manitoba experience.

OBJECTIVE: To study the developmental, behavioral, and medical features in a cohort of Romanian children adopted by Manitoba families. DESIGN: A prospective longitudinal study. SETTING: The Child Development Clinic, Children's Hospital, Winnipeg, Manitoba, from September 1990 to June 1992. PATIENTS: Developmental, behavioral, and medical features were assessed in 22 Romanian children adopted by 18 Manitoba families. RESULTS: Mean (+/- SD) age at adoption was 15.5 +/- 13 months. Mean (+/- SD) age at initial assessment was 19 +/- 12 months and at follow-up, 35 +/- 13 months. Medical complications included 6 children (27%) who were positive for the hepatitis B surface antigen, 5 with intestinal parasites (23%), 1 positive for the human immunodeficiency virus, 1 with rickets (5%), and 1 with monoplegia and cleft palate (5%). Initial growth parameters were less than the fifth percentile for age for head circumference in 10 children (45%), for weight in 8 (36%), and for height in 7 (32%). At follow-up, statistically significant improvement was seen in height and weight. Initial mean (+/- SD) developmental quotients were 82 +/- 20 for gross motor, 83 +/- 23 for fine motor, 83 +/- 19 for cognitive, and 79 +/- 18 for language domains. Follow-up mean developmental quotients improved in all domains (P < .05). Twelve children (55%) displayed abnormal behavior at the initial assessment; behavioral findings persisted in 8 (36%). Initial appropriate activity level and play behavior predicted normal cognitive outcome (P < .05). CONCLUSIONS: This longitudinal study of Romanian adoptees delineates improvements in growth and development once the children are placed in a nurturing environment. The persistence of abnormal behavior in some children underscores the importance of further follow-up.

Acceptability and usefulness of vaginal washes in premenarcheal girls as a diagnostic procedure for sexually transmitted diseases. The Child Protection Centre at the Winnipeg Children's Hospital.

OBJECTIVE: To assess the suitability of vaginal washes as specimens for sexually transmitted disease diagnosis and determine the usefulness of PCR technology for Chlamydia trachomatis diagnosis in prepubertal girls. STUDY DESIGN: Paired sets of vaginal secretions were collected with swabs and by vaginal wash from 138 prepubertal girls for evaluation because of alleged sexual abuse. Detection by culture of Neisseria gonorrhoeae and C. trachomatis was compared between the two sampling techniques. PCR techniques were also used to test 29 vaginal wash specimens for C. trachomatis. RESULTS: In the prepubertal girls N. gonorrhoeae was detected in two wash specimens but in only one swab specimen; C. trachomatis was detected by culture in both paired specimens from two children and by PCR in vaginal washes from both of the two children positive by culture; PCR identified two other infected children. CONCLUSIONS: A vaginal wash technique coupled with newer molecular amplification technology may be useful in the assessment of sexually abused children.

Prostaglandin F2 alpha output by amnion-chorion-decidua: relationship with labor and prostaglandin E2 concentration at the amniotic surface.

OBJECTIVE: Our purpose was to evaluate prostaglandin F2 alpha output at fetal membrane surfaces relative to labor and to assess amniotic prostaglandin E2 concentration changes on prostaglandin F2 alpha output. STUDY DESIGN: Intact and separated fetal membranes from 10 elective cesarean sections and nine vaginal deliveries were incubated in double-sided perfusion chambers. Prostaglandin F2 alpha and 13,14-dihydro-15-keto-prostaglandin F2 alpha output was measured by radioimmunoassay. Alterations of prostaglandin F2 alpha and 13,14-dihydro-15-keto-prostaglandin F2 alpha output were assessed after exogenous prostaglandin E2 addition at amniotic surfaces of intact membranes. RESULTS: Prostaglandin F2 alpha concentration was higher at maternal surfaces of intact but not separated membranes after labor (p = 0.0001). Amniotic 13,14-dihydro-15-keto-prostaglandin F2 alpha was increased in association with preceding labor (p = 0.038). Addition of prostaglandin E2 at the amniotic surface did not alter prostaglandin F2 alpha or 13,14-dihydro-15-keto-prostaglandin F2 alpha production. CONCLUSION: Prostaglandin F2 alpha concentration at the maternal surface of fetal membranes likely plays a critical role in induction or maintenance of myometrial contractions associated with term labor independent of amniotic fluid prostaglandin E2 concentrations.

Transmission of Ureaplasma urealyticum from mothers to full and preterm infants.

This study assessed maternal genital colonization and subsequent neonatal transmission rate of Ureaplasma urealyticum in pregnant women in an average socioeconomic population. In addition very low birth weight infants were assessed to determine whether the presence of U. urealyticum correlated with increased risk of developing respiratory problems. The study group consisted of 108 sequential full term mothers and 104 preterm mothers delivering in a tertiary care hospital in central Canada. The genital carriage rates (assessed using placental sampling) of ureaplasmas in term and preterm mothers were 25.9 and 19.2%, respectively (P = 0.3185). Acquisition of ureaplasmas in the neonatal respiratory tract of neonates occurred significantly (P = 0.0182) more often in preterm neonates (11 of 130; 8.5%) than in term neonates (2 of 110; 0.9%). Very low birth weight (VLBW) infants (< or = 1500 g) were at greater risk (P = 0.042) of acquiring ureaplasmas in their respiratory tracts (5 of 26; 19%) than larger preterm neonates (6 of 104; 5.8%). All VLBW infants with respiratory colonization by ureaplasmas (5 of 5) developed bronchopulmonary dysplasia compared with 33% (7 of 21) of VLBW neonates without ureaplasmas (P = 0.028). This difference in bronchopulmonary dysplasia development among VLBW infants was independent of further stratification by birth weight. These VLBW neonates with ureaplasmas also stayed significantly (P = 0.037) longer in the neonatal intensive care unit (43.6 +/- 10.4 days) than did other preterm neonates (22.1 +/- 20.8 days). Our results demonstrate that VLBW preterm neonates have increased risk of acquiring U. urealyticum.(ABSTRACT TRUNCATED AT 250 WORDS)

Pediatric gonococcal infection: case report demonstrating diagnostic problems in remote populations.

The inability of Neisseria gonorrhoeae to survive prolonged transit times and hostile ambient temperatures has made its detection at referral laboratories by cultural methods untenable. In this situation, reliance upon antigen detection systems is attractive but when these tests are performed on vaginal specimens from children, false positive results are a significant concern. Some of the difficulties associated with the investigation of a gonococcal infection resulting from sexual abuse of a child in an isolated community are illustrated in this report.

The duration of breastfeeding by HIV-1-infected mothers in developing countries: balancing benefits and risks.

How best to advise mothers infected with human immunodeficiency virus type 1 (HIV-1) in developing countries regarding breastfeeding is an important issue that has generated considerable debate. Previous studies have addressed this problem by means of mathematical models, but without considering the issue of the duration of breastfeeding. A mathematical model was developed to compare the age-specific risks of mother-to-child HIV transmission versus the excess mortality due to not breastfeeding. In this model it is assumed that both the risk of mother-to-child transmission of HIV through breast milk and the relative risk of not breastfeeding do not vary with age. The model indicates that, in HIV-1-seropositive mothers, the decrease in child mortality afforded by breastfeeding may exceed the risk of mother-to-child HIV-1 transmission only during the first 3-7 months of life. Thereafter the risk of HIV-1 transmission probably exceeds the mortality benefit of breastfeeding. Experimental studies of counselling HIV-1-infected mothers to limit their duration of breastfeeding should be considered in the setting of developing countries.

Mother-to-child transmission of human immunodeficiency virus type 1: report from the Nairobi Study.

Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) is a significant problem in countries with endemic HIV-1 infection. Between 1986 and 1991, 365 children of HIV-1-infected mothers and 363 control children were studied in Kenya. The overall risk of transmission from mother to child, determined by serologic evidence of infection by age > or = 12 months and excess mortality in the HIV-1-exposed group, was 42.8% (range, 27.6%-62.2%). Marriage was the only maternal characteristic associated with transmission (odds ratio, 2.2; 95% confidence interval, 1.2-4.2; P < .05). Children who experienced growth failure were more likely to be infected. In 44% of children ultimately infected, the pattern of antibody response implied intrapartum or postnatal exposure to HIV-1. Of potential postnatal exposures examined, duration of breast-feeding beyond age 15 months and the mother being married were independently associated with increased risk of infection and seroconversion of children. The percentage of HIV infection attributable to breast-feeding > or = 15 months was 32%. The frequency of mother-to-child transmission of HIV-1 was high; a substantial proportion of infection occurred postnatally, possibly through breast-feeding.

Human immunodeficiency virus type 1 IgA antibody in breast milk and serum.

Breast-feeding plays a potentially significant role in mother to child transmission of human immunodeficiency virus type 1 (HIV-1). The additional transmission risk attributable to breast-feeding and the factors that enhance or inhibit transmission are presently unknown. One mechanism by which breast milk might inhibit HIV-1 transmission is the presence of specific antibodies directed against HIV-1 in breast milk of seropositive mothers. In this study serum and breast milk samples from women in Nairobi, Kenya, were tested to determine the prevalence of HIV-1 IgA antibodies. A Western blot test developed in our laboratory was used to detect anti-HIV-1 immunoglobulin A in serum and anti-HIV-1 secretory IgA (sIgA) in breast milk. Ninety-four percent of 63 HIV-1 seropositive women had anti-HIV-1 IgA in serum and 59% had anti-HIV-1 sIgA in their breast milk. No significant associations with maternal characteristics or serum anti-HIV-1 IgA or IgG banding patterns and the presence of anti-HIV-1 sIgA in breast milk were found. No protective effect of anti-HIV-1 sIgA was seen regarding mother to child transmission; however, further studies are necessary to determine the effect of these antibodies in maternal sera or in breast milk on the efficacy of HIV-1 transmission.

Throat colonization of neonatal nursery staff by Ureaplasma urealyticum: An infection control or occupational health consideration?

Very low birth weight infants often have protracted respiratory tract colonization with Ureaplasma urealyticum. To determine whether prolonged contact with very low birth weight infants resulted in higher rates of upper respiratory tract colonization with this organism for caregivers, throat swabs for U urealyticum culture were obtained from medical, nursing and other support staff working in the neonatal intensive care and level II nurseries at the Health Sciences Centre and the St Boniface Hospital in Winnipeg, Manitoba. Throat colonization by U urealyticum was demonstrated in 7.3% (95% ci 0 to 15.6%) of 41 nurses working in the intensive care nurseries but in none of the 48 nurses working in other locations or the 66 other individuals tested (P=0.02). However, throat colonization was not significantly higher among the neonatal intensive care nurses than among the women delivering at one of the study institutions. Close contact with very low birth weight infants appears to constitute a minimal risk for increased throat colonization with U urealyticum among hospital staff members.

Streptococcus pneumoniae: A cause of primary lung abscess in a child.

A case of primary pneumococcal lung abscess in a five-year-old child is described. Secondary anaerobic infection as a cause of cavitation was excluded by bronchoscopic culture of the cavity. Streptococcus pneumoniae is a rare but recognized cause of lung abscess in healthy children.