Kenneth McIntosh

Evolution and transmission of stable CTL escape mutations in HIV infection

Increasing evidence indicates that potent anti-HIV-1 activity is mediated by cytotoxic T lymphocytes (CTLs); however, the effects of this immune pressure on viral transmission and evolution have not been determined. Here we investigate mother–child transmission in the setting of human leukocyte antigen (HLA)-B27 expression, selected for analysis because it is associated with prolonged immune containment in adult infection. In adults, mutations in a dominant and highly conserved B27-restricted Gag CTL epitope lead to loss of recognition and disease progression. In mothers expressing HLA-B27 who transmit HIV-1 perinatally, we document transmission of viruses encoding CTL escape variants in this dominant Gag epitope that no longer bind to B27. Their infected infants target an otherwise subdominant B27-restricted epitope and fail to contain HIV replication. These CTL escape variants remain stable without reversion in the absence of the evolutionary pressure that originally selected the mutation. These data suggest that CTL escape mutations in epitopes associated with suppression of viraemia will accumulate as the epidemic progresses, and therefore have important implications for vaccine design.

The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children

The relationship between exacerbations of wheezing and infection of the respiratory tract was studied prospectively in 32 young hospitalized asthmatic children. Of 139 episodes of wheezing, 58 (42 per cent) were associated with identifiable viral infections. There were 25 respiratory syncytial virus infections; wheezing occurred in 24 of these and pneumonia in 13. Parainfluenza type 2 infection appeared to be next most likely to be associated with wheezing, followed by coronavirus infection. Influenza A. (Hong Kong) was not associated with wheezing in any of the children. Infection with “pathogenic” bacteria was not statistically associated with wheezing.

Cytomegalovirus Infection and HIV-1 Disease Progression in Infants Born to HIV-1–Infected Women

Background and Methods Cytomegalovirus (CMV) has been implicated as a cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We assessed 440 infants (75 of whom were HIV-1–infected and 365 of whom were not) whose CMV status was known, who were born to HIV-1–infected women, and who were followed prospectively. HIV-1 disease progression was defined as the presence of class C symptoms (according to the criteria of the Centers for Disease Control and Prevention [CDC]) or CD4 counts of less than 750 cells per cubic millimeter by 1 year of age and less than 500 cells per cubic millimeter by 18 months of age.

Immune Escape Precedes Breakthrough Human Immunodeficiency Virus Type 1 Viremia and Broadening of the Cytotoxic T-Lymphocyte Response in an HLA-B27-Positive Long-Term-Nonprogressing Child

ABSTRACT The emergence of cytotoxic T-lymphocyte (CTL) escape mutations in human immunodeficiency virus type 1 (HIV-1) proteins has been anecdotally associated with progression to AIDS, but it has been difficult to determine whether viral mutation is the cause or the result of increased viral replication. Here we describe a perinatally HIV-infected child who maintained a plasma viral load of <400 copies/ml for almost a decade until a nonbinding escape mutation emerged within the immunodominant CTL epitope. The child subsequently experienced a reemergence of HIV-1 viremia accompanied by a marked increase in the number of CTL epitopes targeted. This temporal pattern suggests that CD8 escape can play a causal role in the loss of immune control.

A Multicenter Trial of Oral Zidovudine in Children with Advanced Human Immunodeficiency Virus Disease

BACKGROUND AND METHODS Zidovudine has been shown to be an effective antiretroviral treatment in adults with human immunodeficiency virus (HIV) infection. We examined the safety of zidovudine and the tolerance of and therapeutic response to the drug in 88 children with advanced HIV disease. During a 24-week outpatient trial, zidovudine (180 mg per square meter of body-surface area per dose) was given by mouth every six hours and serial measurements were made of clinical, immunologic, and virologic indexes. Children who completed 24 weeks of treatment were permitted to continue receiving zidovudine. RESULTS Of the 88 children (mean age, 3.9 years; range, 4 months to 11 years), 61 completed the initial 24-week trial, and 49 continued to receive zidovudine for up to 90 weeks (median follow-up, 56 weeks). The patients generally tolerated zidovudine well. One or more episodes of hematologic toxicity occurred in 54 children (61 percent)--anemia (hemoglobin level, less than 75 g per liter) in 23 children (26 percent) and neutropenia (neutrophil count, less than 0.75 x 10(9) per liter) in 42 (48 percent). Many of these abnormalities resolved spontaneously, but 30 children required transfusions or a modification of the dose of zidovudine. Only three children had to stop receiving the drug because of hematologic toxicity. Kaplan-Meier analysis demonstrated that the probability of survival was 0.89 after 24 weeks and 0.79 after 52 weeks. There was marked improvement in weight gain, cognitive function (mainly in children less than 3 years old), serum and cerebrospinal fluid concentrations of p24 antigen, and the proportion of cerebrospinal fluid cultures negative for HIV. CD4+ lymphocyte counts (mean at base line, 0.263 x 10(9) per liter) improved during the first 12 weeks, although the improvement was not sustained through the 24th week. CONCLUSIONS Zidovudine in a dose of 180 mg per square meter every six hours can be safely administered to children with advanced HIV disease. The resultant clinical, immunologic, and virologic improvements in children are similar to those reported with zidovudine in adults.

Long-Term Effectiveness of Highly Active Antiretroviral Therapy on the Survival of Children and Adolescents with HIV Infection: A 10-Year Follow-Up Study

BACKGROUND Previous observational studies found highly active antiretroviral therapy (HAART) to be associated with improved survival among human immunodeficiency virus (HIV)-infected children and adolescents. However, these studies had limited follow-up of HIV-infected children undergoing HAART. Given that HIV infection is chronic and that exposure to HAART is likely to be life-long, there is a need to evaluate the long-term effect of HAART on survival in this population. METHODS The study included 1236 children and adolescents who were perinatally infected with HIV, who were on study or enrolled after January 1996 in a United States-based multicenter prospective cohort study (Pediatric AIDS Clinical Trials Group 219/219C), and who were not receiving HAART at baseline; subjects were observed for a maximum of 10 years through June 2006. A weighted Cox regression model was used to estimate the effect of HAART on survival, appropriately adjusted for time-varying confounding by severity. RESULTS At the end of the 10-year follow-up period (median duration of follow-up, 6.3 years; interquartile range, 4.3-9.8 years), 70% of participants had initiated HAART. Lower CD4 cell percentages, total lymphocyte counts, and albumin levels were associated with an increased probability of initiating HAART. Eighty-five deaths were observed, and the mortality hazard ratio associated with HAART, compared with non-HAART regimens, was 0.24 after adjusting for measured confounding by severity (95% confidence interval, 0.11-0.51). CONCLUSIONS The use of HAART was highly effective in reducing mortality during the period 1996-2006 among children and adolescents infected with HIV. With improved long-term survival, continued follow-up is necessary to evaluate the effects of prolonged use of HAART on potential adverse events, immune function, growth, sexual maturation, and quality of life in this population.

Apnea associated with respiratory syncytial virus infection in young infants

The hospital charts of 274 infants under 6 months of age with culture-proved respiratory syncytial virus infections were reviewed. Fifty-six infants (20.4%) demonstrated apnea in association with RSV infection. Predisposing factors significantly correlated with apnea included premature birth and young chronologic age at the time of virus infection. The clinical implications of this association are discussed.

Enterovirus infections in neonates

Twenty-seven ill neonates with enterovirus infections were studied to learn if enterovirus infection can be distinguished from neonatal sepsis. Enterovirus infection was associated with the summer-fall season (93%), recent maternal illness (59%), absence of other perinatal problems (81%), and findings of fever (93%), viral meningitis (62%), diarrhea (81%), and rash (41%). Four children developed thrombocytopenia and three necrotizing enterocolitis. Three children died, all with Coxsackie B virus infections that likely were acquired in utero. Although no single feature is pathognomonic, this constellation of epidemiologic and clinical findings, coupled with negative bacterial cultures, should suggest the possibility of neonatal enterovirus infection.

Coronaviruses: A Comparative Review

The coronaviruses have been recently classified as a separate virus genus on the basis of several fundamental characteristics, which include their nucleic acid type, the presence of a lipid envelope, and, in particular, their distinctive morphology (Tyrrell et al., 1968a). Members of the genus infect a number of different animal species, and until their reclassification were considered to belong to the myxovirus group although they possessed many atypical features. It was through detailed studies of their morphology in negatively stained preparations that they were finally differentiated and set out as a separate genus. When properly prepared, Coronavirus particles appear medium-sized, round, and moderately pleomorphic, and bear characteristic widely-spaced club-shaped surface projections. Coronaviruses naturally infect man, chickens, pigs, mice and rats, causing a wide variety of disorders involving a number of different organ systems. Indeed, new species are being added at frequent intervals as the techniques of electron microscopy and modern virology are applied to diseases which have often been clinically recognized for decades. A tentative scheme of the Coronavirus genus is shown in Table 1, with a listing of serotypes and strains. The list of types is not complete, but those of importance to this review are shown.

Left Ventricular Structure and Function in Children Infected With Human Immunodeficiency Virus The Prospective P2C2 HIV Multicenter Study

BACKGROUND The frequency of, course of, and factors associated with cardiovascular abnormalities in pediatric HIV are incompletely understood. METHODS AND RESULTS A baseline echocardiogram (median age, 2.1 years) and 2 years of follow-up every 4 months were obtained as part of a prospective study on 196 vertically HIV-infected children. Age- or body surface area-adjusted z scores were calculated by use of data from normal control subjects. Although 88% had symptomatic HIV infection, only 2 had CHF at enrollment, with a 2-year cumulative incidence of 4.7% (95% CI, 1.5% to 7.9%). All mean cardiac measurements were abnormal at baseline (decreased left ventricular fractional shortening [LV FS] and contractility and increased heart rate and LV dimension, mass, and wall stresses). Most of the abnormal baseline cardiac measurements correlated with depressed CD4 cell count z scores and the presence of HIV encephalopathy. Heart rate and LV mass showed significantly progressive abnormalities, whereas FS and contractility tended to decline. No association was seen between longitudinal changes in FS and CD4 cell count z score. Children who developed encephalopathy during follow-up had depressed initial FS, and FS continued to decline during follow-up. CONCLUSIONS Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. Dilated cardiomyopathy (depressed contractility and dilatation) and inappropriate LV hypertrophy (elevated LV mass in the setting of decreased height and weight) were noted. Depressed LV function correlated with immune dysfunction at baseline but not longitudinally, suggesting that the CD4 cell count may not be a useful surrogate marker of HIV-associated LV dysfunction. However, the development of encephalopathy may signal a decline in FS.