Immunology/Infectious Disease Copyright (c) 2013 University of Massachusetts Medical School All rights reserved. http://escholarship.umassmed.edu/peds_immunology Recent documents in Immunology/Infectious Disease en-us Mon, 22 Apr 2013 08:56:42 PDT 3600 First-in-class small molecule inhibitors of the single-strand DNA cytosine deaminase APOBEC3G http://escholarship.umassmed.edu/peds_immunology/73 http://escholarship.umassmed.edu/peds_immunology/73 Fri, 08 Jun 2012 12:53:00 PDT APOBEC3G is a single-stranded DNA cytosine deaminase that comprises part of the innate immune response to viruses and transposons. Although APOBEC3G is the prototype for understanding the larger mammalian polynucleotide deaminase family, no specific chemical inhibitors exist to modulate its activity. High-throughput screening identified 34 compounds that inhibit APOBEC3G catalytic activity. Twenty of 34 small molecules contained catechol moieties, which are known to be sulfhydryl reactive following oxidation to the orthoquinone. Located proximal to the active site, C321 was identified as the binding site for the inhibitors by a combination of mutational screening, structural analysis, and mass spectrometry. Bulkier substitutions C321-to-L, F, Y, or W mimicked chemical inhibition. A strong specificity for APOBEC3G was evident, as most compounds failed to inhibit the related APOBEC3A enzyme or the unrelated enzymes E. coli uracil DNA glycosylase, HIV-1 RNase H, or HIV-1 integrase. Partial, but not complete, sensitivity could be conferred to APOBEC3A by introducing the entire C321 loop from APOBEC3G. Thus, a structural model is presented in which the mechanism of inhibition is both specific and competitive, by binding a pocket adjacent to the APOBEC3G active site, reacting with C321, and blocking access to substrate DNA cytosines.

]]> Ming Li et al. Cytidine Deaminase Enzyme Inhibitors Early age at time of primary Epstein-Barr virus infection results in poorly controlled viral infection in infants from Western Kenya: clues to the etiology of endemic Burkitt lymphoma http://escholarship.umassmed.edu/peds_immunology/72 http://escholarship.umassmed.edu/peds_immunology/72 Fri, 08 Jun 2012 12:52:59 PDT BACKGROUND: Infection with Epstein-Barr virus (EBV) early in life and repeated malaria exposure have been proposed as risk factors for endemic Burkitt lymphoma (eBL).

METHODS: Infants were enrolled from 2 rural sites in Kenya: the Kisumu District, where malaria transmission is holoendemic and risk for eBL is high, and the Nandi District, where malaria transmission is limited and the risk for eBL is low. Blood samples were taken from infants through 2 years of age to measure EBV viral load, EBV antibodies, and malaria parasitemia.

RESULTS: We observed a significantly younger age at time of primary EBV infection in children from Kisumu compared with children from Nandi (mean age, 7.28 months [±0.33 SEM] in Kisumu vs 8.39 months [±0.26 SEM] in Nandi), with 35.3% of children in Kisumu infected before 6 months of age. To analyze how different predictors affected EBV viral load over time, we performed multilevel mixed modeling. This modeling revealed that residence in Kisumu and younger age at first EBV infection were significant predictors for having a higher EBV viral load throughout the period of observation.

CONCLUSIONS: Children from a region at high risk for eBL were infected very early in life with EBV, resulting in higher viral loads throughout infancy.

]]> Erwan Piriou et al. Antibodies, Viral Burkitt Lymphoma Child, Preschool DNA, Protozoan DNA, Viral Epstein-Barr Virus Infections Female Geography Herpesvirus 4, Human Humans Infant Kenya Longitudinal Studies Malaria Male Parasitemia Viral Load Effect of therapeutic HIV recombinant poxvirus vaccines on the size of the resting CD4+ T-cell latent HIV reservoir http://escholarship.umassmed.edu/peds_immunology/71 http://escholarship.umassmed.edu/peds_immunology/71 Fri, 08 Jun 2012 12:52:58 PDT OBJECTIVES: Therapeutic HIV vaccinations may alter the size of the resting memory CD4 T-cell latent HIV reservoir as HIV establishes latency when memory responses are formed, including those toward HIV. Alternatively, latently infected CD4 T cells maybe killed, while exiting the reservoir upon activation.

METHODS: The effect of therapeutic immunization with modified vaccinia Ankara and Fowlpox-based HIV vaccines on the latent reservoir was examined in 19 young adults who were receiving effective antiretroviral therapy. Correlations between size of the reservoir [measured in infectious units per million (IUPM)] resting CD4 T cells and HIV-specific immune responses, including immune activation were examined. Decay of the reservoir was assessed using random-effects model.

RESULTS: A modest transient decrease in the size of the reservoir was observed at week 40 [mean -0.31 log(10) IUPM (95% confidence interval: -0.60 to -0.03; P = 0.03] following HIV vaccinations. The estimated half-life (T1/2) of the reservoir during the 40 weeks following vaccination was 9.8 months and statistically different from zero (P = 0.02), but 35.3 months and not different from zero (P = 0.21) over 72 weeks of study. Latent reservoir size at baseline was not correlated with HIV-specific CD4, CD8 responses or immune activation, but became correlated with CD4 IFNγ (r = 0.54, P = 0.02) and IL-2 responses at 6 weeks after immunization (r = 0.48, P = 0.04).

CONCLUSION: Therapeutic HIV vaccinations led to a transient increase in decay of latently infected CD4 T cells. Further studies of therapeutic HIV vaccines may provide important insights into facilitating decay of the latent reservoir.

]]> Deborah Persaud et al. AIDS Vaccines CD4-Positive T-Lymphocytes HIV Infections Humans Treatment Outcome Vaccination Vaccines, Synthetic Young Adult Pediatric HIV-1 infection: advances and remaining challenges http://escholarship.umassmed.edu/peds_immunology/70 http://escholarship.umassmed.edu/peds_immunology/70 Mon, 14 May 2012 13:18:48 PDT HIV-1 infection is one of the leading causes of childhood morbidity and mortality globally and mother-to-child transmission (MTCT) is the major mode of infection. Over the past decade, natural history and interventional studies have improved our understanding of the pathogenesis of MTCT and pediatric HIV-1 infection. This has resulted in the development of effective preventive strategies to reduce new infections and therapeutic strategies to improve outcome following infection. However, successful implementation of these preventive and therapeutic strategies has been limited in resource-poor settings, where the majority of new pediatric infections occur. In addition, toxicities and antiretroviral resistance may limit the long-term utility of currently available strategies. Continued efforts to understand MTCT and pediatric HIV-1 pathogenesis and to refine preventive and therapeutic strategies are of high priority.

]]> Katherine Luzuriaga et al. Adolescent Anti-HIV Agents Child Child, Preschool Female *HIV Infections *HIV-1 Humans Infant Infant, Newborn Infectious Disease Transmission, Vertical Pregnancy Pregnancy Complications, Infectious Reverse Transcriptase Inhibitors Efficacy model for antibody-mediated pre-erythrocytic malaria vaccines http://escholarship.umassmed.edu/peds_immunology/69 http://escholarship.umassmed.edu/peds_immunology/69 Mon, 14 May 2012 13:18:44 PDT Antibodies to the pre-erythrocytic antigens, circumsporozoite protein (CSP), thrombospondin-related adhesive protein (TRAP) and liver-stage antigen 1, have been measured in field studies of semi-immune adults and shown to correlate with protection from Plasmodium falciparum infection. A mathematical model is formulated to estimate the probability of sporozoite infection as a function of antibody titres to multiple pre-erythrocytic antigens. The variation in antibody titres from field data was used to estimate the relationship between the probability of P. falciparum infection per infectious mosquito bite and antibody titre. Using this relationship, we predict the effect of vaccinations that boost baseline CSP or TRAP antibody titres. Assuming the estimated relationship applies to vaccine-induced antibody titres, then single-component CSP or TRAP antibody-mediated pre-erythrocytic vaccines are likely to provide partial protection from infection, with vaccine efficacy of approximately 50 per cent depending on the magnitude of the vaccine-induced boost to antibody titres. It is possible that the addition of a TRAP component to a CSP-based vaccine such as RTS,S would provide an increase in infection-blocking efficacy of approximately 25 per cent should the problem of immunological interference between antigens be overcome.

]]> Michael T. White et al. Adult Antibodies, Protozoan Antigens, Protozoan Erythrocytes Female Humans Immunoglobulin G Kenya Malaria Vaccines Malaria, Falciparum Male *Models, Biological Plasmodium falciparum Protozoan Proteins Sporozoites Virologic and immunologic outcomes in HIV-infected Cambodian children after 18 months of highly active antiretroviral therapy (HAART) http://escholarship.umassmed.edu/peds_immunology/67 http://escholarship.umassmed.edu/peds_immunology/67 Mon, 14 May 2012 13:18:36 PDT This observational cohort study was conducted among HIV-infected, antiretroviral therapy (ART) naive children in Phnom Penh, Cambodia, to evaluate the feasibility and efficacy of highly active antiretroviral therapy (HAART) delivered using a modified directly observed therapy (MDOT) protocol. From August 2004 to March 2006, 26 children were enrolled and started on a first-line HAART regimen, which was continued for 18 months. The study included a directly observed therapy phase (months 1-3) and a medication self-administration phase (months 4-18). CD4 percentage (CD4%) and HIV-1 RNA plasma viral load (PVL) were measured at baseline and at months 6, 12, and 18. At baseline, the median age was 5.5 years (range: 13 months-12 years), the median CD4% was 4, and the median PVL was 7.5x10(5) copies/ml. At 18 months, 23 (88%) children were alive and participating in the study. Of these children, 20 (87%) had a PVL /ml and 12 (52%) had PVL < 50 copies/ml. The median CD4% increased to 23, while the median change in height-for-weight z-score was 0.64. Genotypic resistance typing in 2 children with PVL > 400 copies/ml at 18 months demonstrated mutations associated with resistance to lamivudine (M184V) and non-nucleoside reverse transcriptase inhibitors (Y181C and G190A). The virologic and immunologic outcomes achieved in this study compare favorably with those reported by other pediatric HIV treatment programs worldwide. The study results suggest that MDOT may be effective for HAART administration in limited-resource settings like Cambodia.

]]> Sam Sophan et al. Adolescent Anti-HIV Agents Antiretroviral Therapy, Highly Active CD4 Lymphocyte Count Cambodia Child Child, Preschool Cohort Studies Directly Observed Therapy Drug Resistance, Viral Female HIV Infections HIV-1 Human Growth Hormone Humans Infant Lamivudine Male Nevirapine Pilot Projects Stavudine Treatment Outcome Treatment with monoclonal antibodies against Clostridium difficile toxins http://escholarship.umassmed.edu/peds_immunology/66 http://escholarship.umassmed.edu/peds_immunology/66 Mon, 14 May 2012 13:18:32 PDT BACKGROUND: New therapies are needed to manage the increasing incidence, severity, and high rate of recurrence of Clostridium difficile infection.

METHODS: We performed a randomized, double-blind, placebo-controlled study of two neutralizing, fully human monoclonal antibodies against C. difficile toxins A (CDA1) and B (CDB1). The antibodies were administered together as a single infusion, each at a dose of 10 mg per kilogram of body weight, in patients with symptomatic C. difficile infection who were receiving either metronidazole or vancomycin. The primary outcome was laboratory-documented recurrence of infection during the 84 days after the administration of monoclonal antibodies or placebo.

RESULTS: Among the 200 patients who were enrolled (101 in the antibody group and 99 in the placebo group), the rate of recurrence of C. difficile infection was lower among patients treated with monoclonal antibodies (7% vs. 25%; 95% confidence interval, 7 to 29; P

CONCLUSIONS: The addition of monoclonal antibodies against C. difficile toxins to antibiotic agents significantly reduced the recurrence of C. difficile infection. (ClinicalTrials.gov number, NCT00350298.)

]]> Israel Lowy et al. Adult Aged Aged, 80 and over Antibodies Antibodies, Monoclonal Antitoxins Bacterial Proteins Bacterial Toxins Clostridium Infections *Clostridium difficile Diarrhea Double-Blind Method Drug Therapy, Combination Enterocolitis, Pseudomembranous Enterotoxins Female Humans Male Metronidazole Middle Aged Recurrence Vancomycin Young Adult Infectious mononucleosis http://escholarship.umassmed.edu/peds_immunology/65 http://escholarship.umassmed.edu/peds_immunology/65 Mon, 14 May 2012 13:18:28 PDT This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations. The case: A 16-year-old, previously healthy girl presents with a several-day history of fever, sore throat, and malaise. She appears very tired and has a temperature of 39°C. A physical examination is remarkable for diffuse pharyngeal erythema with moderately enlarged tonsils and the presence of several enlarged, tender anterior and posterior cervical lymph nodes. How should this case be managed?

]]> Katherine Luzuriaga et al. Adolescent Adrenal Cortex Hormones Antibodies, Viral Antiviral Agents Diagnosis, Differential Female *Herpesvirus 4, Human Humans *Infectious Mononucleosis Male Pharyngitis Streptococcal Infections Streptococcus pyogenes Impaired generation of hepatitis B virus-specific memory B cells in HIV infected individuals following vaccination http://escholarship.umassmed.edu/peds_immunology/64 http://escholarship.umassmed.edu/peds_immunology/64 Mon, 14 May 2012 13:18:24 PDT Hepatitis B-specific memory B cell (HSMBC) frequencies were measured following hepatitis B vaccination in 15 HIV uninfected and 12 HIV infected adolescents. HSMBC were detected at significantly lower frequencies in HIV infected than in HIV uninfected individuals. The detection of HBsAb >10mIU/ml at study week 28 was strongly associated with the detection of HSMBC and a direct correlation between HBsAb titers and HSMBC frequencies was observed. In HIV uninfected individuals, antibody titers >1000mIU/ml were associated with higher HSMC frequencies. Lower HSMBC frequencies, reduced memory B cell (MBC) proliferation, and altered B cell phenotypes were measured in viremic HIV infected individuals compared with aviremic HIV infected or HIV uninfected individuals.

]]> Nishaki Mehta et al. Adolescent B-Lymphocytes Cell Proliferation Female HIV Infections Hepatitis B Hepatitis B Antibodies Hepatitis B Surface Antigens Hepatitis B Vaccines Humans Immunologic Memory Longitudinal Studies Male Young Adult Identification of ongoing human immunodeficiency virus type 1 (HIV-1) replication in residual viremia during recombinant HIV-1 poxvirus immunizations in patients with clinically undetectable viral loads on durable suppressive highly active antiretroviral therapy http://escholarship.umassmed.edu/peds_immunology/63 http://escholarship.umassmed.edu/peds_immunology/63 Mon, 14 May 2012 13:18:21 PDT In most human immunodeficiency virus type 1 (HIV-1)-infected individuals who achieve viral loads of /ml during highly active antiretroviral therapy (HAART), low levels of plasma virus remain detectable for years by ultrasensitive methods. The relative contributions of ongoing virus replication and virus production from HIV-1 reservoirs to persistent low-level viremia during HAART remain controversial. HIV-1 vaccination of HAART-treated individuals provides a model for examining low-level viremia, as immunizations may facilitate virus replication and sequence evolution. In a phase 1 trial of modified vaccinia virus Ankara/fowlpox virus-based HIV-1 vaccines in 20 HIV-infected young adults receiving HAART, we assessed the prevalence of low-level viremia and sequence evolution, using ultrasensitive viral load (

]]> Carlum Shiu et al. Adult Anti-Retroviral Agents Antiretroviral Therapy, Highly Active CD4-Positive T-Lymphocytes CD8-Positive T-Lymphocytes Cohort Studies Female Genotype HIV Infections HIV-1 Humans Immunization Male Poxviridae Sequence Analysis, DNA Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy http://escholarship.umassmed.edu/peds_immunology/62 http://escholarship.umassmed.edu/peds_immunology/62 Mon, 14 May 2012 13:18:17 PDT BACKGROUND: With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r).

METHODS: A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m twice daily plus 2 nucleoside analogs in HIV-1-infected infants > or =14 days to /r therapy, and doses were modified to maintain LPV predose concentrations >1 microg/mL and area under the curve (AUC) /mL.

RESULTS: Ten infants enrolled [median age 5.7 (range, 3.6-5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7-7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246-305) mg/m q12 hours; median measures were AUC = 36.6 (range, 27.9-62.6) microg hr/mL; predose concentration = 2.2 (range, 0.99-4.9) microg/mL; maximum concentration = 4.76 (range, 2.84-7.28) microg/mL and apparent clearance (L/h/m) = 6.75 (range, 2.79-12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure.

CONCLUSIONS: Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.

]]> Ellen Gould Chadwick et al. Area Under Curve Drug Administration Schedule Female HIV Infections *HIV Protease Inhibitors effects HIV-1 Humans Infant Male *Pyrimidinones effects RNA, Viral *Ritonavir effects Treatment Outcome Viral Load On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis http://escholarship.umassmed.edu/peds_immunology/60 http://escholarship.umassmed.edu/peds_immunology/60 Mon, 14 May 2012 13:18:09 PDT Memory B cells latently infected with Epstein-Barr virus (mB(Lats)) in the blood disappear rapidly on presentation with acute symptomatic primary infection (acute infectious mononucleosis [AIM]). They undergo a simple exponential decay (average half-life: 7.5 +/- 3.7 days) similar to that of normal memory B cells. The cytotoxic T lymphocyte (CTL) response to immediate early (IE) lytic antigens (CTL(IEs)) also decays over this time period, but no such correlation was observed for the CTL response to lytic or latent antigens or to the levels of virions shed into saliva. We have estimated the average half-life of CTL(IEs) to be 73 (+/- 23) days. We propose that cycles of infection and reactivation occur in the initial stages of infection that produce high levels of mB(Lats) in the circulation. Eventually the immune response arises and minimizes these cycles leaving the high levels of mB(Lats) in the blood to decay through simple memory B-cell homeostasis mechanisms. This triggers the cells to reactivate the virus whereupon most are killed by CTL(IEs) before they can release virus and infect new cells. The release of antigens caused by this large-scale destruction of infected cells may trigger the symptoms of AIM and be a cofactor in other AIM-associated diseases.

]]> Vey Hadinoto et al. Acute Disease Cell Proliferation Cytotoxicity, Immunologic Herpesvirus 4, Human Immunologic Memory Infectious Mononucleosis Time Factors Lack of alternative coreceptor use by pediatric HIV-1 R5 isolates for infection of primary cord or adult peripheral blood mononuclear cells http://escholarship.umassmed.edu/peds_immunology/59 http://escholarship.umassmed.edu/peds_immunology/59 Mon, 14 May 2012 13:18:04 PDT HIV-1 infection of neonates results in an extended acute period of virus replication, frequent neurological problems and reduced survival compared to adults. In adults, R5 viruses mainly infect CCR5(+) CD4(+) memory T-cells. In neonates, CCR5(+) memory T-cells form a substantially smaller fraction of total lymphocytes. We therefore tested whether alternative coreceptors confer infection of lymphocytes by pediatric isolates. Pediatric HIV-1 R5 isolates failed to replicate in Delta32/Delta32 CCR5 PBMCs or in cord PBMCs treated with a CCR5 inhibitor. These results do not indicate a role for alternative coreceptors and provide support for CCR5 inhibitors in the therapy of HIV-1(+) neonates.

]]> W. Matthew Sullivan et al. HIV Infections HIV Reverse Transcriptase HIV-1 Humans Infant Infant, Newborn Leukocytes, Mononuclear Receptors, CCR5 Receptors, Virus *Virus Internalization Virus Replication Diminished human immunodeficiency virus type 1 DNA yield from dried blood spots after storage in a humid incubator at 37 degrees C compared to -20 degrees C http://escholarship.umassmed.edu/peds_immunology/58 http://escholarship.umassmed.edu/peds_immunology/58 Mon, 14 May 2012 13:18:00 PDT Collecting whole blood on filter paper simplifies the processing, transport, and storage of specimens used for the diagnosis of human immunodeficiency virus type 1 (HIV-1) and other tests. Specimens may be collected in tropical or rural areas with minimal facilities for handling specimens. To compare simulated tropical conditions with freezer storage, we examined the stability of HIV-1 DNA in dried blood spots (DBS) stored in humid heat and at -20 degrees C. DBS were created by spotting 50-microl aliquots of whole blood on 903 filter paper. DNA was extracted from DBS at baseline and after 2, 6, or 12 months of storage at -20 degrees C or at 37 degrees C with approximately 85% humidity. The DNA was tested undiluted or diluted using the Amplicor HIV-1 DNA PCR (Roche), version 1.5. Each reaction was scored positive, negative, or indeterminate based on optical density. Results were compared between storage conditions and over time. A total of 1,832 reactions from 916 DBS were analyzed, including 100 DBS at baseline, 418 stored at -20 degrees C, and 398 stored at 37 degrees C. A chi-square test showed fewer positive reactions for DBS stored at 37 degrees C (55%) than for those stored at -20 degrees C (78%) (P < 0.0001). Samples stored at -20 degrees C showed little change in the probability of detection of HIV-1 DNA over time; the odds ratio (OR) was 0.93 after storage for 1 year. Samples stored at 37 degrees C demonstrated a significant change in detection at 1 year (OR, 0.29). We conclude that exposure of DBS to 37 degrees C and high humidity impaired the recovery of HIV-1 DNA from DBS, whereas DNA recovery was preserved when DBS were stored frozen.

]]> Caroline Mitchell et al. *Cryopreservation DNA, Viral HIV-1 Hot Temperature Humans Humidity *Specimen Handling Safety and immunogenicity of recombinant poxvirus HIV-1 vaccines in young adults on highly active antiretroviral therapy http://escholarship.umassmed.edu/peds_immunology/57 http://escholarship.umassmed.edu/peds_immunology/57 Mon, 14 May 2012 13:17:55 PDT A trial to evaluate the safety and immunogenicity of recombinant modified vaccinia Ankara (MVA) and fowlpox (FP) vectors expressing multiple HIV-1 proteins was conducted in twenty HIV-1 infected youth with suppressed viral replication on HAART. The MVA and FP-based multigene HIV-1 vaccines were safe and well tolerated. Increased frequencies of HIV-1 specific CD4+ proliferative responses and cytokine secreting cells were detected following immunization. Increased frequencies and breadth of HIV-1 specific CD8 T-cell responses were also detected. Plasma HIV-1-specific antibody levels and neutralizing activity were unchanged following vaccination. Poxvirus-based vaccines may merit further study in therapeutic vaccine protocols.

]]> Thomas C. Greenough et al. AIDS Vaccines Adolescent *Antiretroviral Therapy, Highly Active CD4 Lymphocyte Count CD4-CD8 Ratio Cytokines Female Flow Cytometry Fowlpox virus Gene Products, gag HIV Antibodies HIV Infections HIV-1 Humans Interferon-gamma Male Prospective Studies RNA, Viral T-Lymphocytes Vaccines, Synthetic Vaccinia Young Adult Cytomegalovirus (CMV) IE1- and pp65-specific CD8+ T cell responses broaden over time after primary CMV infection in infants http://escholarship.umassmed.edu/peds_immunology/56 http://escholarship.umassmed.edu/peds_immunology/56 Mon, 14 May 2012 13:17:52 PDT Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in young children. We have previously shown that CD8+ T cell responses to CMV pp65 or IE1 protein were readily detectable in children with congenital or postnatal CMV infection. Here, we have further characterized the evolution of the peptide specificity of these responses in 7 infants(median, 5 peptides/infant) were targeted, and most (61%) represented sequences not previously reported. Peptide specificity remained stable or broadened over time despite the clearance of CMV viremia. Loss of peptide recognition was not observed. Responses with the highest functional peptide avidity were not necessarily detected earliest. These data provide additional evidence that young infants can generate diverse CMV-specific CD8+ T cell responses but show that early responses may exhibit relatively focused peptide specificity and lower peptide avidity.

]]> Laura L. Gibson et al. Alleles Amino Acid Sequence Antigens, Viral CD8-Positive T-Lymphocytes Cell Line Cohort Studies Cytomegalovirus Cytomegalovirus Infections Humans Immediate-Early Proteins Infant Leukocytes, Mononuclear Peptide Mapping Phosphoproteins Time Factors Viral Load Viral Matrix Proteins Viral Proteins Virologic response to potent antiretroviral therapy and modeling of HIV dynamics in early pediatric infection http://escholarship.umassmed.edu/peds_immunology/55 http://escholarship.umassmed.edu/peds_immunology/55 Mon, 14 May 2012 13:17:48 PDT BACKGROUND: Human immunodeficiency virus (HIV) infection in infancy features a persistently high viral load and elevated antiretroviral drug clearance rates, which pose significant therapeutic challenges to the clinician. Viral and cellular kinetic analyses performed in HIV-infected adults have yielded significant insights into the dynamic setting of this viral infection. Similar studies are needed in pediatric populations, in whom differing dynamics might translate into age-specific treatment approaches.

METHODS: Viral and cellular kinetic analyses were performed using a nonlinear mixed-effects model in a cohort of 48 infants 1-24 months of age enrolled in a trial of ritonavir-based highly active antiretroviral therapy (HAART).

RESULTS: Infected cell compartment kinetics were comparable with reported adult values, with no age-specific differences demonstrated--suggesting the ability to suppress viral replication in infants receiving HAART. Comparisons between 2 ritonavir dosing schedules revealed significant improvement in phase 1/2 decay constants in favor of the higher dose. A negative correlation was established between plasma RNA levels and phase 1 decay rates, which has worrisome implications for infant therapeutics given high infant pretreatment plasma virus levels.

CONCLUSIONS: Ritonavir-based HAART regimens in infancy result in HIV decay constants comparable to those reported in adults, without age-specific variability. Despite higher plasma HIV levels and CD4 lymphocyte counts in infancy, HAART can result in timely, effective control of viral replication.

]]> Paul Palumbo et al. Anti-HIV Agents Antiretroviral Therapy, Highly Active CD4 Lymphocyte Count HIV Infections HIV-1 Humans Infant Infant, Newborn RNA, Viral Ritonavir *Viral Load Virus Replication Influence of EBV on the peripheral blood memory B cell compartment http://escholarship.umassmed.edu/peds_immunology/54 http://escholarship.umassmed.edu/peds_immunology/54 Mon, 14 May 2012 13:17:44 PDT Peripheral blood memory B cells latently infected with EBV bear somatic mutations and are typically isotype switched consistent with being classical Ag-selected memory B cells. In this work, we performed a comparative analysis of the expressed Ig genes between large sets of EBV-infected and uninfected peripheral blood B cells, isolated from the same infectious mononucleosis patients, to determine whether differences exist that could reveal the influence of EBV on the production and maintenance of these cells. We observed that EBV(+) cells on average accumulated more somatic hypermutations than EBV(-) cells. In addition, they had more replacement mutations and a higher replacement-silent ratio of mutations in their CDRs. We also found that EBV occupies a skewed niche within the memory compartment, due to its exclusion from the CD27(+)IgD(+)IgM(+) subset, but this skewing does not affect the overall structure of the compartment. These results indicate that EBV impacts the mutation and selection process of infected cells but that once they enter memory they cannot be distinguished from uninfected cells by host homeostasis mechanisms.

]]> Tatyana A. Souza et al. Antigens, CD27 B-Lymphocytes Epstein-Barr Virus Infections Gene Expression *Genes, Immunoglobulin Herpesvirus 4, Human Humans Immunoglobulin D Immunoglobulin M *Immunologic Memory Molecular Sequence Data Mutagenesis Mutation *Virus Latency Characteristics and management of HIV-1-infected pregnant women enrolled in a randomised trial: differences between Europe and the USA http://escholarship.umassmed.edu/peds_immunology/53 http://escholarship.umassmed.edu/peds_immunology/53 Mon, 14 May 2012 13:17:40 PDT BACKGROUND: Rates of mother-to-child transmission of HIV-1 (MTCT) have historically been lower in European than in American cohort studies, possibly due to differences in population characteristics. The Pediatric AIDS Clinical Trials Group Protocol (PACTG) 316 trial evaluated the effectiveness of the addition of intrapartum/neonatal nevirapine in reducing MTCT in women already receiving antiretroviral prophylaxis. Participation of large numbers of pregnant HIV-infected women from the US and Western Europe enrolling in the same clinical trial provided the opportunity to identify and explore differences in their characteristics and in the use of non-study interventions to reduce MTCT.

METHODS: In this secondary analysis, 1350 women were categorized according to enrollment in centres in the USA (n = 978) or in Europe (n = 372). Factors associated with receipt of highly active antiretroviral therapy and with elective caesarean delivery were identified with logistic regression.

RESULTS: In Europe, women enrolled were more likely to be white and those of black race were mainly born in Sub-Saharan Africa. Women in the US were younger and more likely to have previous pregnancies and miscarriages and a history of sexually transmitted infections. More than 90% of women did not report symptoms of their HIV infection; however, more women from the US had symptoms (8%), compared to women from Europe (4%). Women in the US were less likely to have HIV RNA levels /ml at delivery than women enrolling in Europe, and more likely to receive highly active antiretroviral therapy, and to start therapy earlier in pregnancy. The elective caesarean delivery rate in Europe was 61%, significantly higher than that in the US (22%). Overall, 1.48% of infants were infected and there was no significant difference in the rate of transmission between Europe and the US despite the different approaches to treatment and delivery.

CONCLUSION: These findings confirm that there are important historical differences between the HIV-infected pregnant populations in Western Europe and the USA, both in terms of the characteristics of the women and their obstetric and therapeutic management. Although highly active antiretroviral therapy predominates in pregnancy in both settings now, population differences are likely to remain.

TRIAL REGISTRATION: NCT00000869.

]]> Marie-Louise Newell et al. Abortion, Spontaneous Adult Antiretroviral Therapy, Highly Active Cesarean Section Cohort Studies Europe Female Gestational Age HIV Infections HIV-1 Humans Infant, Newborn Infectious Disease Transmission, Vertical and numerical data Pregnancy Pregnancy Complications, Infectious Pregnancy Outcome Risk Factors United States Viral Load Population pharmacokinetics of lamivudine in human immunodeficiency virus-exposed and -infected infants http://escholarship.umassmed.edu/peds_immunology/52 http://escholarship.umassmed.edu/peds_immunology/52 Mon, 14 May 2012 13:17:35 PDT This study aimed to determine lamivudine disposition in infants and to construct an appropriate dose adjustment for age, given the widespread use of lamivudine for both the prevention of mother-to-child transmission of human immunodeficiency virus (HIV) and the treatment of HIV-infected infants. Using a pooled-population approach, the pharmacokinetics of lamivudine in HIV-exposed or -infected infants from four Pediatric AIDS Clinical Trials Group studies were assessed. Ninety-nine infants provided 559 plasma samples for measurement of lamivudine concentrations. All infants received combination antiretroviral therapy including lamivudine dosed at 2 mg/kg of body weight every 12 h (q12h) for the first 4 to 6 weeks of life and at 4 mg/kg q12h thereafter. Lamivudine's apparent clearance was 0.25 liter/h/kg at birth, doubling by 28 days. In the final model, age and weight were the only significant covariates for lamivudine clearance. While lamivudine is predominantly renally eliminated, the serum creatinine level was not an independent covariate in the final model, possibly because it was confounded by age. Inclusion of interoccasion variability for bioavailability improved the individual subject clearance prediction over the age range studies. Simulations based on the final model predicted that by the age of 4 weeks, 90% of infant lamivudine concentrations with the standard 2 mg/kg dose of lamivudine fell below the adult median concentration. This population pharmacokinetic analysis affirms that adjusting the dose of lamivudine from 2 mg/kg to 4 mg/kg q12 h at the age of 4 weeks for infants with normal maturation of renal function will provide optimal lamivudine exposure, potentially contributing to more successful therapy.

]]> Adriana H. Tremoulet et al. Anti-HIV Agents Area Under Curve Clinical Trials as Topic Creatinine Drug Administration Schedule Female HIV HIV Infections Humans Infant Infant, Newborn Lamivudine Male Meta-Analysis as Topic Metabolic Clearance Rate