Immunodeficiency Virus Infection In Infants Research Articles

Functional Perturbation of Mucosal Group 3 Innate Lymphoid and Natural Killer Cells in Simian-Human Immunodeficiency Virus/Simian Immunodeficiency Virus-Infected Infant Rhesus Macaques.

Mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) via breastfeeding is responsible for nearly half of new infections of children with HIV. Although innate lymphoid cells (ILC) and natural killer (NK) cells are found throughout the oral mucosae, the effects of HIV/simian-human immunodeficiency virus (SHIV) in these tissues are largely unknown. To better understand the mechanics of postnatal transmission, we performed a comprehensive study of simian immunodeficiency virus (SIV)/SHIV-infected infant rhesus macaques (RM) and tracked changes in frequency, trafficking, and function of group 3 ILC (ILC3) and NK cells using polychromatic flow cytometry and cell stimulation assays in colon, tonsil, and oral lymph node samples. Infection led to a 3-fold depletion of ILC3 in the colon and an increase in the levels of NK cells in tonsils and oral lymph nodes. ILC3 and NK cells exhibited alterations in their trafficking repertoires as a result of infection, with increased expression of CD103 in colon NK cells and curtailment of CXCR3, and a significant decrease in α4β7 expression in colon ILC3. SPICE analyses revealed that ILC3 and NK cells displayed distinct functional profiles by tissue in naive samples. Infection perturbed these profiles, with a nearly total loss of interleukin-22 (IL-22) production in the tonsil and colon; an increase in the levels of CD107a, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) from ILC3; and an increase in the levels of CD107a, macrophage inflammatory protein 1 beta (MIP-1β), and TNF-α from NK cells. Collectively, these data reveal that lentivirus infection alters the frequencies, receptor repertoires, and functions of innate cells in the oral and gut mucosa of infants. Further study will be required to delineate the full extent of the effect that these changes have on oral and gut homeostasis, SHIV/SIV pathogenesis, and oral opportunistic disease.IMPORTANCE Vertical transmission of HIV from mother to child accounts for many of the new cases seen worldwide. There is currently no vaccine to mitigate this transmission, and there has been limited research on the effects that lentiviral infection has on the innate immune system in oral tissues of infected children. To fill this knowledge gap, our laboratory studied infant rhesus macaques to evaluate how acute SIV/SHIV infections impacted ILC3 and NK cells, which are immune cells critical for mucosal homeostasis and antimicrobial defense. Our data revealed that SIV/SHIV infection led to a depletion of ILC3 and an increase of NK cells and to a functional shift from a homeostatic to a multifunctional proinflammatory state. Taking the results together, we describe how lentiviral infection perturbs the oral and gastrointestinal mucosae of infant macaques through alterations of resident innate immune cells giving rise to chronic inflammation and potentially exacerbating morbidity and mortality in children living with HIV.

Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model.

To achieve long-term viral remission in human immunodeficiency virus (HIV)-infected children, novel strategies beyond early antiretroviral therapy (ART) will be necessary. Identifying clinical predictors of the time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and the potential risks of treatment interruption. To facilitate the identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral simian-human immunodeficiency virus (SHIV) SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or after ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we monitored SHIV replication and rebound kinetics in infant and adult RMs and found that both infants and adults demonstrated equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of the time to viral rebound, namely, the pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to preclinically assess novel therapies to achieve a pediatric HIV functional cure.IMPORTANCE Novel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children, who currently rely on lifelong ART. Considering the risks and expense associated with ART interruption trials, the identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant nonhuman primate models of HIV rebound. In this study, we developed an infant RM model of oral infection with simian-human immunodeficiency virus expressing clade C HIV Env and short-term ART followed by ATI, longitudinally characterizing the immune responses to viral infection during ART and after ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of the time to viral rebound after ATI.

Higher Exposure to Household Air Pollution Is Associated With Acute Lower Respiratory Illness in Human Immunodeficiency Virus-Infected Kenyan Infants

Higher Exposure to Household Air Pollution Is Associated With Acute Lower Respiratory Illness in Human Immunodeficiency Virus-Infected Kenyan Infants

High Viremia and Wasting Before Antiretroviral Therapy Are Associated With Pneumonia in Early-Treated HIV-Infected Kenyan Infants.

Human immunodeficiency virus (HIV)-infected children are particularly susceptible to acute respiratory infections (ARIs). We determined incidence and cofactors for ARIs in HIV-infected infants receiving antiretroviral therapy (ART). Human immunodeficiency virus-infected infants initiated ART at ≤12 months of age and were observed monthly for 2 years in Nairobi. Acute respiratory infection rates and cofactors were determined using Andersen-Gill models, allowing for multiple events per infant. Among 111 HIV-infected infants, median age at ART initiation was 4.5 months. Pre-ART median CD4% was 19%, and 29% had wasting. During 24-months follow-up while on ART, upper respiratory infection (URI) and pneumonia rates were 122.6 and 34.7 per 100 person-years (py), respectively. Infants with higher pre-ART viral load (VL) (plasma HIV ribonucleic acid [RNA] ≥7 log10 copies/mL) had 4.12-fold increased risk of pneumonia (95% confidence interval [CI], 2.17-7.80), and infants with wasting (weight-for-height z-score < -2) had 2.87-fold increased risk (95% CI, 1.56-5.28). Infants with both high pre-ART VL and wasting had a higher pneumonia rate (166.8 per 100 py) than those with only 1 of these risk factors (44.4 per 100 py) or neither (17.0 per 100 py). Infants with exposure to wood fuel had significantly higher risk of URI (hazard ratio [HR] = 1.82; 95% CI, 1.44-2.28) and pneumonia (HR = 3.31; 95% CI, 1.76-6.21). In early ART-treated HIV-infected infants, higher HIV RNA and wasting before ART were independent risk factors for pneumonia. Wood fuel use was associated with URI and pneumonia. Additional data on air pollution and respiratory outcomes in HIV-infected children may help optimize interventions to improve their lung health.

Cytomegalovirus-Associated Intussusception with Florid Vascular Proliferation in an Infant

Intussusception is usually idiopathic, with no pathologic lead point except for the presence of reactive lymphoid hyperplasia, which is probably associated with gastrointestinal infection or a reaction to newly introduced food proteins. Viral infections, such as those caused by non-enteric adenovirus, human herpes virus (HHV)-6, HHV-7, and Epstein-Barr virus, are known etiologic factors of intussusception. Cytomegalovirus (CMV)-associated intussusception has been reported rarely; there have been three case reports in immunocompetent and human immunodeficiency virus–infected infants [1-3]. None of these three case reports described a detailed histologic pattern, except ischemic necrosis of the small intestine due to a prolonged clinical history and delayed surgery. Here, we report a case of a CMV-associated inflammatory polyp with unique gross and microscopic findings as a leading cause of ileoileal intussusception in an 8-week-old healthy female.

Accelerated Suppression of Primary Epstein-Barr Virus Infection in HIV-Infected Infants Initiating Lopinavir/Ritonavir-Based Versus Nevirapine-Based Combination Antiretroviral Therapy

We compared primary Epstein-Barr virus (EBV) infection and suppression between Kenyan human immunodeficiency virus-infected infants starting nevirapine-based vs lopinavir/ritonavir-based antiretroviral regimens. Although the rate of EBV infection was similar between groups, infants receiving lopinavir/ritonavir suppressed EBV more rapidly. Our findings suggest that specific antiretrovirals may potentially impact the risk of future EBV-associated malignancies.

Validation of the Gen-Probe Aptima Qualitative HIV-1 RNA Assay for Diagnosis of Human Immunodeficiency Virus Infection in Infants

The qualitative Roche HIV-1 DNA Amplicor assay has been used for the past 20 years to diagnose HIV infection in infants and young children but is being phased out; hence, alternative assays must be found. The Gen-Probe Aptima qualitative HIV-1 RNA assay is currently the only FDA-cleared HIV-1 nucleic acid assay approved for diagnosis, but data on the use of this assay with infant plasma are limited. We assessed Aptima's performance using control material for reproducibility and limit of detection and 394 plasma samples (0.2 to 0.5 ml) from HIV-exposed infected and uninfected infants and children for analytical sensitivity and specificity. Assays to assess within-run repeatability and between-run reproducibility indicated that the controls with 10,000 (5 of 5), 200 (5 of 5), 100 (16 of 16), 50 (12 of 12), and 25 (20 of 20) HIV-1 RNA copies/ml (cp/ml) were always positive, and negatives were always negative (20 of 20). The limit of detection was 14 cp/ml, as determined by probit analysis. The analytic sensitivity of the assay was 99.5% (189/190 samples; 95% confidence interval [CI], 97.1 to 99.9%) and specificity was 99.5% (199/200 samples; 95% CI, 97.2 to 99.9%). These results suggest that the assay is suitable for early infant diagnosis of HIV-1.

Validation of the Gen-Probe Aptima Qualitative HIV-1 RNA Assay for Diagnosis of Human Immunodeficiency Virus Infection in Infants

Validation of the Gen-Probe Aptima Qualitative HIV-1 RNA Assay for Diagnosis of Human Immunodeficiency Virus Infection in Infants

The role of polymerase chain reaction in early diagnosis of human immunodeficiency virus infection in infants

The prevalence of human immunodeficiency virus (HIV) infection is rising in Sub- Saharan Africa. The various indirect tests readily available have not been helpful in neonatal and early infant diagnosis of the disease. Polymerase chain reaction (PCR) is a direct test that can be used in these groups of children. Early infant diagnosis is important in achieving good outcome in the management of HIV infection. The aim of this article was to examine the role of PCR in the evaluation HIV-infected infants, with a view to achieve early diagnosis, early treatment, and good outcome. This was a prospective review of 174 infants delivered by HIV-infected mothers in a rural hospital from January 2007 to September 2008. The blood samples of the patients were collected and subjected to PCR analysis for detection of viral antigen. Two samples were collected, the first at 6 weeks and the second 6 weeks after that. The results were recorded, collated, and analyzed using SPSS version 17. There were 174 infants, 100 boys, and 74 girls. The age range was 6-8 weeks (median 6 weeks). PCR was positive for both the samples in 12 (6.9%) infants. PCR was negative in both samples in 162 (93.1%) infants. All infants who were negative in the first sampling were found to be negative in the second sampling as well. None of the infant was positive for only one sample. Analysis of 12 positive infants revealed that 5 (2.9%) infants were placed on anti-retroviral drugs, 3 (1.7%) infants were not placed on anti-retroviral drugs because of low CD+ count, and 1 (1.0%) infant was lost to follow-up, while 3 (1.7%) infants died from sepsis. PCR has a role as a direct test in early diagnosis of HIV infection in infancy, particularly where the other direct test are not readily available.

A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed simian immunodeficiency virus-infected infant macaques.

Many resource-poor countries are faced with concurrent epidemics of AIDS and tuberculosis (TB) caused by human immunodeficiency virus (HIV) and Mycobacterium tuberculosis, respectively. Dual infections with HIV and M. tuberculosis are especially severe in infants. There is, however, no effective HIV vaccine, and the only licensed TB vaccine, the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine, can cause disseminated mycobacterial disease in HIV-infected children. Thus, a pediatric vaccine to prevent HIV and M. tuberculosis infections is urgently needed. We hypothesized that a highly attenuated M. tuberculosis strain containing HIV antigens could be safely administered at birth and induce mucosal and systemic immune responses to protect against HIV and TB infections, and we rationalized that vaccine safety could be most rigorously assessed in immunocompromised hosts. Of three vaccine candidates tested, the recombinant attenuated M. tuberculosis strain mc(2)6435 carrying a simian immunodeficiency virus (SIV) Gag expression plasmid and harboring attenuations of genes critical for replication (panCD and leuCD) and immune evasion (secA2), was found to be safe for oral or intradermal administration to non-SIV-infected and SIV-infected infant macaques. Safety was defined as the absence of clinical symptoms, a lack of histopathological changes indicative of M. tuberculosis infection, and a lack of mycobacterial dissemination. These data represent an important step in the development of novel TB vaccines and suggest that a combination recombinant attenuated M. tuberculosis-HIV vaccine could be a safe alternative to BCG for the pediatric population as a whole and, more importantly, for the extreme at-risk group of HIV-infected infants.

Bubble continuous positive airway pressure in a human immunodeficiency virus-infected infant [Case study

World Health Organization-classified very severe pneumonia due to Pneumocystis jirovecii infection is recognized as a life-threatening condition in human immunodeficiency virus (HIV) infected infants. We recount the use of nasal bubble continuous positive airway pressure (BCPAP) in an HIV-infected African infant with very severe pneumonia and treatment failure due to suspected infection with P. jirovecii. We also examine the potential implications of BCPAP use in resource-poor settings with a high case index of acute respiratory failure due to HIV-related pneumonia, but limited access to mechanical ventilation.

P07-07. Non-progressive paediatric HIV infection is associated with virus attenuation and increase in CD8+ specific T cell responses over time

Background The majority of Human Immunodeficiency Virus (HIV)infected infants in the developing world progress to AIDS or death within the first year of life. Although a small minority become slow-progressors, the determinants of slow-progression remain to be elucidated. In this context the interactions between the characteristics of the maternal virus transmitted and the infants' adaptive immune responses are likely to be important. We undertook this study to elucidate the contribution of viral and host factors to HIV progression in perinatally-infected infants.

Affordable diagnosis of human immunodeficiency virus infection in infants by p24 antigen detection.

The expense of PCR testing limits diagnosis of HIV infection in infancy in low resource settings. The ultrasensitive p24 antigen assay has been proposed as an accurate substitute; however, its ability to detect different HIV viral subtypes remains to be determined. A sensitivity of 98.1% and specificity of 98.7% was obtained testing 203 samples from 24 HIV-infected and 66 uninfected infants born to HIV subtype C-infected women.

Disseminated Acanthamoeba infection in a human immunodeficiency virus-infected infant

Disseminated Acanthamoeba infection in a human immunodeficiency virus-infected infant

Disseminated Acanthamoeba infection in a human immunodeficiency virus-infected infant.

Infection with Acanthamoeba is difficult to diagnose and treat. We present the first case of disseminated Acanthamoeba infection in an HIV-infected infant. The infant survived 2 years with treatment with several agents having anti-Acanthamoeba activity in vitro.

Anthropometric indicators of human immunodeficiency virus infection in infants with early and late symptoms in the first months of life.

Standardised growth indices (Z-scores of weight-for-age, WA, length-for-age, LA, weight-for-length, WL, according to the reference data of the World Health Organization) have been compared for the first 4 months of life among 119 infants born to mothers affected by the type-1 human immunodeficiency virus (HIV). Infants were subdivided according to their HIV serostatus and the clinical expression of the disease. Uninfected status (n = 92), late (>6 months, n = 18) and early (<3 months, n = 9) onset of symptoms among the HIV infected defined three groups. Infants with early symptoms showed the lowest median WA and LA Z-scores at all times and the LA difference with their uninfected counterparts was already significant at birth. Infants with late symptoms showed early differences in WL and then in WA also compared with the uninfected ones. A < -0.40 LA Z-score at birth gave a 5.9 relative risk (RR) to be an infant with early symptoms (95% CI = 1.2-27.4) while a negative WL Z-score at 2 months of age gave a 4.2 RR for the HIV seropositivity (95% CI = 2.1-8.3). Linear growth is the first parameter to be negatively affected among human immunodeficiency virus seropositive infants with early symptoms. In infants with late symptoms the lack of rapid WA and WL increase found among uninfected patients may be viewed as an early anthropometric indicator of HIV status.

Thymic dysfunction and time of infection predict mortality in human immunodeficiency virus-infected infants. CDC Perinatal AIDS Collaborative Transmission Study Group.

The effect of human immunodeficiency virus (HIV)-induced thymic dysfunction (TD) on mortality was studied in 265 infected infants in the CDC Perinatal AIDS Collaborative Transmission Study. TD was defined as both CD4 and CD8 T cell counts below the 5th percentile of joint distribution for uninfected infants within 6 months of life. The 40 HIV-infected infants with TD (15%) had a significantly greater mortality than did the 225 children without TD (44% vs. 9% within 2 years). Infants with TD infected in utero had higher mortality than did those infected intrapartum (70% vs. 37% within 2 years), while no significant difference was noted between infants without TD with either mode of transmission. The TD profile was independent of plasma virus load. Virus-induced TD by particular HIV strains and the time of transmission are likely to explain the variation in pathogenesis and patterns of disease progression and suggest the need for early aggressive therapies for HIV-infected infants with TD.

Evaluation of a human immunodeficiency virus specific IgA capture enzyme immunoassay for the diagnosis of human immunodeficiency virus infection in infants.

Evaluation of a human immunodeficiency virus specific IgA capture enzyme immunoassay for the diagnosis of human immunodeficiency virus infection in infants.

Abstract

The number of children with symptomatic human immunodeficiency virus syndrome-related cardiac disease is increasing, as children live longer secondary to improved treatment. There is increased morbidity and mortality in the subpopulation of infants and children with congestive heart failure secondary to left ventricular dysfunction. Left ventricular dysfunction is characterized by left ventricular dilatation and decreased wall thickness, resulting in inadequate left ventricular hypertrophy. The clinical course of these infants and children can be improved by treatments such as intravenous gammaglobulin, which is known to normalize left ventricular structure and function in this subpopulation, provided treatment is implemented early in the course of the cardiac disease. It is therefore necessary to be able to identify those high risk patients by non-invasive methods, such as echocardiography. Nearly all published investigations examining left ventricular performance in human immunodeficiency virus-infected patients have used measurements, such as left ventricular fractional shortening, that depend on both preload and afterload. These measurements may determine who requires the need for intervention; fractional shortening may determine who is treated in protocols implemented by the AIDS Clinical Trial Group. Numerous studies have documented that fractional shortening may not be a sufficiently reliable indicator of intrinsic myocardial function in human immunodeficiency virus-infected infants and children. Contractility may not be accurately described by fractional shortening in these patients, who tend to have abnormal preload and afterload. The magnitude of the discrepancy between fractional shortening and contractility must be taken into consideration when treating infants and children infected with the human immunodeficiency virus.

Left ventricular dysfunction in infants and children infected with the human immunodeficiency virus

The number of children with symptomatic human immunodeficiency virus syndrome-related cardiac disease is increasing, as children live longer secondary to improved treatment. There is increased morbidity and mortality in the subpopulation of infants and children with congestive heart failure secondary to left ventricular dysfunction. Left ventricular dysfunction is characterized by left ventricular dilatation and decreased wall thickness, resulting in inadequate left ventricular hypertrophy. The clinical course of these infants and children can be improved by treatments such as intravenous gammaglobulin, which is known to normalize left ventricular structure and function in this subpopulation, provided treatment is implemented early in the course of the cardiac disease. It is therefore necessary to be able to identify those high risk patients by non-invasive methods, such as echocardiography. Nearly all published investigations examining left ventricular performance in human immunodeficiency virus-infected patients have used measurements, such as left ventricular fractional shortening, that depend on both preload and afterload. These measurements may determine who requires the need for intervention; fractional shortening may determine who is treated in protocols implemented by the AIDS Clinical Trial Group. Numerous studies have documented that fractional shortening may not be a sufficiently reliable indicator of intrinsic myocardial function in human immunodeficiency virus-infected infants and children. Contractility may not be accurately described by fractional shortening in these patients, who tend to have abnormal preload and afterload. The magnitude of the discrepancy between fractional shortening and contractility must be taken into consideration when treating infants and children infected with the human immunodeficiency virus.