HIV viral sequences in seronegative people at risk detected by in situ hybridisation and polymerase chain reaction.

A study was conducted to assess the occurrence of latent infection with the human immunodeficiency virus (HIV) among seronegative people at high risk of infection. The presence of HIV genomes was analysed by molecular techniques in two seronegative children born to mothers infected with HIV and in three regular sexual partners of seropositive drug addicts. The adults were selected from a seronegative cohort at high risk of infection because of their sexual contacts and the children selected because of impaired growth. HIV retroviral sequences were detected in four of the five subjects directly at the cellular level by in situ hybridisation in peripheral blood mononuclear cells. HIV genomic sequences were confirmed by in vitro amplification of viral DNA with the polymerase chain reaction technique. The existence of a latent viral infection state in these seronegative subjects indicates the unreliability of standard serological analysis in people who have been in regular contact with infected patients.     

An intrahospital outbreak of HIV infection in Elista

For the first time a nosocomial focus of HIV infection was established. Out of 83,000 inhabitants of the Kalmyck ASSR who underwent planned examination in the course of epidemiological investigation, 65 cases of HIV infection were detected and all of them were traced to the focus of hospital infection (56 children and 9 adults: 1 man and 8 women; of these, 7 women contacted the infection from their infected children in the process of breast feeding). The children were infected during their stay in two hospitals of Elista where they received multiple intravenous and intramuscular injections. The infection spread from the infant department of the regional pediatric hospital to 4 more departments and to the infectious diseases hospital. Transmission of this infection was maintained for several months by the use of nonsterile syringes in parenteral manipulations.     

Hyperviscosity in HIV infected children--a potential hazard during intravenous immunoglobulin therapy

A four year old boy with symptoms of HIV infection and serum IgG of 53.2 g/l had been treated for 16 months with regular infusions of intravenous immunoglobulin (IV IgG). During one such infusion he developed temporary neurological symptoms and signs suggestive of the hyperviscosity syndrome. Serum relative viscosity was raised at 5.0 (normal range 0.42-2.78). Subsequent IV IgG infusions given at a slower rate have been without adverse reactions. In a study of eight HIV infected children including the index case, and 20 children not infected with HIV, serum relative viscosity was significantly raised in the HIV infected children (p less than 0.01; students t-test). Viscosity correlated with total serum IgG, which was raised in all HIV infected children, and with serum IgM. In HIV infected children with very high levels of serum IgG a slow rate of IV IgG infusion should therefore be chosen due to the possibility of hyperviscosity.     

Vertically transmitted HIV infection in the British Isles.

OBJECTIVE--To describe the epidemiology of vertically acquired HIV infection in the British Isles, the level of underreporting, the vertical transmission rate, and clinical spectrum of paediatric AIDS. DESIGN--Confidential, linked registers based on reporting from obstetricians and paediatricians; anonymous unlinked neonatal HIV serosurveys. SETTING--British Isles. SUBJECTS--Children born to mothers with HIV infection. MAIN OUTCOME MEASURES--Trends in HIV infection and vertical transmission rate. RESULTS--In Scotland and the Irish Republic, where most maternal HIV infection is related to drug misuse, the annual number of reports of children born to infected mothers has fallen since 1989. In England and Wales nearly half of maternal infections have been acquired overseas, and the number of children born to these women, and to women who became infected in Britain, is increasing. In south east England the proportion of live births to women whose infection was identified before delivery was only 17% (50/287), compared with 68% (26/38) in Scotland. The vertical transmission rate was 13.7% (23/168), and 23% of infected children developed AIDS in the first year of life. 41% (38/92) of children born to infected mothers who were ascertained after delivery were breast fed, compared with 5% (12/236) of those ascertained before delivery. CONCLUSIONS--The incidence of vertically transmitted HIV infection is increasing in England and Wales. More extensive antenatal testing would enable infected women to be counselled against breast feeding, which could prevent a substantial proportion of vertical transmission in some areas, and would increase opportunities for early diagnosis and treatment of infected children.     

一个HIV感染的动力学模型

考虑到人体免疫缺损病毒(HIV)能感染和杀每T4细胞,病毒颗粒能从感染细胞膜上发芽而出以及感染细胞能与未感染细胞融合等实验事实,建议了一个细胞水平的人体免疫缺损病毒感染的动力学模型。利用这个模型,我们对HIV感染的动力学行为进行了分析。结果表明:在潜伏期,感染细胞的溶度和病毒的溶度都渐渐地趋于一个暂态的平衡值;在表达期,病毒溶度大幅度增加,正常T4细胞溶度渐渐减少,这也许正是AIDS病致病的原因。     

Children, adolescents and HIV infection

The analysis of the occurrence of HIV infection in adults, children and adolescents under 18 years of age on the basis of statistical data by February 1, 1997, is presented. The total number HIV-infected persons registered by this date was 6,232; among them 902 (14.5%) were children and adolescents. 267 children were infected in the hospital focus of HIV infection; of these, 80 children (30%) died of AIDS during the period of 1989-1997. In 1992 only 16 adolescents, HIV infected were registered, while in 1995 the number of HIV-infected adolescents was 34, in 1996 their number rose to 144 and in 1997, to 435. The main cause of adolescent infections (80%) was the intravenous injection of narcotic drugs.     

Cardiac Effects of Antiretroviral-Na?ve versus Antiretroviral-Exposed HIV Infection in Children

Background

Cardiac involvement in HIV infected children has been frequently reported, but whether this is due to HIV infection itself or to antiretroviral treatment (ART) is unknown.

Methods

This cross sectional study involved 114 vertically-acquired HIV-infected (56 ART-naive, 58 ART-exposed) and 51 healthy children in Jakarta, Indonesia. Echocardiography was performed to measure dimensions of the left ventricle (LV) and systolic functions. We applied general linear modeling to evaluate the associations between HIV infection/treatment status and cardiac parameters with further adjustment for potential confounders or explanatory variables. Findings are presented as (adjusted) mean differences between each of the two HIV groups and healthy children, with 95% confidence intervals and p values.

Results

Compared to healthy children, ART-naïve HIV-infected children did not show significant differences in age-and-height adjusted cardiac dimensions apart from larger LV internal diameter (difference 2.0 mm, 95%CI 0.2 to 3.7), whereas ART exposed HIV infection showed thicker LV posterior walls (difference = 1.1 mm, 95%CI 0.5 to 1.6), larger LV internal diameter (difference = 1.7 mm, 95%CI 0.2 to 3.2) and higher LV mass (difference = 14.0 g, 7.4 to 20.5). With respect to systolic function, reduced LV ejection fraction was seen in both ART-naïve HIV infected (adjusted difference = -6.7%, -11.4 to -2.0) and, to a lesser extent, in ART-exposed HIV infected children (difference = -4.5%, -8.5 to -0.4). Inflammation level seemed to be involved in most associations in ART-exposed HIV-infected, but few, if any, for decreased function in the ART-naive ones, whereas lower hemoglobin appeared to partially mediate chamber dilation in both groups and reduced function, mainly in ART-exposed children.

Conclusions

ART-naive HIV infected children have a substantial decrease in cardiac systolic function, whereas the ART-exposed have thicker ventricular walls with larger internal diameter and higher mass, but less functional impairment.     

Screening for HIV-1 antibodies in pregnancy: results from the Swedish national programme.

OBJECTIVE--To determine the effectiveness of a national screening programme for HIV infection in pregnant women. DESIGN--Observational study. SUBJECTS--All pregnant women presenting to antenatal or abortion clinics. SETTING--Sweden, September 1987 to December 1991. MAIN OUTCOME MEASURES--Number and characteristics of infected women. RESULTS--By the end of the study period 510,000 tests had been performed and 54 women with HIV infection identified (1.06/10,000). Of the 33 women identified in Stockholm, 14 women (4.4/10,000) had attended abortion clinics and 19 antenatal clinics (1.8/10,000; p < 0.05). Three women had been intravenous drug users, one was infected through a blood transfusion, and 50 were probably infected sexually. Of the 20 women who attended antenatal clinics early enough to allow an abortion, 12 continued with their pregnancies. CONCLUSIONS--Testing of all women, not just those perceived to be at risk, probably contributed to the high uptake of HIV testing. With high uptake such screening provides valuable data on spread of HIV in the heterosexual population and presents opportunity for preventing transmission of HIV to children and partners.     

Replication of human immunodeficiency virus in two T-cell lines and their application as antigens for immunofluorescence

Two T-cell lines, TALL-1 and CCRF-CEM, were infected with human immunodeficiency virus (HIV), strain LAV, to explore the time course of the appearance of various virus specific antigens, and to establish an antibody assay system by indirect immunofluorescence (IF). These cells were infected with LAV at two different input multiplicity of infection (MOI). Antigens were tested by Western blot analysis (WB) and IF. Antigens for WB were extracted from the infected cells at various times after infection, but pooled sera of American HIV carriers could not recognize gp41 or gp160. Antigen expression was highest in CCRF-CEM, but, as the antigen for IF, TALL-1 infected at the MOI of 8.0 was the most suitable 7 days after infection, because it includes a fairly large number of uninfected cells, which served as the internal control.     

Children who acquire HIV infection perinatally are at higher risk of early death than those acquiring infection through breastmilk: a meta-analysis

BACKGROUND: Assumptions about survival of HIV-infected children in Africa without antiretroviral therapy need to be updated to inform ongoing UNAIDS modelling of paediatric HIV epidemics among children. Improved estimates of infant survival by timing of HIV-infection (perinatally or postnatally) are thus needed. METHODOLOGY/PRINCIPAL FINDINGS: A pooled analysis was conducted of individual data of all available intervention cohorts and randomized trials on prevention of HIV mother-to-child transmission in Africa. Studies were right-censored at the time of infant antiretroviral initiation. Overall mortality rate per 1000 child-years of follow-up was calculated by selected maternal and infant characteristics. The Kaplan-Meier method was used to estimate survival curves by child's HIV infection status and timing of HIV infection. Individual data from 12 studies were pooled, with 12,112 children of HIV-infected women. Mortality rates per 1,000 child-years follow-up were 39.3 and 381.6 for HIV-uninfected and infected children respectively. One year after acquisition of HIV infection, an estimated 26% postnatally and 52% perinatally infected children would have died; and 4% uninfected children by age 1 year. Mortality was independently associated with maternal death (adjusted hazard ratio 2.2, 95%CI 1.6-3.0), maternal CD4<350 cells/ml (1.4, 1.1-1.7), postnatal (3.1, 2.1-4.1) or peri-partum HIV-infection (12.4, 10.1-15.3). CONCLUSIONS/RESULTS: These results update previous work and inform future UNAIDS modelling by providing survival estimates for HIV-infected untreated African children by timing of infection. We highlight the urgent need for the prevention of peri-partum and postnatal transmission and timely assessment of HIV infection in infants to initiate antiretroviral care and support for HIV-infected children.     

Immunological evaluation of human immunodeficiency virus infected individuals by flow cytometry

Human immunodeficiency virus (HIV) infection heavily compromises the immune system. The decrease of the T cell CD4+ subset along the evolution to acquired immunodeficiency syndrome has been considered as a hallmark of HIV infection. In this paper we review some aspects of the immunopathology of HIV infection and discuss the importance of the flow cytometry for the evaluation of the T lymphocyte subsets in the follow-up of HIV infected children and adults, and for the monitoring of the immune reconstitution upon antiretroviral therapy.     

The Trophoblastic Epithelial Barrier Is Not Infected in Full-Term Placentae of Human Immunodeficiency Virus-Seropositive Mothers Undergoing Antiretroviral Therapy

To study the mechanism of the placental barrier function, we examined 10 matched samples of term placentae, cord blood, and maternal blood obtained at delivery from human immunodeficiency virus (HIV)-infected mothers with children diagnosed as HIV negative in Sweden. All placentae were histologically normal, and immunochemistry for HIV type 1 p24 and gp120 antigens was negative. Highly purified trophoblasts (93 to 99% purity) were negative for HIV DNA and RNA, indicating that the trophoblasts were uninfected. Although HIV DNA was detected in placenta-derived T lymphocytes and monocytes, microsatellite analysis showed that these cells were a mixture of maternal and fetal cells. Our study indicates that the placental barrier, i.e., the trophoblastic layer, is not HIV infected and, consequently, HIV infection of the fetus is likely to occur through other routes, such as breaks in the placental barrier.     

Characterization of GP120 binding to CD4 and an assay that measures ability of sera to inhibit this binding

There is evidence that the initial interaction between HIV-1 and the host that is essential for infection is the specific binding of the viral envelope glycoprotein, gp120, to the CD4 molecule found on certain T cells and monocytes. Most individuals infected with HIV develop antibodies against the gp120 protein. Although in vitro treatment of CD4+ T cells with mAb to a specific epitope of the CD4 molecule (T4a) blocks virus binding, syncytia formation, and infectivity, it is unclear if antibodies to gp120 from an infected individual that can inhibit the binding of gp120 to CD4 is in any way related to the clinical course of disease. Our present study characterizes the binding of 125I-labeled rgp120 to CD4+ cells, and describes an assay system that measures a potentially relevant form of immunity to HIV infection, i.e., the blocking of HIV binding to CD4+ cells. Optimal binding conditions included a 2-h incubation at 22 degrees C, 4 x 10(6) CD4+ cells, and 1 nM gp120. The dissociation constant (KD) for gp120 binding to cell surface CD4 was 5 nM, and was inhibited by soluble CD4 and by mAb to T4a but not to T3 or T4. For the binding inhibition assay, negative controls included healthy seronegatives, seronegatives with connective tissue diseases, patients with HTLV-1 disease, and patients infected with HIV-2. In studying over 100 sera, the assay was highly sensitive (98%) and specific (100%). The majority of HIV+ sera could inhibit binding at dilutions of 1/100 to 1/1000. No correlation was noted between binding inhibition (BI) titer in this assay and clinical stage of HIV infection. In addition, there was no correlation between BI titer and HIV neutralizing activity. The BI titer was correlated with the titer of anti-gp160 (r = 0.63) and the titer of anti-gp120 (r = 0.52) antibodies determined by Western blot dilution. As with neutralizing antibodies and other forms of immune response to HIV, it is unclear what role antibody blocking of HIV binding to CD4+ cells may play in active immunity to HIV in infected individuals. This activity may prove to have some value in protection against initial HIV infection and, thus, the assay may be of use in monitoring vaccine trials.     

CD4 T cell count as predictor of Pneumocystis carinii pneumonia in children born to mothers infected with HIV. European Collaborative Study Group.

OBJECTIVE--To assess the value of CD4 T cell count in predicting Pneumocystis carinii pneumonia in infants born to mothers infected with HIV, with reference to the guidelines from the Centers for Disease Control on prophylaxis against pneumocystis. DESIGN--Prospective birth cohort study. SETTING--Hospitals in 10 European cities participating in the European collaborative study. SUBJECTS--924 children born to mothers known to be infected with HIV at or before delivery. MAIN OUTCOME MEASURES--The incidence of P carinii pneumonia. CD4 T cell counts in children before diagnosis of the pneumonia. The proportions of children infected and uninfected with HIV who fulfilled the criteria for primary prophylaxis. RESULTS--Fourteen children were diagnosed with P carinii pneumonia. The cumulative incidence by the age of 6 years was 2% (95% confidence interval 0.9 to 3.0%). Of the 11 children with a CD4 T cell count predating diagnosis, only three fulfilled the criteria from the Centers for Disease Control for prophylaxis. Prophylaxis was indicated by 1 year of age for 62% of infected children who had not developed P carinii pneumonia and for at least 10% of uninfected children. CONCLUSIONS--Monitoring CD4 T cell count seems to be of limited value in deciding when to start prophylaxis against P carinii pneumonia in children born to mothers infected with HIV. The alternative approach of giving prophylaxis to all children born to infected mothers would be difficult to justify given the low incidence of the pneumonia.     

Impact of cytokines on replication in the thymus of primary human immunodeficiency virus type 1 isolates from infants

Early infection of the thymus with the human immunodeficiency virus (HIV) may explain the more rapid disease progression among children infected in utero than in children infected intrapartum. Therefore, we analyzed infection of thymocytes in vitro by HIV type 1 primary isolates, obtained at or near birth, from 10 children with different disease outcomes. HIV isolates able to replicate in the thymus and impact thymopoiesis were present in all infants, regardless of the timing of viral transmission and the rate of disease progression. Isolates from newborns utilized CCR5, CXCR4, or both chemokine receptors to enter thymocytes. Viral expression was observed in discrete thymocyte subsets postinfection with HIV isolates using CXCR4 (X4) and isolates using CCR5 (R5), despite the wider distribution of CXCR4 in the thymus. In contrast to previous findings, the X4 primary isolates were not more cytopathic for thymocytes than were the R5 isolates. The cytokines interleukin-2 (IL-2), IL-4, and IL-7 increased HIV replication in the thymus by inducing differentiation and expansion of mature CD27(+) thymocytes expressing CXCR4 or CCR5. IL-2 and IL-4 together increased expression of CXCR4 and CCR5 in this population, whereas IL-4 and IL-7 increased CXCR4 but not CCR5 expression. IL-2 plus IL-4 increased the viral production of all pediatric isolates, but IL-4 and IL-7 had a significantly higher impact on the replication of X4 isolates compared to R5 isolates. Our studies suggest that coreceptor use by HIV primary isolates is important but is not the sole determinant of HIV pathogenesis in the thymus.     

Decline in mortality,AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland

Objective To describe changes in demographic factors, disease progression, hospital admissions, and use of antiretroviral therapy in children with HIV.Design Active surveillance through the national study of HIV in pregnancy and childhood (NSHPC) and additional data from a subset of children in the collaborative HIV paediatric study (CHIPS).Setting United Kingdom and Ireland.Participants 944 children with perinatally acquired HIV-1 under clinical care.Main outcome measures Changes over time in progression to AIDS and death, hospital admission rates, and use of antiretroviral therapy.Results 944 children with perinatally acquired HIV were reported in the United Kingdom and Ireland by October 2002; 628 (67%) were black African, 205 (22%) were aged ≥ 10 years at last follow up, 193 (20%) are known to have died. The proportion of children presenting who were born abroad increased from 20% in 1994-5 to 60% during 2000-2. Mortality was stable before 1997 at 9.3 per 100 child years at risk but fell to 2.0 in 2001-2 (trend P < 0.001). Progression to AIDS also declined (P < 0.001). From 1997 onwards the proportion of children on three or four drug antiretroviral therapy increased. Hospital admission rates declined by 80%, but with more children in follow up the absolute number of admissions fell by only 26%.Conclusion In children with HIV infection, mortality, AIDS, and hospital admission rates have declined substantially since the introduction of three or four drug antiretroviral therapy in 1997. As infected children in the United Kingdom and Ireland are living longer, there is an increasing need to address their medical, social, and psychological needs as they enter adolescence and adult life.     

HIV Populations Are Large and Accumulate High Genetic Diversity in a Nonlinear Fashion

HIV infection is characterized by rapid and error-prone viral replication resulting in genetically diverse virus populations. The rate of accumulation of diversity and the mechanisms involved are under intense study to provide useful information to understand immune evasion and the development of drug resistance. To characterize the development of viral diversity after infection, we carried out an in-depth analysis of single genome sequences of HIV pro-pol to assess diversity and divergence and to estimate replicating population sizes in a group of treatment-naive HIV-infected individuals sampled at single (n = 22) or multiple, longitudinal (n = 11) time points. Analysis of single genome sequences revealed nonlinear accumulation of sequence diversity during the course of infection. Diversity accumulated in recently infected individuals at rates 30-fold higher than in patients with chronic infection. Accumulation of synonymous changes accounted for most of the diversity during chronic infection. Accumulation of diversity resulted in population shifts, but the rates of change were low relative to estimated replication cycle times, consistent with relatively large population sizes. Analysis of changes in allele frequencies revealed effective population sizes that are substantially higher than previous estimates of approximately 1,000 infectious particles/infected individual. Taken together, these observations indicate that HIV populations are large, diverse, and slow to change in chronic infection and that the emergence of new mutations, including drug resistance mutations, is governed by both selection forces and drift.     

Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression

Genetic variants of human and simian immunodeficiency virus (HIV and SIV) that evolve during the course of infection and progression to AIDS are phenotypically and antigenically distinct from their progenitor viruses present at early stages of infection. However, it has been unclear how these late variants, which are typically T-cell tropic, cytopathic and resistant to neutralizing antibodies, influence the development of clinical AIDS. To address this, we infected macaques with cloned SIVs representing prototype variants from early-, intermediate- and late-stage infection having biological characteristics typical of viruses found at similar stages of HIV infection in humans. These studies demonstrate that sequential, phenotypic and antigenic variants represent viruses that have become increasingly fit for replication in the host, and our data support the hypothesis that emerging variants have increased pathogenicity and drive disease progression in SIV and HIV infection.     

Vertical transmission rates for HIV in the British Isles: estimates based on surveillance data

ObjectiveTo estimate and interpret time trends in vertical transmission rates for HIV using data from national obstetric and paediatric surveillance registers.DesignProspective study of HIV infected women reported through obstetric surveillance. HIV infection status of the child and onset of AIDS were reported through paediatric surveillance. Rates of vertical transmission and progression to AIDS rate were estimated by methods that take account of incomplete follow up of children with indeterminate infection status and delay in AIDS reporting.SettingBritish Isles.SubjectsPregnant women infected with HIV whose infection was diagnosed before delivery, and their babies.ResultsBy January 1999, 800 children born to diagnosed HIV infected women who had not breast fed had been reported. Vertical transmission rates rose to 19.6% (95% confidence interval 8.0% to 32.5%) in 1993 before falling to 2.2% (0% to 7.8%) in 1998. Between 1995 and 1998 use of antiretroviral treatment increased significantly each year, reaching 97% of live births in 1998. The rate of elective caesarean section remained constant, at around 40%, up to 1997 but increased to 62% in 1998. Caesarean section and antiretroviral treatment together were estimated to reduce risk of transmission from 31.6% (13.6% to 52.2%) to 4.2% (0.8% to 8.5%). The proportion of infected children developing AIDS in the first 6 months fell from 17.7% (6.8% to 30.8%) before 1994 to 7.2% (0% to 15.7%) after, coinciding with increased use of prophylaxis against Pneumocystis carinii pneumonia.ConclusionsIn the British Isles both HIV related morbidity and vertical transmission are being reduced through increased use of interventions.

Key messages

• Reliable estimates of HIV vertical transmission rates can be derived from surveillance data
• Infected pregnant women are increasingly taking up elective caesarean section and antiretroviral treatment to reduce the risk of transmitting HIV to their babies
• Vertical transmission rates have fallen greatly over the past four years and progression to AIDS among infected children may also have slowed
• These benefits can occur only if infected women are diagnosed before or during pregnancy