Human immunodeficiency virus (HIV) type 1 antibodies in perinatal HIV-1 infection: association with human HIV-1 transmission, infection, and disease progression. For the Women and Infants Transmission Study.

Anti -human immunodeficiency virus (HIV) type 1 antibodies in 242 pregnant women and 238 infants were measured at birth and at 1, 2, 4, and 6 months after birth, to estimate their association with perinatal transmission and infant disease progression. Maternal anti-p24 (P=.01) and anti-gp120 (P=.04) antibodies were inversely associated with vertical transmission rates, independent of maternal percentage of CD4 cells, hard drug use, duration of ruptured membranes, serum albumin levels, serum vitamin A levels, and quantitative HIV-1 peripheral mononuclear blood cell culture, but not with maternal plasma immune complex dissociated p24 or HIV-1 RNA copy number, both of which were highly correlated with antibodies. From ages 1-2 months, anti-gp120, -gp41, -p31, and -p66 decayed to a greater extent in infected than in uninfected infants. Infected infants produced anti-p24 antibody by age 2 months, anti-p17 by 4 months, and anti-p41 and anti-gp120 by 6 months. As early as birth, infants with rapid disease progression had lower levels of anti-p24 than did infants whose disease did not rapidly progress, but not independently of HIV-1 RNA levels.

Quantification of human immunodeficiency virus type 1 p24 antigen and antibody rivals human immunodeficiency virus type 1 RNA and CD4+ enumeration for prognosis. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group.

BACKGROUND: The sensitivity, specificity and positive predictive value of baseline serum concentrations of HIV-1 immune complex-dissociated (ICD) p24 antigen for predicting disease progression and mortality were assessed and compared with results obtained for HIV-1 ICD p24 antigen with HIV-1 p24 antibody and for HIV-1 RNA with CD4+ lymphocyte percent. METHODS: Data from HIV-infected children enrolled in a North American clinical trial (National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial) were analyzed. Disease progression was defined as growth failure, CD4+ lymphocyte percent decline to <15% after study entry or development of an AIDS-defining opportunistic infection. RESULTS: Baseline samples were available for ICD p24 antigen testing (median concentration, 319 pg/ml; range, <50 to 15,640) in 240 children. The combination of detectable ICD p24 antigen and low p24 antibody was more sensitive but less specific than the combination of high HIV-1 RNA and low CD4+ lymphocyte percent in predicting disease progression and mortality. Using receiver operating characteristic curves, the specificity of ICD p24 antigen with p24 antibody for classifying children's disease progression or mortality was as great as, or greater than, HIV-1 RNA with CD4+ lymphocyte percent at points on the curve corresponding to higher sensitivity. CONCLUSIONS: The use of ICD p24 antigen with p24 antibody to identify children at high risk of disease progression or mortality could be a viable alternative to the more expensive and technically difficult HIV-1 RNA and CD4+ lymphocyte assays in resource-poor settings, including developing countries where the majority of children with HIV-1 infection reside.

HIV-1 genotypic zidovudine drug resistance and the risk of maternal--infant transmission in the women and infants transmission study. The Women and Infants Transmission Study Group.

OBJECTIVES: Although the treatment of pregnant women and their infants with zidovudine (ZDV) has been remarkably effective in preventing the perinatal transmission of human HIV-1, many potentially preventable infections still occur. To examine whether the risk of perinatal infection is increased among women who carry ZDV-resistant HIV-1, the role of genotypic ZDV resistance in perinatal transmission was evaluated. METHODS: The reverse transcriptase (RT) region of clinical isolates from culture supernatants of 142 HIV-1-infected women enrolled in the Women and Infants Transmission Study (WITS), who had been treated with ZDV during pregnancy was sequenced. Results from genotypic sequencing were linked to demographic, laboratory, and obstetrical databases, and the magnitude of association of having consensus drug-resistant HIV-1 RT mutations with transmission was estimated. RESULTS: Twenty-five per cent (34/142) of maternal isolates had at least one ZDV-associated resistance mutation. A lower CD4 cell percentage and count (P= 0.0001) and higher plasma HIV-1 RNA (P=0.006) were associated with having any ZDV resistance mutation at delivery. Having any RT resistance mutation [odds ratio (OR): 5.16; 95% confidence interval (CI): 1.40, 18.97; P=0 0.01], duration of ruptured membranes [OR: 1.13 (1.02, 1.26) per 4 h duration; P= 0.02], and total lymphocyte count [OR: 1.06 (1.01, 1.10) per 50 cells higher level; P=0.009] were independently associated with transmission in multivariate analysis. CONCLUSION: Maternal ZDV resistant virus was predictive of transmission, independent of viral load, in these mothers with moderately advanced HIV-1 disease, many of whom had been treated with ZDV before pregnancy.

Maternal and infant factors predicting disease progression in human immunodeficiency virus type 1-infected infants. Women and Infants Transmission Study Group.

BACKGROUND: Infants with perinatally acquired human immunodeficiency virus type 1 (HIV-1) infection have widely variable courses. Previous studies showed that a number of maternal and infant factors, when analyzed separately, are associated with infant HIV-1 disease progression. In this study, clincal, virologic, and immunologic characteristics in the mothers and infants were examined together to determine the predictors of disease progression by 18 months of age and the associations with rapid progression during the first 6 months of life. METHODS: One hundred twenty-two HIV-1-infected women whose infants were HIV-1 infected were identified from the Women and Infants Transmission Study (WITS) cohort. WITS is a longitudinal natural history study of perinatal HIV-1 infection carried out in 6 sites in the continental United States and in Puerto Rico. The women were enrolled during pregnancy and their infants were enrolled at the time of delivery and followed prospectively by a standardized protocol. Virologic and immunologic studies were performed in laboratories certified by National Institutes of Health-sponsored quality assurance programs. Maternal factors in pregnancy were used as potential predictors of infant disease progression (progression to Centers for Disease Control and Prevention [CDC] Clinical Class C disease or death by 18 months of age) or as correlates of progression at <6 months of age. Infant factors defined during the first 6 months of life were used as potential predictors of progression during 6 to 18 months of age and as correlates of progression at <6 months of age. RESULTS: Progression by 18 months of age occurred in 32% of infants and by 6 months of age in 15%. Maternal characteristics that, by univariate analysis, were significant predictors of infant disease progression by 18 months of age were elevated viral load, depressed CD4(+)%, and depressed vitamin A. CD8(+)%, CD8(+) activation markers, zidovudine (ZDV) use, hard drug use, and gestational age at delivery were not. When examined in a combined multivariate analysis of maternal characteristics, only vitamin A concentration independently predicted infant progression. Infant characteristics during the first 6 months of life that, by univariate analysis, were associated with disease progression included elevated mean viral load at 1 to 6 months of age, depressed CD4(+)%, CDC Clinical Disease Category B, and growth delay. Early HIV-1 culture positivity (<48 hours), CD8(+)%, CD8(+) activation markers, and ZDV use during the first month of life did not predict progression. Multivariate analysis of infant characteristics showed that the only independent predictors were progression to CDC Category B by 6 months of age (odds ratio [OR], 5.80) and mean viral load from 1 to 6 months of age (OR, 1.99). The final combined maternal and infant analysis included the significant maternal and infant characteristics in a multivariate analysis. It showed that factors independently predicting infant progression by 18 months of age were progression to CDC Category B by 6 months of age (OR, 5.80) and elevated mean HIV-1 RNA copy number at 1 to 6 months of age (OR, 1.99). The characteristics associated with rapid progression to CDC Category C disease or death by 6 months of age were also examined. The only maternal characteristic associated with progression by 6 months in multivariate analysis was low maternal CD4(+)%. The infant characteristics associated with progression by 6 months of age in multivariate analysis were depressed mean CD4(+)% from birth through 2 months and the presence of lymphadenopathy, hepatomegaly, or splenomegaly by 3 months. Infant ZDV use was not assocciated with rapid progression. CONCLUSION: The strongest predictors of progression by 18 months are the presence of moderate clinical symptoms and elevated RNA copy number in the infants in the first 6 months of life. In contrast, progression by 6 months is associated with maternal and infant immun

Evaluation of human immunodeficiency virus (HIV) type 1 load, CD4 T cell level, and clinical class as time-fixed and time-varying markers of disease progression in HIV-1-infected children.

Human immunodeficiency virus (HIV) type 1 RNA load, CD4 T cell level, and Centers for Disease Control and Prevention (CDC) clinical class history were measured as potential correlates of a CDC class C diagnosis or death in 165 HIV-1-infected children followed from birth. These covariates were assessed at fixed "landmark" ages from 6 to 24 months and were also assessed as time-varying values. Virus load was associated with progression in all analyses, even after adjusting for immunologic and clinical status. This confirms its importance for monitoring pediatric disease progression. CD4 T cell level was associated with disease progression in time-varying but not in adjusted landmark analysis, suggesting that CD4 cells reflects immediate risk more than long-term risk. The distinction between clinical class B and lower classes is prognostic during the first 18 months of life; class C versus classes N/A/B becomes more important as the patient ages. Virologic, immunologic, and clinical status all provide information regarding disease progression risk.

CD8+ lymphocytes in pregnancy and HIV infection: characterization of CD8+ subpopulations and CD8+ noncytotoxic antiviral activity.

The distribution and function of lymphocytes vary in different clinical states. The object of this study was to characterize the CD8+ lymphocyte subpopulations and CD8+ anti-HIV suppressor activity in HIV-infected and uninfected pregnant and nonpregnant women. The total percentage of CD8+ lymphocytes was not altered by pregnancy but the percentage of activated CD8+ T cells increased during pregnancy and decreased postpartum. HIV infection in pregnant women resulted in both an increased percentage of CD8+ lymphocytes and a marked increase in activated and memory CD8+ lymphocyte subsets, which did not change in the postpartum period. Most HIV-infected women had CD8+-mediated noncytotoxic antiviral activity. However, the activity was not correlated with alterations in CD8+ lymphocyte subsets. This study provides baseline information on changes in CD8 immunologic parameters during pregnancy and HIV infection for further studies that employ antiretroviral therapeutic regimens capable of impacting the immune response.

Lymphocyte phenotyping in infants: maturation of lymphocyte subpopulations and the effects of HIV infection.

Changes in the distribution of lymphocyte subpopulations in infants with perinatally acquired HIV infection are confounded by the rapid changes that are the result of normal maturation of the immune system. We describe the changes in seven lymphocyte phenotypes (CD3+ CD4+, CD3+ CD8+, CD8+ HLA- DR+, CD8+ CD38+, CD8+ CD57+, CD3-/ CD16+ 56+, and CD19+) over the first 2 years of life in 390 HIV-1 exposed but uninfected and 98 HIV-1-infected infants enrolled in the Women and Infants Transmission Study. The greatest changes in uninfected infants were declines in the CD3+ CD4+ lymphocytes and increases in CD8+ HLA- DR+ and CD19+ lymphocytes. All phenotypes were affected by HIV infection but the greatest changes were declines in the CD3+ CD4+ subset and increases in the CD3+ CD8+ and CD8+ HLA- DR+ subsets. Thus, this study provides reference data for the maturational changes in lymphocyte phenotypes in HIV-exposed but uninfected infants and describes the overall changes that occur with perinatally acquired HIV infection.

Immune complex-dissociated p24 antigen in congenital or perinatal HIV infection: role in the diagnosis and assessment of risk of infection in infants.

Immune complex-dissociated (ICD) HIV-1 p24 antigen assay is a rapid technique for assessing the presence of HIV gag or core protein in plasma or serum. In this study, ICD p24 antigen detection in HIV-1 infected mothers and their infants enrolled in the Women and Infants Transmission Study (WITS) was evaluated primarily as a diagnostic assay for HIV-1 detection in young infants and for its association with perinatal transmission. Plasma from 47 infected infants and 160 uninfected infants was examined, along with plasma from 197 of their mothers who had a delivery or close-to-delivery specimen. ICD p24 antigen was detected in plasma of 27.3% of infected infants at birth and in 70% to 81% at 1 to 6 months. The diagnostic specificity at birth was 90% and 98% to 100.0% at 1 to 6 months. The ICD p24 antigen concentration correlated with concurrent quantitative HIV culture results. The risk of transmission from mother to infant was higher if the mother had detectable ICD p24 antigen at or near the time of delivery (p = 0.002), but its presence did not accurately predict transmission (positive predictive value of 36%, negative predictive values of 85%). The relative ease of performing the ICD p24 antigen assay and the low cost compared with that of HIV culture or DNA PCR makes this test a useful adjunct for the diagnosis of perinatal HIV infection and for enhancing understanding of its pathogenesis, particularly where cost and availability limit access to more sensitive assays.

Elevated CD8+DR+ lymphocytes in HIV-exposed infants with early positive HIV cultures: a possible early marker of intrauterine transmission. Women and Infants Transmission Study Group.

The associations among timing of maternal-fetal human immunodeficiency virus (HIV) transmission, infant age at first positive HIV culture, and CD8+ lymphocyte activation were examined for 74 perinatally infected infants. Nineteen of the infected infants had positive HIV cultures at < or =7 days of life, and 55 had negative HIV cultures at < or =7 days but were positive later. Of the infants with early positive HIV-1 cultures, 15 of the 17 tested with DNA polymerase chain reaction methods had concordant results. The percentage of CD8+ and HLA-DR+ lymphocytes (CD8+DR+%) during the first week of life was significantly higher in infants with early compared with late positive cultures (median CD8+DR+% of 5.0% versus 2.0%, p = 0.0006). The CD8+DR+% was similar between uninfected infants and infants with late positive cultures during the first week of life (median 2%) but increased in infants with late positive cultures to 6% by 1 month. The CD4+% during the first 6 months of life was not different between infants with early or with late positive cultures, but infants with the highest CD8+DR+% at < or =7 days of life had significantly lower CD4+% at < or =7 days and at 1, 2, and 4 months of age. These data show that early CD8+ lymphocyte activation is associated with early positive HIV cultures and lower CD4+ percentages during early infancy and are consistent with the hypothesis that early positive cultures positivity may indicate in utero HIV infection.

Function and phenotype of immature CD4+ lymphocytes in healthy infants and early lymphocyte activation in uninfected infants of human immunodeficiency virus-infected mothers.

The function and phenotypes of CD4+ lymphocytes in infants are different than in adults and are modulated by maturational changes and exposure to environmental antigens. Infants of non-human immunodeficiency virus (HIV)-infected mothers and uninfected infants of HIV-infected mothers, 0 to 6 months of age, were examined for CD4+ lymphocyte function by in vitro interleukin-2 (IL-2) production and for CD4+ phenotypes by three-color flow cytometry. A minority of these uninfected infants (28%) had functional responses similar to those of healthy adult women (IL-2 production in response to anti-CD3, alloantigen, and mitogen), while the remainder were capable of responding to alloantigen and mitogen but not to anti-CD3. We did demonstrate reduced phytohemagglutinin-stimulated IL-2 production in uninfected infants born to HIV-seropositive mothers compared to that in infants from seronegative mothers. The proportions of CD3+ CD4+, CD4+ HLA-DR- CD38+, and CD4+ CD45RA+ RO- (naive) lymphocytes were much higher in infants than in adults, and the proportions of CD4+ CD45RA- RO+ (memory) and CD4+ CD25+ (IL-2 receptor-bearing) lymphocytes were lower in infants than in adults. The proportions of activated (CD4+ HLA-DR+ CD38+) and memory (CD4+ CD45RA- RO+) lymphocytes were increased in uninfected infants of HIV-infected mothers compared to infants of uninfected mothers. Therefore, T-helper-cell function is immature in many infants, but the CD4+ lymphocytes of some HIV-exposed, uninfected infants have been stimulated by antigen at an early age.

Association of maternal drug use during pregnancy with maternal HIV culture positivity and perinatal HIV transmission.

OBJECTIVE: To evaluate the relationship of drug use with maternal HIV culture positivity at delivery and perinatal HIV transmission. DESIGN: Multicenter prospective cohort study. SETTING: Obstetric and pediatric clinics in five cities in the United States. PARTICIPANTS: Five hundred and thirty HIV-infected pregnant women and their infants. MAIN OUTCOME MEASURES: Multivariate logistic regression was used to evaluate the association of 'hard drug' use (one or more of the following: cocaine, heroin/opiates, methadone, injecting drug use) assessed by self-report and urine toxicology with positive maternal HIV culture at delivery and perinatal HIV transmission. RESULTS: Forty-two per cent of women used hard drugs during pregnancy. Increased probability of a positive maternal delivery HIV culture was significantly associated with prenatal hard drug use [odds ratio (OR), 3.08] and maternal cocaine use (OR, 2.98) among HIV-infected women with > 29% CD4+ lymphocytes. After adjusting for maternal culture positivity at delivery, CD4+ lymphocyte percentage and gestational age, significantly greater transmission risk was observed with hard drug use among women with membrane rupture > 4 h. CONCLUSIONS: On the basis of self-report and urine toxicology, overall maternal hard drug use and cocaine use in the WITS cohort were associated with maternal HIV culture positivity at delivery, and maternal hard drug use was associated with perinatal transmission.

Natural history of somatic growth in infants born to women infected by human immunodeficiency virus. Women and Infants Transmission Study Group.

OBJECTIVE: To evaluate the nature and magnitude of the effect of congenitally or perinatally acquired human immunodeficiency virus (HIV) infection on somatic growth from birth through 18 months of age. STUDY DESIGN: Anthropometry was performed serially in 282 term infants born to HIV-infected women in a multicenter prospective natural history cohort study. Repeated measures analysis was used to compare z-score anthropometric indexes of weight-for-age, length-for-age, weight-for-length, and head circumference-for-age between infected and uninfected infants, with adjustment for covariates including infant gender; maternal education; prenatal alcohol, tobacco, and/or illicit drug exposure; and mean prenatal CD4+ T-lymphocyte count. A separate repeated measures model was used to assess the effect of infant zidovudine treatment on growth. RESULTS: Infants infected with HIV were an estimated average 0.28 kg lighter and 1.64 cm shorter than uninfected infants at birth, were 0.71 kg lighter and 2.25 cm shorter by 18 months of age, and had a sustained estimated average decrement of 0.70 to 0.75 cm in head circumference. Patterns of growth were similar in male and female infants. Infected infants had a progressive decrement in body mass index from birth through 6 months of age. Infection with HIV was associated with significant decrements across all standardized growth outcome measures after adjustment for covariates. Mean z scores were lower for weight by 0.612 (p < 0.001), for length by 0.735 (p < 0.001), for weight-for-length by 0.255 (p = 0.02), and for head circumference by 0.563 (p < 0.001) SD units compared with uninfected infants. Zidovudine treatment was not associated with improved growth. CONCLUSION: The effect of congenitally or perinatally acquired HIV infection on infant growth is one of early and progressive decrements in attained linear growth and growth in mass, early and sustained decrements in head growth, and marked early decrements in body mass index.

CD4+ lymphocytes in perinatal human immunodeficiency virus (HIV) infection: evidence for pregnancy-induced immune depression in uninfected and HIV-infected women.

Immune function changes during pregnancy and human immunodeficiency virus (HIV) infection. T helper function and phenotypes in HIV-infected and -uninfected pregnant and postpartum women and nonpregnant uninfected control women were studied. T helper function was assessed by interleukin-2 (IL-2) production in vitro and three-color flow cytometry. All uninfected nonpregnant subjects, 74% of uninfected pregnant subjects, and only 54% of HIV-infected pregnant subjects responded to all stimuli. All uninfected subjects 2-6 months postpartum had normal function versus 27% of infected subjects (trend P < .001). Uninfected pregnant subjects had reduced levels of CD4+CD45RA-RO+ (memory) and elevated levels of CD4+CD45RA+RO- (naive) lymphocytes. Infected pregnant subjects had elevated levels of memory, reduced levels of naive, and increased levels of CD4+HLA-DR+CD38+ (activated) lymphocytes. Increased CD4+DR+CD38+ cells correlated best with poor IL-2 function, HIV infection, and being postpartum (R2 = .79). Thus, T helper function and phenotypes are altered in pregnancy and return to baseline postpartum in uninfected but not HIV-infected women.

Perinatal substance abuse and AIDS: subject selection, recruitment, and retention.

Studies that involve subjects who are HIV infected as well as chemically dependent present special challenges to the study team. HIV infection is now so common in many parts of the country and infection can potentially influence so many commonly used endpoints for perinatal chemical dependence studies that HIV must be considered in these studies. Some of the factors that need to be taken into account in the design of studies include the staging of HIV illness, the consequences of HIV-induced CNS disease, the effects of HIV treatment, and the biases in subject selection that arise due to inaccurate information about risk factors and imbalance in sources of subjects and controls. In addition, the study team needs to remember the community and staff fear and bias that are often encountered in the care of HIV-infected patients. Fruitful sources of subjects for perinatal studies include prenatal clinics and delivery rooms, chemical dependence programs, and the network of community social agencies. Retention of this challenging group is strongly aided by the establishment of a seamless system of services that includes all aspects of general medical care, HIV specialty care, access to treatment protocols, and psychosocial care.

The frequency of antinuclear antibody (ANA) in children by use of mouse kidney (MK) and human epithelial cells (HEp-2) as substrates.

The purpose of this study was to determine the frequency of antinuclear antibody (ANA) in a normal pediatric population. Sera from 241 children (age range 4 months to 16 years) were tested for IgG ANA by use of indirect immunofluorescence and two commercially available substrates, mouse kidney and human epithelial cells. Patients' sera were tested at three different dilutions. The positivity of the ANA was related to the substrate used. When a screening dilution of 1:5 or 1:10 was used, 2.0% and 1.6% were positive with the mouse kidney or human epithelial cell substrates, respectively, but the positivity dropped to 0.4% when the dilution was 1:20 and 1:40, respectively. Only one serum was positive with both substrates.

Familial hypogammaglobulinemia with variable serum immunoglobulins. Concordance with lymphocyte ecto-5'-nucleotidase deficiency.

Four male subjects from two generations of a black family were found to have variable expression of hypogammaglobulinemia (IgG, IgM, and IgA deficiency in two, IgA deficiency in one, and IgM and IgA deficiency in another) and also to be moderately deficient in the lymphocyte plasma membrane enzyme, 5'-nucleotidase. The inheritance pattern of the immune abnormality is compatible with X linkage. The affected patients had normal numbers of complement receptor-bearing lymphocytes, variably depressed proportions of IgM- and IgD-bearing lymphocytes, and impaired ability to synthesize antibody after specific antigenic stimulation. In this family, the 5'-nucleotidase deficiency and the pattern of inheritance suggest that the different types of hypogammaglobulinemia may represent a variable expression of a common underlying genetic abnormality.

Procoagulant activity of human mononuclear leukocytes: dissociation of the effect of mitogens on procoagulant activity and mitogen-stimulated lymphocyte proliferation.

The role of mononuclear cells in generating procoagulant activity was examined by incubating Ficoll-Hypaque-separated mononuclear leukocytes with or without mitogens (phytohemagglutinin, pokeweed mitogen, and concanavalin A). The procoagulant activity was assayed by a modification of a one-stage plasma recalcification time. Significant procoagulant activity developed after 24 hr incubation and was dose dependent; mitogens alone had no effect on the clotting time. The increase in activity was paralleled by the increase in tritiated thymidine incorporation into replication DNA. However, mitomycin C had little inhibitory effect on the development of procoagulant activity, whereas thymidine incorporation was inhibited. The major procoagulant activity was associated with intact cells and not the conditioned supernatant. The removal of adherent mononuclear cells (mostly monocytes) by polystyrene bead columns abolished the procoagulant activity, whereas purification of mononuclear leukocyte populations for monocytes markedly increased the activity as compared to purified lymphocytes. The procoagulant activity was shown to act by the extrinsic limb of the coagulation sequence because of substitution factor VII-deficient plasma for normal plasma resulted in marked depression of procoagulant activity, whereas factor VIII-deficient plasma resulted in a clotting time only minimally longer then normal plasma. Thus, although procoagulant activity in cultures of mononuclear cells is stimulated by the mitogen reagent, these studies suggest that the activity may not be the result of the mitogenic effect on lymphocytes per se. Whether it is a direct effect of the mitogen on the adherent cell or is an effect of a contaminant of the mitogen reagent, such as endotoxin, remains to be determined.