Plasma viremia and virus phenotype are correlates of disease progression in vertically human immunodeficiency virus type 1-infected children.

OBJECTIVE: To analyze the relationships among HIV-1 plasma viremia, phenotype and CD4 T cell counts in vertically infected children. METHODS: Plasma viremia was quantified in 37 vertically infected children at different stages of the disease by a standardized molecular assay. Virus isolation and non-syncytia-inducing or syncytia-inducing (SI) HIV-1 phenotype evaluation were performed in parallel. RESULTS: HIV-1 RNA genomes were found to be significantly different in CDC clinical classes N, A, B and C (P = 0.0135) and in immunologic classes 1, 2 and 3 (P = 0.0110). None of the children in Class N or A harbored HIV-1 isolates with SI phenotype, whereas SI primary isolates were detected in 2 of 7 (29%) and 7 of 10 (70%) Class B and C children, respectively. Similarly SI variants were present in only 9 of 13 children in immunologic Class 3 (70%). When stratified according to the increasing severity of virologic status, the children showed a significant difference (P = 0.0458) in viral burden. CONCLUSIONS: Clinical symptoms, the most dramatic being reduction in the number of CD4 lymphocytes, and the highest plasma viremia levels were observed in the children in whom fast replicating, highly cytopathic SI variants were isolated. These data extend the virologic characterization of vertically HIV-1 infected children and suggest that both the plasma viremia levels and phenotype of primary isolates are viral correlates of disease progression in vertically infected children.

Long-term resistance to HIV infection in vertical HIV infection: cytokine production, HIV isolation, and HIV phenotype define long-term resistant hosts.

We analyzed immunologic (CD4 and CD8 slopes; interferon-gamma, interleukin-2, interleukin-10, and chemokines production; concentration of IgE; beta 2-microglobulin) and virologic (p24; HIV isolability and phenotype; plasma viremia) parameters in HIV vertically infected children > or = 8 years of age without disease progression or mild symptoms and an absolute CD4+ count > or = 500/microliter with CD4+ percentage > or = 25%. The results were compared to those of two control groups: (1) slow progressors, children > or = 8 years of age with moderate symptomatology and/or moderate CD4 depletion, and (2) progressors, children > or = 8 years of age with severe clinical disease and/or severe CD4 depletion. Pediatric long-term resistant hosts were characterized by higher production of interleukin-2 and interferon-gamma and lower production of interleukin-10, normal concentration of IgE, HIV isolates with a non-syncytium-inducing phenotype, and lower plasma viremia. This condition was not associated with the concentration of beta 2-microglobulin, p24, and chemokines, or with HIV isolability. The IL-10/IL-2 ratio best correlated with both CD4 counts and disease progression. Thus, vertically infected children showing resistance to disease progression are immunologically and virologically distinct from those in whom progressive HIV infection is observed.

HIV type 1 phenotype correlates with the stage of infection in vertically infected children.

A cohort of 39 vertically infected children (class N, A, B, and C of the CDC HIV classification for pediatric infection) was studied by virus isolation and non-syncytium inducing (NSI)/syncytium inducing (SI) HIV-1 phenotype evaluation. The HIV-1 isolates were recovered from PBMCs and the MT-2 cell line was used to perform the syncytium assay. HIV-1 could be isolated in 34 of 39 (87%) infected children, regardless of the clinical and immunological stage of the disease. Class N and A subjects harbored exclusively NSI strains, whereas the SI phenotype was detected in two of eight class B and five of nine class C patients. All of the SI variants were observed in severely CD4-depleted children (class 3 patients). The capability of pediatric HIV-1 isolates to induce a cytopathic effect is associated with the clinical status and the degree of CD4 depletion. These data suggest that the biological properties of HIV-1 isolates in children do not differ from those observed in adults, and that viral phenotype strictly correlates with disease progression in vertically infected children.

Virologic and immunologic markers of disease progression in pediatric HIV infection.

Correlates of progression of human immunodeficiency virus (HIV) infection to AIDS include the reduction in CD4+ T cells and the emergence of syncytium-inducing (SI) HIV variants. It has been suggested that progressive defects in interleukin 2 (IL-2), IL-12, and IFN- gamma production (type 1 cytokines), and increased production of IL-4 (and of IL-4-driven hyper-IgE), IL-6, and IL-10 (type 2 cytokines), could provide another correlate of disease progression. To determine the possible association among these markers, viral phenotype, cytokine production, IgE serum concentration, and rate of CD4 depletion were analyzed in a cohort of vertically HIV-infected children. We report that significantly higher production of type 2 cytokines and augmented IgE concentration are observed in children in whom HIV SI is isolated. In addition, we observed that the isolation of HIV SI and the production of high quantities of type 2 cytokines are correlated with increased loss of CD4 T cells in the 12 months preceding the determinations. These data suggest that the virologic and immunologic parameters characteristic of advanced HIV infection may be associated in pediatric HIV infection, and indicate a virologic-immunologic pathogenesis leading to the appearance of AIDS.

Immunologic characterization of children vertically infected with human immunodeficiency virus, with slow or rapid disease progression.

Cytokine production of unstimulated and mitogen-stimulated peripheral blood mononuclear cells of 31 children vertically infected with human immunodeficiency virus type 1 (HIV) and with different patterns of disease progression was evaluated to establish possible correlations between the immunologic and the clinical findings. Production of interferon gamma and interleukin-2 (type 1 cytokines), and of interleukin-4 and interleukin-10 (type 2 cytokines), was analyzed in seven symptom-free patients (Centers for Disease Control and Prevention class P-1B), 10 patients with mild symptoms (class P-2A), and 14 patients with severe symptoms (class P-2B-F). Cytokine production was compared with that of 10 age- and sex-matched control subjects who were seronegative for HIV. The HIV-infected patients produced significantly fewer type 1 cytokines and significantly more type 2 cytokines than the uninfected control subjects. No differences in the production of interferon gamma and interleukin-2 were detected among the different clinical categories of HIV-infected patients. In contrast, interleukin-4 production was augmented in the patients with class P-2A (p < 0.05) and class P-2B-F HIV infection (p < 0.03), in comparison with the children with class P-1B infection. The increase in interleukin-4 production was paralleled by an increase in the number of children with hyperimmunoglobulinemia E in each of the clinical groups (0% in class P-1B; 40% in class P-2A; and 71% in class P-2 B-F infection). Similarly, interleukin-10 production was increased both in patients with class P-2A and in those with class P-2B-F infection, in comparison with the children with class P-1B disease (p < 0.006 and < 0.04, respectively). These data indicate (1) that vertically acquired HIV infection results in decreased production of type 1 cytokines and in increased production of type 2 cytokines, and (2) that an increased production of type 2 cytokines correlates with hyperimmunoglobulinemia E and is present in, and may be characteristic of, the symptomatic phases of childhood HIV infection.

Elevation of IgE in HIV-infected children and its correlation with the progression of disease.

BACKGROUND: According to recent data, a switch from a TH1 to a TH2 pattern of cytokines might be a critical step in the progression of human immunodeficiency virus (HIV) infection. Previous studies have demonstrated a disturbance in IgE synthesis in HIV-infected adults. METHODS: Fifty-eight children infected vertically with HIV and 35 children with seroreversion, aged 4 months to 11 years, were evaluated for IgE serum level, CD4+ cell count, skin prick test responses to common airborne and food allergens, individual and family history of atopy, and presence of opportunistic infections. In thirty of the 58 HIV-infected children serum interleukin-4 and interferon-gamma levels were assessed. Thirty-three of the 58 HIV-infected children had a follow-up of 1 year for IgE levels, CD4+ cell count, and occurrence of opportunistic infections and recurrent bacterial infections. RESULTS: Both IgE concentration and the percentage of children with IgE elevation were markedly increased (with no correlation to skin prick test responses or opportunistic infections) in the group of 58 HIV-infected children as compared with the 35 children with seroreversion (p < 0.05). The same parameters were higher in children with acquired immunodeficiency syndrome as compared with children with asymptomatic or mildly symptomatic disease (p < 0.05). Serum interleukin-4 and interferon-gamma levels do not account for IgE hyperproduction. There was a significant association between persistent IgE elevation and severe decline ( > or = 30% over 1 year) in CD4+ counts, as well as increased susceptibility to bacterial infections. CONCLUSIONS: Our study demonstrates a spectrum of IgE dysfunction in children, which is similar to that observed in adults. A persistent IgE hyperproduction appears to be associated with a severe decline in CD4+ cell count, suggesting that this clinical test is a useful marker of disease progression.