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Identification of three immunologic correlates for HIV type 1 pathogenesis in youth.

ABSTRACT: To evaluate the stability and heterogeneity of cytokine and chemokine profiles in 80 youth with and without HIV-1 infection, we tested plasma samples at repeated visits without antiretroviral therapy. Among nine analytes that were quantified using multiplexing assays, interleukin 10 (IL-10), IL-18, and soluble CD30 persistently showed a positive correlation with HIV-1 viral load (Spearman ? = 0.40-0.59, p < 0.01 for all). A negative correlation with CD4(+) T cell counts (? = -0.40 to -0.60, p < 0.01 for all) was also persistent for the three analytes. Analyses restricted to 48 AIDS-free youth (96 visits) yielded similar findings, as did multivariable models in which race, sex, age, body mass index, and time interval between visits were treated as covariates. These relationships reflected two novel features observed for all three analytes. First, their presence in plasma was relatively stable between visits (? = 0.50-0.90, p < 0.03), regardless of HIV-1 infection status. Second, pairwise correlation was strong and persistent in HIV-1-seropositive youth (? = 0.40-0.59, p < 0.01), but not in HIV-1, seronegatives (p > 0.13). Additional analytes, especially eotaxin/CCL11 and SDF-1?/CXCL12, had no correlation with HIV-1-related outcomes despite their stability between visits. Overall, circulating IL-10, IL-18, and soluble CD30 could partially track unfavorable responses to HIV-1 infection in youth. These markers of persistent immune activation are individually and collectively indicative of HIV-1 pathogenesis.

SUBMITTER: Song W

PROVIDER: S-EPMC3101082 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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Identification of three immunologic correlates for HIV type 1 pathogenesis in youth.

Song Wei W Li Yufeng Y Wilson Craig M CM Tang Jianming J

AIDS research and human retroviruses 20101213 6

To evaluate the stability and heterogeneity of cytokine and chemokine profiles in 80 youth with and without HIV-1 infection, we tested plasma samples at repeated visits without antiretroviral therapy. Among nine analytes that were quantified using multiplexing assays, interleukin 10 (IL-10), IL-18, and soluble CD30 persistently showed a positive correlation with HIV-1 viral load (Spearman ρ = 0.40-0.59, p < 0.01 for all). A negative correlation with CD4(+) T cell counts (ρ = -0.40 to -0.60, p < ...[more]

PMID: 20969482

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Project description:Inducing broad spectrum neutralizing antibodies against challenging pathogens such as HIV-1 is a major vaccine design goal, but may be hindered by conformational instability within viral envelope glycoproteins (Env). Chemical cross-linking is widely used for vaccine antigen stabilization, but how this process affects structure, antigenicity and immunogenicity is poorly understood and its use remains entirely empirical. We have solved the first cryo-EM structure of a cross-linked vaccine antigen. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a CD4 binding site-specific broadly neutralizing antibody (bNAb) Fab fragment reveals how cross-linking affects key properties of the trimer. We observed density corresponding to highly specific glutaraldehyde (GLA) cross-links between gp120 monomers at the trimer apex and between gp120 and gp41 at the trimer interface that had strikingly little impact on overall trimer conformation, but critically enhanced trimer stability and improved Env antigenicity. Cross-links were also observed within gp120 at sites associated with the N241/N289 glycan hole that locally modified trimer antigenicity. In immunogenicity studies, the neutralizing antibody response to cross-linked trimers showed modest but significantly greater breadth against a global panel of difficult-to-neutralize Tier-2 heterologous viruses. Moreover, the specificity of autologous Tier-2 neutralization was modified away from the N241/N289 glycan hole, implying a novel specificity. Finally, we have investigated for the first time T helper cell responses to next-generation soluble trimers, and report on vaccine-relevant immunodominant responses to epitopes within BG505 that are modified by cross-linking. Elucidation of the structural correlates of a cross-linked viral glycoprotein will allow more rational use of this methodology for vaccine design, and reveals a strategy with promise for eliciting neutralizing antibodies needed for an effective HIV-1 vaccine.

Project description:The objectives of this study were to examine differences in physical activity behaviors as a function of human immunodeficiency virus (HIV) status and sex, to test differences in physical activity self-efficacy (PASE), body weight satisfaction (BWS), and enjoyment of physical activity as a function of HIV status, and to determine if PASE, BWS, and enjoyment are associated with daily physical activity (daily PA), muscle strengthening activities, and sedentary behavior of youth with and without HIV. A total of 250 HIV positive (HIV+) and HIV negative (HIV-) youth from Botswana aged 12-23 years (Mean = 17.87, SD = 2.24) participated in the study. The HIV+ group (n = 88) was recruited from a previous 12-month antiretroviral therapy (ART) and nutrition intervention study. The HIV- group (n = 162) was randomly selected from public junior and senior (secondary) high schools in and around Gaborone. Participants' PASE, BWS, enjoyment of physical activity, daily PA, muscle strengthening, body mass index (BMI), and sedentary behavior were obtained using items from the Youth Risk Behavior Surveillance Survey. Multivariate analysis of variance (MANOVA) showed that the HIV- group (M = 1.20, SE = 0.06, CI = 1.08 to 1.32) had significantly higher daily PA than the HIV+ group (M = 0.99, SE = 0.08, CI = 0.82 to 1.15). The HIV- group (M = 0.91, SE = 0.06, CI = 0.79 to 1.03) also reported participating significantly more in muscle strengthening activities than the HIV+ group (M = 0.63, SD = 0.08, CI = 0.47 to 0.78). Multiple regression analyses showed that higher PASE (p < .001) and greater enjoyment of PA (p < .01) were predictive of higher daily PA. HIV- participants had higher PASE but lower BWS compared to HIV+ participants. Sex and age differences were observed in muscle strengthening activities and sedentary behavior. This study supports previous findings on the association of efficacy beliefs to daily PA and muscle strengthening activities. The findings have implications for PA interventions aimed at health promotion and mitigation of the effects of living with HIV/AIDS.

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Identification of three immunologic correlates for HIV type 1 pathogenesis in youth.

Publications

Identification of three immunologic correlates for HIV type 1 pathogenesis in youth.

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