Protection versus pathology in aviremic and high viral load HIV-2 infection-the pivotal role of immune activation and T-cell kinetics.

BACKGROUND: Many human immunodeficiency virus (HIV)-2-infected individuals remain aviremic and behave as long-term non-progressors but some progress to AIDS. We hypothesized that immune activation and T-cell turnover would be critical determinants of non-progressor/progressor status. METHODS: We studied 37 subjects in The Gambia, West Africa: 10 HIV-negative controls, 10 HIV-2-infected subjects with low viral loads (HIV-2-LV), 7 HIV-2-infected subjects with high viral loads (HIV-2-HV), and 10 with HIV-1 infection. We measured in vivo T-cell turnover using deuterium-glucose labeling, and correlated results with T-cell phenotype (by flow cytometry) and T-cell receptor excision circle (TREC) abundance. RESULTS: Immune activation (HLA-DR/CD38 coexpression) differed between groups with a significant trend: controls

Comparing HIV-1 and HIV-2 infection: Lessons for viral immunopathogenesis.

HIV-1 and HIV-2 share many similarities including their basic gene arrangement, modes of transmission, intracellular replication pathways and clinical consequences: both result in AIDS. However, HIV-2 is characterised by lower transmissibility and reduced likelihood of progression to AIDS. The underlying mechanistic differences between these two infections illuminate broader issues of retroviral pathogenesis, which remain incompletely understood. Comparisons between these two infections from epidemiological, clinical, virologic and immunologic viewpoints provide a basis for hypothesis generation and testing in this 'natural experiment' in viral pathogenesis. In terms of epidemiology, HIV-2 remains largely confined to West Africa, whereas HIV-1 extends worldwide. Clinically, HIV-2 infected individuals seem to dichotomise, most remaining long-term non-progressors, whereas most HIV-1 infected individuals progress. When clinical progression occurs, both diseases demonstrate very similar pathological processes, although progression in HIV-2 occurs at higher CD4 counts. Plasma viral loads are consistently lower in HIV-2, as are average levels of immune activation. Significant differences exist between the two infections in all components of the immune system. For example, cellular responses to HIV-2 tend to be more polyfunctional and produce more IL-2; humoral responses appear broader with lower magnitude intratype neutralisation responses; innate responses appear more robust, possibly through differential effects of tripartite motif protein isoform 5 alpha. Overall, the immune response to HIV-2 appears more protective against disease progression suggesting that pivotal immune factors limit viral pathology. If such immune responses could be replicated or induced in HIV-1 infected patients, they might extend survival and reduce requirements for antiretroviral therapy.

Cytomegalovirus infection induces T-cell differentiation without impairing antigen-specific responses in Gambian infants.

Cytomegalovirus (CMV) infection induces profound differentiation of T cells, and is associated with impaired responses to other immune challenges. We therefore considered whether CMV infection and the consequent T-cell differentiation in Gambian infants was associated with impaired specific responses to measles vaccination or polyclonal responses to the superantigen staphylococcal enterotoxin B (SEB). While the concentration of undifferentiated (CD27(+) CD28(+) CCR7(+)) T-cells in peripheral blood was unaffected by CMV, there was a large increase in differentiated (CD28(-) CD57(+)) CD8 T-cells and a smaller increase in differentiated CD4 cells. One week post-vaccination, the CD4 cell interferon-gamma (IFN-gamma) response to measles was lower among CMV-infected infants, but there were no other differences between the cytokine responses, or between the cytokine or proliferative responses 4 months post-vaccination. However, the CD8 T cells of CMV-infected infants proliferated more in response to SEB and the antibody response to measles correlated with the IFN-gamma response to CMV, indicating that CMV infection actually enhances some immune responses in infancy.

Association of Met439Thr substitution in heat shock protein 70 gene with postoperative atrial fibrillation and serum HSP70 protein levels.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia encountered following cardiac surgery. Previously, we have shown that higher expression of heat shock protein (HSP) 70 was associated with decreased incidence of postoperative AF (PoAF), suggestive of an antiarrhythmic role. OBJECTIVE: We have hypothesised that Met493Thr substitution of one of the important hsp70 genes may cause loss of these protective antiarrhythmic effects. We therefore set out to examine the influence of hsp70 genotype on the incidence of PoAF. METHODS AND RESULTS: We prospectively recruited 244 Caucasian patients undergoing elective coronary artery bypass surgery. The median age was 65 years (40-80 years). PoAF was defined as the characteristic arrhythmia lasting for at least 15 min, occurring within first week following surgery and requiring treatment. This occurred in 48 patients (19.7%). Validated Met493Thr substitution in hsp70-Hom was determined using established techniques. Of 244 patients, genotype was determined for 242 cases. The three genotypes (MM, MT, and TT) were present at frequencies of 0.66, 0.31, and 0.03, respectively, and were in Hardy-Weinberg equilibrium. In unifactorial analysis patients carrier or homozygous for 493Thr mutation had significantly higher incidence of PoAF (Pearson chi(2) = 4.3, p = 0.037). Multivariate analysis confirmed the positive association of hsp70-Hom with PoAF (OR, 2.43; p = 0.016) independent of age, sex, previous myocardial infarction, number of distal anastomoses, and duration of ventilation, respectively. Serum HSP70 was ranging from 0.74 to 31.91 ng/ml (median, 2.89) and was not correlated with PoAF. Presence of 493Thr mutation was also significantly correlated with higher levels of serum HSP70 (p = 0.009). CONCLUSIONS: Our data show that a mutation in hsp70-Hom gene is associated with higher incidence of PoAF. These findings are consistent with our previous results and may suggest that patients harbouring this substitution will have less endogenous myocardial protection against AF in stressful situations.

Are plasma biomarkers of immune activation predictive of HIV progression: a longitudinal comparison and analyses in HIV-1 and HIV-2 infections?

BACKGROUND: Chronic immune activation is a hallmark of HIV infection and has been associated with disease progression. Assessment of soluble biomarkers indicating immune activation provide clues into pathogenesis and hold promise for the development of point-of-care monitoring of HIV in resource-poor-settings. Their evaluation in cohort resources is therefore needed to further their development and use in HIV research. METHODOLOGY/PRINCIPAL FINDINGS: Longitudinal evaluation of ßeta-2 microglobulin (ß-2 m), neopterin and suPAR soluble urokinase-type plasminogen activator receptor (suPAR) was performed with archived plasma samples to predict disease progression and provided the first direct comparison of levels in HIV-1 and HIV-2 infections. At least 2095 samples from 137 HIV-1 and 198 HIV-2 subjects with starting CD4% of ≥ 28 and median follow up of 4 years were analysed. All biomarkers were correlated negatively to CD4% and positively to viral load and to each other. Analyses in subjects living for ≥ 5 years revealed increases in median ß-2 m and neopterin and decreases in CD4% over this period and the odds of death within 5 years were positively associated with baseline levels of ß-2 m and neopterin. ROC analyses strengthened the evidence of elevation of biomarkers in patients approaching death in both HIV-1 and HIV-2 infections. Regression models showed that rates of biomarker fold change accelerated from 6-8 years before death with no significant differences between biomarker levels in HIV-1 and HIV-2 at equal time points prior to death.An 'immune activation index' analysis indicative of biomarker levels at equivalent viral loads also showed no differences between the two infections. CONCLUSIONS/SIGNIFICANCE: Our results suggest that ß-2 m and neopterin are useful tools for disease monitoring in both HIV-1 and HIV-2 infections, whereas sUPAR performed less well. Levels of immune activation per amount of virus were comparable in HIV-1 and HIV-2 infected subjects.

Immunological impact of an additional early measles vaccine in Gambian children: responses to a boost at 3 years.

BACKGROUND: Measles vaccine in early infancy followed by a dose at 9 months of age protects against measles and enhances child survival through non-specific effects. Little is known of immune responses in the short or long term after booster doses. METHODS: Infants were randomized to receive measles vaccine at 9 months of age (group 1) or 4 and 9 months of age (group 2). Both groups received a boost at 36 months of age. T-cell effector and memory responses using IFN-γ ELIspot and cytokine assays and antibody titres using a haemagglutination-inhibition assay were compared at various times. RESULTS: Vaccination at 4 months of age elicited antibody and CD4 T-cell mediated immune responses .Two weeks after vaccination at 9 months of age group 2 had much higher antibody titres than group1 infants; cell-mediated effector responses were similar. At 36 months of age group 2 antibody titres exceeded protective levels but were 4-fold lower than group 1; effector and cytokine responses were similar. Re-vaccination resulted in similar rapid and high antibody titres in both groups (median 512); cellular immunity changed little. At 48 months of age group 2 antibody concentrations remained well above protective levels though 2-fold lower than group 1; T-cell memory was readily detectable and similar in both groups. CONCLUSIONS: An additional early measles vaccine given to children at 4 months of age induced a predominant CD4 T-cell response at 9 months and rapid development of high antibody concentrations after booster doses. However, antibody decayed faster in these children than in the group given primary vaccination at 9 months of age. Cellular responses after 9 months were generally insignificantly different.