Browsing by Author "Ouma, Benson J."

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    Elevated Natural Killer Cell Activity Despite Altered Functional and Phenotypic Profile in Ugandans With HIV-1 Clade A or Clade D Infection
    (JAIDS Journal of Acquired Immune Deficiency Syndromes, 2009) Eller, Michael A.; Eller, Leigh Anne; Ouma, Benson J.; Thelian, Doris; Gonzalez, Veronica D.; Guwatudde, David; McCutchan, Francine E.; Marovich, Mary A.; Michael, Nelson L.; Souza, Mark S. de; Wabwire-Mangen, Fred; Robb, Merlin L.; Currier, Jeffrey R.; Sandberg, Johan K.
    Natural killer (NK) cells most likely contribute toward limiting HIV-1 replication, and investigation into their function throughout the course of infection is therefore important. We here aimed to determine the state of the NK cell compartment in Ugandans with untreated HIV-1 clade A or D infection in comparison with matched uninfected controls. Methods and Results: The function and phenotype of NK cells were investigated using 10-color flow cytometry. Surprisingly, NK cells displayed elevated production of interferon-g and macrophage inflammatory protein 1b, as well as CD107a degranulation in infected subjects. This included unexpected levels of degranulation in the CD56bright subset of NK cells and high levels of macrophage inflammatory protein 1b in CD56negative NK cells. HIV-1 infection was associated with reduced expression of KIR2DL1, NKG2A, CD161, and NKp30 in CD56dim and CD56negative NK cells, whereas lowered CD161 expression was the only alteration in the CD56bright subset. Interestingly, low CD4 counts were associated with increased levels of interferon-g and degranulation in CD56bright NK cells, as well as increased NKp44 expression in the CD56dim cells. NK cells in HIV-1–infected Ugandans display elevated activity, despite an altered functional and phenotypic profile. Furthermore, specific alterations in the CD56bright and CD56dim subsets occur in patients with severe CD4 loss.
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    Endothelial Activation, Acute Kidney Injury, and Cognitive Impairment in Pediatric Severe Malaria
    (Critical care medicine, 2020) Ouma, Benson J.; Ssenkusu, John M.; Shabani, Estela; Datta, Dibyadyuti; Opoka, Robert O.; Idro, Richard; Bangirana, Paul; Park, Gregory; Joloba, Moses L.; Kain, Kevin C.; John, Chandy C.; Conroy, Andrea L.
    Evaluate the relationship between endothelial activation, malaria complications, and long-term cognitive outcomes in severe malaria survivors.Prospectively cohort study of children with cerebral malaria, severe malarial anemia, or community children. Mulago National Referral Hospital in Kampala, Uganda.Children 18 months to 12 years old with severe malaria (cerebral malaria, n = 253 or severe malarial anemia, n = 211) or community children (n = 206) were followed for 24 months.Children underwent neurocognitive evaluation at enrollment (community children) or a week following hospital discharge (severe malaria) and 6, 12, and 24 months follow-up. Endothelial activation was assessed at admission on plasma samples (von Willebrand factor, angiopoietin-1 and angiopoietin-2, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, soluble E-Selectin, and P-Selectin). False discovery rate was used to adjust for multiple comparisons. Severe malaria was associated with widespread endothelial activation compared with community children (p < 0.0001 for all markers). Acute kidney injury was independently associated with changes in von Willebrand factor, soluble intercellular adhesion molecule-1, soluble E-Selectin, P-Selectin, and angiopoietin-2 (p < 0.0001 for all). A log10 increase in angiopoietin-2 was associated with lower cognitive z scores across age groups (children < 5, β −0.42, 95% CI, −0.69 to −0.15, p = 0.002; children ≥ 5, β −0.39, 95% CI, −0.67 to −0.11, p = 0.007) independent of disease severity (coma, number of seizures, acute kidney injury) and sociodemographic factors. Angiopoietin-2 was associated with hemolysis (lactate dehydrogenase, total bilirubin) and inflammation (tumor necrosis factor-α, interleukin-10). In children with cerebral malaria who had a lumbar puncture performed, angiopoietin-2 was associated with blood-brain barrier dysfunction, and markers of neuroinflammation and injury in the cerebrospinal fluid (tumor necrosis factor-α, kynurenic acid, tau).These data support angiopoietin-2 as a measure of disease severity and a risk factor for long-term cognitive injury in children with severe malaria.
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    Single-Cell Level Response of HIV-Specific and Cytomegalovirus-Specific CD4 T Cells Correlate With Viral Control in Chronic HIV-1 Subtype A Infection
    (JAIDS Journal of Acquired Immune Deficiency Syndromes, 2012) Eller, Michael A.; Eller, Leigh Anne; Ratto-Kim, Silvia; Ouma, Benson J.; Lo, Vicky; Souza, Mark de; Guwatudde, David; Nails, Barbara; Michael, Nelson L.; Wabwire-Mangen, Fred; Robb, Merlin L.; Marovich, Mary A.; Sandberg, Johan K.; Currier, Jeffrey R.
    HIV-1 subtype A is the second most prevalent subtype globally and is associated with reduced viral load, higher CD4 absolute counts, and slower disease progression. To study the possible role of T cells associated with better outcome, we examined CD4 and CD8 T-cell responses against HIV-1 and cytomegalovirus (CMV) in Ugandans infected with subtype A HIV-1. Methods: T-cell responses were investigated using flow cytometry and novel subtype A variant inclusive peptide (VIP) sets designed for this evaluation. CD4 T-cell responses focused primarily on Gag, whereas CD8 T-cell responses were broadly directed against Gag, gp41, and Nef VIP sets. CD4 T cells primarily responded with interferon (IFN)-g, whereas CD8 cells were more diverse with degranulation (CD107a), IFN-g, and macrophage inflammatory protein (MIP)-1b production. Results: No relationship was observed between CD8 T-cell responses and the HIV-1 load. Similarly, the frequency of CD4 T cells responding to these antigens did not associate with viral control. However, in CD4 T cells responding against Gag or CMV, the IFN-g intensity, indicative of the production at the singlecell level, was inversely proportional to viral load. No significant relationship was found between T-cell effector/memory phenotype and viral control. Conclusions: The per cell production of IFN-g in CD4 T cells responding to HIV-1 or CMV correlated with viral control in chronic HIV-1 subtype A infection. These data suggest that quantitative aspects at the single-cell level may be more important than the frequency of antigen-specific CD4 T cells in HIV-1 subtype A infection control.