RESUMO
BACKGROUND: India is hyperendemic to dengue and over 50% of adults are seropositive. There is limited information on the association between neutralizing antibody profiles from prior exposure and viral RNA levels during subsequent infection. METHODS: Samples collected from patients with febrile illness was used to assess seropositivity by indirect ELISA. Dengue virus (DENV) RNA copy numbers were estimated by quantitative RT-PCR and serotype of the infecting DENV was determined by nested PCR. Focus reduction neutralizing antibody titer (FRNT) assay was established using Indian isolates to measure the levels of neutralizing antibodies and also to assess the cross-reactivity to related flaviviruses namely Zika virus (ZIKV), Japanese encephalitis virus (JEV) and West Nile virus (WNV). RESULTS: In this cross-sectional study, we show that dengue seropositivity increased from 52% in the 0-15 years group to 89% in >45 years group. Antibody levels negatively correlate with dengue RNAemia on the day of sample collection and higher RNAemia is observed in primary dengue as compared to secondary dengue. The geometric mean FRNT50 titers for DENV-2 is significantly higher as compared to the other three DENV serotypes. We observe cross-reactivity with ZIKV and significantly lower or no neutralizing antibodies against JEV and WNV. The FRNT50 values for international isolates of DENV-1, DENV-3 and DENV-4 is significantly lower as compared to Indian isolates. CONCLUSIONS: Majority of the adult population in India have neutralizing antibodies to all the four DENV serotypes which correlates with reduced RNAemia during subsequent infection suggesting that antibodies can be considered as a good correlate of protection.
India is one of the hotspots of dengue infection. The objective of the study was to assess whether having previous exposure to dengue virus could influence how the body will respond to repeat infections with dengue virus. Here, we analysed samples from febrile patients to measure the amount of dengue virus genetic material in the blood, the type of virus and the amount of antibodies, which are proteins produced by the host in response to dengue virus infection. The majority of patient samples demonstrated the capability to restrict all four types of dengue virus in circulation within the country, but reduced capacity to restrict when it comes to international dengue virus types. These data will help to inform future dengue vaccine design and clinical studies in India.
RESUMO
BACKGROUND: Adaptive or memory natural killer (NK) cells with epigenetic imprints similar to memory T cells have been shown to develop in response to cytomegalovirus (CMV) infection with upregulation of activating receptor NKG2C. These cells have been shown to possess strong anti-tumour efficacy both in-vitro as well as in-vivo. OBJECTIVES: To determine if reconstitution of adaptive NK cells (CD56dimNKG2C+NKG2A-) in patients with advanced leukemia undergoing haploidentical HCT had any impact on disease progression (DP). STUDY DESIGN: The study cohort comprised of 60 patients with advanced acute leukemia, aged 2-65 years, receiving myeloablative PTCy based haploidentical transplantation from CMV seropositive donors, followed by CTLA4Ig-primed donor lymphocyte infusions (DLI). They were evaluated for the kinetics of reconstitution of adaptive NK cells, both phenotypic and functional, at days +30,+60, +90 and at regular intervals, to 3 years of follow-up, in relation to DP. Reconstitution of adaptive NK cells was compared with a retrospective cohort of patients in the same protocol receiving DLI without CTLA4Ig. RESULTS: Non-relapse mortality, acute and chronic GVHD were 5.1%, 10.3% and 14.5%. DP was 17.5% at a median follow-up of 28 months. Adaptive NK cells were significantly higher in patients without DP at days+30, +60 and +90 (p = 0.0001), irrespective of CMV reactivation and remained elevated until 36 months post-HCT. These cells maintained their functional competence as measured by robust interferon-gamma production with higher expressions of KIR, NKG2D and CD57, without any increase in PD1 expression. Grafts from donors with higher adaptive NK cells were associated with a lower risk of DP (p = 0.0001). In multivariate analysis, adaptive NK cell recovery at day +90 had the most favorable impact on DP (HR-0.7). Tregs reconstituted briskly along with the adaptive NK cells and were sustained as well, without compromising the GVL effect. Comparison with a retrospective cohort receiving the same protocol with DLI without CTLA4Ig, showed a superior reconstitution of adaptive NK cells in those receiving CTLA4Ig-DLI (p < 0.0001). CONCLUSION: Our study suggests that myeloablative transplantation from CMV seropositive haploidentical donors augmented with CTLA4Ig-primed DLI might favor early and sustained expansion of functionally competent adaptive NK cells irrespective of CMV reactivation, with a favorable outcome.