Abstract
Despite effective antiretroviral therapy (ART), HIV-infected individuals with apparently similar clinical and immunological characteristics can vary in responsiveness to vaccinations. However, molecular mechanisms responsible for such impairment, as well as biomarkers able to predict vaccine responsiveness in HIV-infected children, remain unknown. Following the hypothesis that a B cell qualitative impairment persists in HIV-infected children (HIV) despite effective ART and phenotypic B cell immune reconstitution, the aim of the current study was to investigate B cell gene expression of HIV compared to age-matched healthy controls (HCs) and to determine whether distinct gene expression patterns could predict the ability to respond to influenza vaccine. To do so, we analyzed prevaccination transcriptional levels of a 96-gene panel in equal numbers of sort-purified B cell subsets (SPBS) isolated from peripheral blood mononuclear cells using multiplexed RT-PCR. Immune responses to H1N1 antigen were determined by hemaglutination inhibition and memory B cell ELISpot assays following trivalent-inactivated influenza vaccination (TIV) for all study participants. Although there were no differences in terms of cell frequencies of SPBS between HIV and HC, the groups were distinguishable based upon gene expression analyses. Indeed, a 28-gene signature, characterized by higher expression of genes involved in the inflammatory response and immune activation was observed in activated memory B cells (CD27+CD21−) from HIV when compared to HC despite long-term viral control (>24 months). Further analysis, taking into account H1N1 responses after TIV in HIV participants, revealed that a 25-gene signature in resting memory (RM) B cells (CD27+CD21+) was able to distinguish vaccine responders from non-responders (NR). In fact, prevaccination RM B cells of responders showed a higher expression of gene sets involved in B cell adaptive immune responses (APRIL, BTK, BLIMP1) and BCR signaling (MTOR, FYN, CD86) when compared to NR. Overall, these data suggest that a perturbation at a transcriptional level in the B cell compartment persists despite stable virus control achieved through ART in HIV-infected children. Additionally, the present study demonstrates the potential utility of transcriptional evaluation of RM B cells before vaccination for identifying predictive correlates of vaccine responses in this population.
Highlights
HIV-1 vertically infected patients (HIV)-infected patients have a lower ability to induce and maintain an effective response to routine vaccinations due to the depletion of central memory CD4 T cells, T follicular helper cells, and perturbation of the B cell compartment with reduced resting memory (RM) B cells [1,2,3,4]
This study represents the first evaluation of gene expression patterns in B cell subsets, total B cells and peripheral blood mononuclear cells (PBMCs) in the field of pediatric HIV infection and in the context of immune responses to H1N1 antigen post-trivalent-inactivated influenza vaccination (TIV)
Gene signatures identified in healthy adults and in the heterogeneous pool of PBMCs [38, 39] are not directly applicable to pediatric studies [40], and most likely not even in patients affected by chronic conditions such as HIV infection [41]
Summary
HIV-infected patients have a lower ability to induce and maintain an effective response to routine vaccinations due to the depletion of central memory CD4 T cells, T follicular helper cells, and perturbation of the B cell compartment with reduced resting memory (RM) B cells [1,2,3,4]. These data have been derived from RNA extracted from whole blood or from the heterogeneous pool of peripheral blood mononuclear cells (PBMCs) of healthy volunteers [18, 23], thereby limiting interpretation due to dilution of gene transcripts derived from individual cell subsets or single cells which may be crucial for adaptive immune responses. To mitigate this drawback, analysis of purified cell subsets of interest is preferred, especially in the context of diseases that alter the distribution of specific cell subsets such as HIV infection [24, 25]
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