Lower peripheral blood CD14+ monocyte frequency and higher CD34+ progenitor cell frequency are associated with HBV vaccine induced response in HIV infected individuals☆
Introduction
Numerous factors are involved in a successful vaccine response to induce long lasting immune memory [1]. The adaptive arm of the immune system requires adequate antigen uptake and presentation by antigen presenting cells (APC) and adequately responsive T and B lymphocytes capable of forming an effective memory response [2], [3]. Among HIV-infected individuals, vaccine responses, including to hepatitis B (HBV) vaccine, are inadequate [4], [5], [6], [7], [8]. Given the increasing incidence of mortality due to hepatic disease among HIV-infected persons, improved HBV vaccine approaches, including alternative adjuvants, are needed to reduce the burden of co-infection among this at risk population [9]. However, the complex milieu of immune defects associated with HIV infection create unique challenges in formulating appropriate vaccine enhancing adjuvants. GM-CSF, when administered as a vaccine adjuvant, has been observed to improve HBV vaccine efficacy in the setting of renal failure [10], [11] and in the setting of HIV infection [12]. In AIDS Clinical Trials Group (ACTG) study A5220, GM-CSF administration was not found to improve HBV vaccine responses [13]. We hypothesized that impairment in antigen presenting cell expansion, differentiation, recruitment, or expansion of a cell population that blocks immune responses in HIV infection underlies the failure of GM-CSF to enhance antibody responses to HBV vaccine.
CD34+ hematopoietic progenitor cells can rapidly differentiate into many cell types, including monocytes and the highly potent APC, dendritic cells [14], [15], [16]. Additionally, CD34+ progenitor cells have been described to have T cell suppressive activity that is influenced by a number of factors, including the presence of GMCSF [17]. These myeloid-derived suppressor cells (MDSCs) have been described to a greater degree in the oncology literature [18] as being a heterogeneous population identified as CD34+, CD33+/lineage marker (including CD14−HLADR−) and CD11b+CD14−CD33+ [18]. Additionally, another sub-population of MDSCs has been described as CD14+HLADR− [19]. These cells have been regularly identified in cancer patients, have been reported as more prevalent in cancer patient vaccine nonresponders compared to responders, and their numbers are increased after administration of GM-CSF. The CD14 marker is commonly used for identification of monocytes. Monocytes can present antigen themselves and differentiate into dendritic cells in the presence of GM-CSF, but are also capable of contributing to an immune suppressive milieu [20], [21]. Based on these previous findings, we asked if the failure of GM-CSF to augment vaccine responses in A5220 might be related to expansion or induction of suppressive cell populations.
In this exploratory analysis from A5220, we measured the frequency of hematopoietic progenitor cells (CD34+), monocytes (CD14+), and MDSCs (CD14+HLADR−CD11b+, CD34+CD14−HLADR−CD11b+, CD34+CD14−HLADR−), as well as the expression of the GM-CSF receptor (CD116) on monocytes and MDSCs at baseline and week 4 of HBV vaccine protocol. We hypothesized that vaccine response was associated with the baseline prevalence or GM-CSF induced change in frequency of these cells.
Section snippets
A5220 study and samples for flow cytometric analysis.
ACTG trial A5220 was a randomized open-label pilot study to evaluate the effectiveness and safety of GM-CSF adjuvant combined with HBV vaccine. Forty-eight HIV-infected subjects, naïve to HBV vaccine, with CD4 T cell counts ≥ 200/mm3, and seronegative for HBV and HCV were randomized to administration of 40 mcg HBV vaccine at weeks 0, 4 and 12, with or without 250 mcg GM-CSF as adjuvant, 24 in each study arm. HBV specific antibody titers (HBsAb) were measured using Vitros Immunodiagnostics Products
Results
Among the 47 subjects with available samples for analysis here, the study subject median age was 47 years; 79% were male; 53% white, 32% black and 15% Hispanic. The median CD4 cell count at entry was 444 cells/mm3, 77% were on antiretroviral treatment and 53% had undetectable HIV-1 RNA (<50 copies/mL).
As recently described [13], there was a modest trend towards a higher proportion of vaccine responders (HBsAb ≥ 10 mIU/mL) in the GM-CSF arm at week 4 (26% vs. 9%, p = 0.24), but by week 8 this trend
Discussion
In the setting of HIV infection, vaccination-induced response to neoantigen has been best predicted by baseline naïve CD4+ cell number, decrease in HIV level after initiation of HIV therapy, nadir CD4+ cell numbers, and increased proportions of CD4+ cells expressing CD28 [6], [8]. Similarly, in uninfected individuals, younger age and greater frequency of naïve CD4+ cell number are associated with better responses to HBV immunization [22]. The numbers and function of antigen presenting cells and
Acknowledgements
The authors thank all of the study participants who have devoted their time and effort to this research. Grant support: This research was supported in part by the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (Grants: AI 68636 and AI 68634), the Case ACTG ISL, NIH R01 DK068361 to DDA, SDAC: AI038855 and AI 068634, NYU: AI069532, UCSF:AI0801, Wash U:AI069495.
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