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Reduced Peripheral a4ß7+ CD4+ T Cells Correlate With Mucosal CD4+ T Cell Loss in AHI
Alexandra Schuetz1; Chayada Sajjaweerawan1; Nittaya Phanuphak2; Rungsun Rerknimitr3; Ponpen Tantivayakul2; Nitiya Chomchey2; Merlin L. Robb4; Robin Dewar5; Mark de Souza2; Jintanat Ananworanich6; for the RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups
1US AFRIMS, Bangkok, Thailand;2SEARCH, Bangkok, Thailand;3Chulalongkorn Univ, Bangkok, Thailand;4US Military HIV Rsr Prog, Walter Reed Army Inst of Rsr, Silver Spring, MD, USA;5Frederick Cancer Rsr and Develop Cntr, Frederick, MD, USA;6Military HIV Rsr Prog, Bethesda, MD, USA
Intestinal CD4+CCR5+ T cells are rapidly and profoundly depleted early during acute HIV infection (AHI) contributing to persistent systemic immune activation. The integrin homing receptor α4β7 is thought to play a major role in the propagation and dissemination of HIV-1. CD4+ T cells expressing high levels of α4β7 (α4β7hi) are CD45RO+ and also express high levels of CCR5 and activation markers. Due to the difficulty monitoring intestinal CD4+ T cells we evaluated α4β7 as a predictive marker for the loss of intestinal CD4+CCR5+ T cells during early AHI.
Thirty-three subjects underwent phlebotomy and sigmoid biopsy at the time of AHI diagnosis. AHI was grouped using the fourth generation (4thG) immunoassay (IA) staging, with all stages being HIV RNA+ (Stage I: 4thGIA-/3rdGIA-; II: 4thGIA+/3rdG-; III: 4thGIA+/3rdGIA+). Of the 33 subjects 14 were 4thGI and 19 4thGIII. Multiparameter flow-cytometry was performed to determine the frequency of mucosal CD4+CCR5+ T cells and the frequency of peripheral β7high CD4+ T cell subsets at the time of AHI diagnosis.
During 4thGI the frequency of mucosal CD4+CCR5+ T cells and peripheral β7high CD4+ T cells remained comparable to HIV-uninfected subjects, however with progression of 4thG stage a significant decrease in frequency was observed (Table 1). The frequency of peripheral β7high CD4+ T cells correlated inversely with plasma (r=-0.52, p<0.001) and sigmoid (r=-0.36, p=0.03) HIV RNA and directly with the loss of mucosal CD4+CCR5+ T cells (r=0.36, p=0.02). Additionally, we observed a loss of peripheral central memory (CM; CD27+CD45RO+) CD4+ T cells expressing CCR5 and β7high during progression of AHI (Table 1). The frequency of CCR5+ β7high CM CD4+ T cells showed a strong direct correlation with the loss of mucosal CD4+CCR5+ T cells (r=0.44, p=0.008) and correlated inversely with plasma HIV RNA (r=-0.51, p=0.002).
The loss of peripheral β7high CD4+ and CCR5+ β7high CM CD4+ T cell subsets closely paralleled the loss of mucosal CD4+CCR5+ T cells during early AHI. This is consistent with the hypothesis that α4β7 has a role in the selective depletion of mucosal CD4+ T cells, and indicates that monitoring β7high expression on peripheral blood CD4+ T cells could be a useful surrogate marker to estimate mucosal CD4+CCR5+ T cell loss.