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. 2018 Jan 24;10(425):eaam6354.
doi: 10.1126/scitranslmed.aam6354.

Integrin α4β7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes

Aida Sivro  1   2 , Alexandra Schuetz  3   4   5 , Daniel Sheward  6 , Vineet Joag  7 , Sergey Yegorov  7 , Lenine J Liebenberg  1 , Nonhlanhla Yende-Zuma  1 , Andrew Stalker  2 , Ruth S Mwatelah  2 , Philippe Selhorst  6 , Nigel Garrett  1 , Natasha Samsunder  1 , Anisha Balgobin  1 , Fatima Nawaz  8 , Claudia Cicala  8 , James Arthos  8 , Anthony S Fauci  8 , Aggrey Omu Anzala  9   10 , Joshua Kimani  2   10 , Bernard S Bagaya  11   12 , Noah Kiwanuka  11   13 , Carolyn Williamson  1   6 , Rupert Kaul  7   14   15 , Jo-Ann S Passmore  1   6   16 , Nittaya Phanuphak  17 , Jintanat Ananworanich  4   17   18 , Aftab Ansari  19 , Quarraisha Abdool Karim  1   20 , Salim S Abdool Karim  1   20 , Lyle R McKinnon  1   2   10 ; CAPRISA004 and RV254 study groups
Affiliations

Integrin α4β7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes

Aida Sivro et al. Sci Transl Med. .

Abstract

The gastrointestinal (GI) mucosa is central to HIV pathogenesis, and the integrin α4β7 promotes the homing of immune cells to this site, including those that serve as viral targets. Data from simian immunodeficiency virus (SIV) animal models suggest that α4β7 blockade provides prophylactic and therapeutic benefits. We show that pre-HIV infection frequencies of α4β7+ peripheral blood CD4+ T cells, independent of other T cell phenotypes and genital inflammation, were associated with increased rates of HIV acquisition in South African women. A similar acquisition effect was observed in a Kenyan cohort and in nonhuman primates (NHPs) after intravaginal SIV challenge. This association was stronger when infection was caused by HIV strains containing V2 envelope motifs with a preference for α4β7 binding. In addition, pre-HIV α4β7+ CD4+ T cells predicted a higher set-point viral load and a greater than twofold increased rate of CD4+ T cell decline. These results were confirmed in SIV-infected NHPs. Increased frequencies of pre-HIV α4β7+ CD4+ T cells were also associated with higher postinfection expression of lipopolysaccharide binding protein, a microbial translocation marker, suggestive of more extensive gut damage. CD4+ T cells expressing α4β7 were rapidly depleted very early in HIV infection, particularly from the GI mucosa, and were not restored by early antiretroviral therapy. This study provides a link between α4β7 expression and HIV clinical outcomes in humans, in line with observations made in NHPs. Given the availability of a clinically approved anti-α4β7 monoclonal antibody for treatment of inflammatory bowel disease, these data support further evaluation of targeting α4β7 integrin as a clinical intervention during HIV infection.

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Conflict of interest statement

Competing interests: The authors do not declare any conflicts of interest.

Figures

Figure 1.
Figure 1.. Effect of pre-infection β7Hi CD45RA− CD4+ T cell frequency on HIV acquisition risk in CAPRISA 004 study.
A) Parent gating strategy for the analysis of frozen PBMCs from the CAPRISA 004 study. The staining profile of PBMC from a representative HIV-uninfected participant is shown. β7 gating is shown for one representative control and one case sample obtained at a HIV-uninfected time point. B) Stability of β7Hi CD4+ T cells overtime. Samples from 10 patients (x axis) were assayed from 3-5 HIV uninfected visits (colored bars) depending on sample availability. Median coefficient of variation (CV) between HIV uninfected time points for every individual was calculated. Individual CVs are indicated in the graph. C) Sampling time points for the pre-HIV β7Hi measurements. The number of days prior to HIV infection that the sample was obtained (x-axis) is plotted against β7Hi frequency (y-axis). The dashed line represents the median Integrin β7Hi expression by CD4+ T cells D) The frequency of β7Hi CD45RA−CD4+ T cells in cases (n=59) and controls (n=106). Conditional logistic regression analysis was used to measure the effect of pre-infection β7Hi levels on HIV acquisition. E) Spearman correlation between α4β7Hi CD4+ T cell frequency between cervix and blood in the Nairobi/Uganda study (n=54) F) Infecting viral V2 motifs and pre-HIV frequencies of β7Hi CD4+ T cells G) Pre-HIV frequencies of β7Hi CD4+ T cells in cases infected by viruses with V2 loops containing the P/SDI/V and LDI/V motifs (n=32). Differences between groups were analyzed using unpaired t-test.
Figure 2.
Figure 2.. Effect of pre-infection β7Hi CD45RA− CD4+ T cell frequency on disease progression in patients that became infected in CAPRISA 004/002 study.
A) Correlation between pre-infection β7Hi frequency and peak VL (n= 49) B) Correlation between pre-infection β7Hi frequency and set point viral load (n=49) C). The frequency of pre-infection β7Hi cells as a predictor of CD4+ T cells decline<500 cells/μl (n=48) analyzed using Cox regression models D) Pre-infection β7Hi cells as a predictor of CD4+ T cells decline<500 cells/μl in a multivariable Cox regression model correcting for age, study site, study arm, set point viral load, DMPA use and HSV-2 status at baseline E) Correlation between pre-infection β7Hi frequency and mean CD4:CD8 ratio < 180 days post infection (n=48) F) Correlation between pre-infection B7Hi frequency and mean CD4:CD8 ratio > 180 days post infection (n=48) G) Median post-infection plasma levels of LBP expression in cases with pre-infection β7Hi CD4+ T cell expression above (n=22) and below(n=22) median. H) Longitudinal plasma LBP levels at 6 month intervals in CAPRISA 002 cases. Linear mixed models were used to compare LBP levels over time. Spearman correlation was used to analyze associations between the two variables.
Figure 3.
Figure 3.. Depletion and post cART recovery of β7Hi and CCR5+ CD4+ T cells in peripheral blood and cells isolated from sigmoid colon during acute infection in RV254.
Frequencies of (A) β7Hi and (B) CCR5+ CD4+ T cells in the peripheral blood at different Fiebig (F) stage [HIV- (n=9), FI (n=8), FII (n=11), FIII(n=20) and chronic HIV infected (CHI, n=5)] C) Frequencies of β7Hi CD4+ T cells in the colon [HIV- (n=9), FI (n=8), FII (n=6), FIII(n=13) and CHI (n=5)] D) Frequencies of CCR5+ CD4+ T cells in the colon [HIV- (n=9), FI (n=8), FII (n=10), FIII(n=18) and CHI (n=8)]. Frequencies of (E) β7Hi and (F) CCR5+ CD4+ T cells in the peripheral blood following ART initiation in either FI [red data points, at baseline (n=8), 6m(n=8), 24m(n=7)] or FIII [black data points, at baseline (n=18), 6m(n=18) and 24m(n=14)]. (G) Frequencies of β7Hi CD4+ T cells in the colon following ART initiation in either FI [red data points, baseline (n=8), 6m(n=5), 24m(n=3)] or FIII [black data points, baseline (n=13), 6m(n=15) and 24m(n=9)] (H) CCR5+ CD4+ T cells in the colon following ART initiation in either FI [red data points, at baseline (n=8), 6m(n=6), 24m(n=4)] or FIII [black data points, at baseline (n=18), 6m(n=17) and 24m(n=9)]. The dashed lines represent the median of cells in healthy control participants (green, n=9) and in CHI patients (red, n=5). For A to D, Kruskal Wallis test was used followed by a Dunn’s multiple comparisons test to look for differences between HIV uninfected (HIV−) group and groups at different Fiebig stages. For E to H Friedman test was used to test for significant differences within each ART initiation group (FI and FIII). *P<0.05, **P< 0.01 and ***P<0.001.
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