Background
With successful antiretroviral therapy (ART), while peripheral CD4+ T cells may reconstitute in most people with HIV (PWH), CD8+ T cells often remain elevated. The resulting inversion of CD4:CD8 ratio (<1) is associated with adverse clinical outcomes including non-AIDS malignancies and cardiovascular disease. The gut-associated lymphoid tissue (GALT) endures significant CD4+ T cell depletion starting during acute HIV infection. Here we determined the heterogeneity in CD4:CD8 ratio in a well-characterized cohort of PWH and investigated the predictors of intestinal CD4:CD8 ratio reconstitution (CD4:CD8>1) and its impact on systemic inflammation.
Methods
We enrolled 52 PWH on ART and with peripheral HIV-RNA<20 copies/ml, as well as 37 HIV-negative controls (HIV-NC) who underwent colonoscopy. T-cell subsets were analyzed via multiparameter flow cytometry. Peripheral inflammatory cytokines with a multiplexed proteomic inflammation panel (Olink®). Descriptive statistics are expressed as n(%) or Median(interquartile range (IQR)) as appropriate. Comparisons were performed with Mann-Whitney U test or Spearman correlation as appropriate. Multiple logistic regression was used to estimate odds ratio (OR).
Results
Overall, PWH had a lower CD4:CD8 ratio both in the peripheral blood [0.8 (0.5 – 1.28) vs 2.05 (1.6 – 3.7) p<0.001] and in the colon [0.9 (0.6-1.4 vs 1.7 (1.2-2.9)), p<0.0001] compared to HIV-NC. Among PWH, 26 (50%) individuals had colonic CD4:CD8 >1. This subset of PWH were more likely female (62% vs 38%, p=0.0158), diagnosed with HIV for a longer time [31 (18-32) vs 19(10-24)years, p=0.0347] have longer duration of most recent viral suppression [7(4-12) vs 4(2-8)years, p=0.0365] higher CD4+ T cells at enrollment [607 (453 – 947) vs 462 (294 – 664) p= 0.0262] and higher CD4+ T cell nadir [200 (92 – 306) vs 162 (39- 193)]. Multiple logistic regression showed that duration of HIV infection [OR 1.13 (95% C.I. 1.02-1.3)] and CD4= T cell nadir[OR 1.01 (95% C.I. 1.001-1.016)] were associated with colonic CD4:CD8 >1. Colonic CD4:CD8 ratio partially correlated with the peripheral blood CD4:CD8 ratio (r=0.274, p=0.068) and with the pro-inflammatory cytokines IL-20 (r= -0.413, p=0.036) and SLAMF-1 (r= -0.329, p=0.074).
Conclusions
In PWH, CD4:CD8 ratio<1 is associated with persistent elevation of inflammatory parameters. Nadir CD4+ T cells and longer duration of HIV infection are the best predictors of normalization of intestinal CD4:CD8 ratio.