Immune activation and exhaustion marker expression on T-cell subsets in ART-treated adolescents and young adults with perinatal HIV-1 infection as correlates of viral persistence

Abstract

HIV-1 infection in memory CD4+ T cells forms a latent reservoir that is a barrier to cure. Identification of immune biomarkers that correlate with HIV-1 reservoir size may aid with evaluating efficacy of HIV-1 eradication strategies, towards ART-free remission and cure. In adults living with non-perinatal HIV-1, the immune exhaustion marker PD-1 on central memory CD4+ T cells (Tcm) correlates with measures of HIV-1 reservoir size. Immune correlates of HIV-1 are less defined in adolescents and young adults with perinatal HIV-1. With multi-parameter flow cytometry, we examined immune activation (CD69, CD25, HLA-DR), and exhaustion (PD-1, TIGIT, TIM-3 and LAG-3) markers on CD4+ T cell subsets (naïve (Tn), central memory (Tcm), and the combination (Ttem) of transitional (Ttm) and effector memory (Tem) cells, in 10 adolescents and young adults living with perinatal HIV-1 (median age 15.9 years; median duration of virologic suppression 7.0 years), in whom HIV-1 reservoir size was measured with the Intact Proviral HIV-1 DNA Assay (IPDA) and an enhanced Tat/Rev limiting dilution assay (TILDA). RNA-seq was also performed on the unstimulated CD4+ T cells. The median total HIV-1 DNA concentration in memory CD4+ T cells was 211.90 copies per million CD4+ T cells. In the 7 participants with subtype B HIV-1 infection, the median intact proviral DNA load was 7.96 copies per million CD4+ T cells. Levels of HLA-DR and TIGIT on the Ttem were correlated with total HIV-1 DNA (r=0.76, p=0.015) and (r=0.72, p=0.023), respectively, but not with intact proviral load or induced reservoir size. HIV-1 DNA load was also positively correlated with transcriptional clusters associated with HLA-DR expression by RNA-seq. In contrast, PD-1 expression on Tcm was inversely correlated with total HIV-1 DNA (r=-0.67, p=0.039). Reservoir size by IPDA and TILDA were correlated (r=0.81, p=0.036). Thus, in this cohort of youths with long-standing treated perinatal infection, HLA-DR and TIGIT on Ttem were the key correlates of HIV-1 infected cell frequencies by total HIV-1 DNA, and not PD-1. Total HIV-1 DNA was negatively correlated with PD-1 expressing Tcm. These differences in longstanding perinatal HIV-1 infection compared with adult infection requires further study in larger cohorts.

Higher HIV-1 Env gp120-Specific Antibody-Dependent Cellular Cytotoxicity (ADCC) Activity Is Associated with Lower Levels of Defective HIV-1 Provirus

“…The results of this study provide evidence to support consideration of ADCC activity as an immune outcome measure in these trials. While our observation that gp120-specific ADCC activity inversely correlates only with levels of defective provirus, an intervention capable of targeting cells with defective provirus could still prove useful in decreasing the overall number of cells capable of contributing to chronic immune activation during long-term ART [10,[29][30][31][32][33].…”

“…Despite viral suppression on ART, people living with HIV tend to have increased immune activation and inflammation markers [16][17][18] which are associated with a litany of adverse health outcomes such as cardiovascular disease [19,20], neurological disorders [21], diabetes [22], cancer [23,24], and accelerated aging [25][26][27][28]. Cells harboring HIV provirus, whether intact or defective [10,[29][30][31][32][33], are drivers of this chronic immune activation due to their ability to persistently produce and present viral antigens [34], with the size of the reservoir positively associated with inflammation markers [35,36] and risk of comorbidities [21]. Additionally, several studies have demonstrated an inverse relationship between HIV reservoir size and time to viral rebound upon ART interruption, fueling speculation that a functional cure for HIV may be possible by limiting the reservoir's size [37][38][39][40].…”

Epigenome-wide characterization reveals aberrant DNA methylation of host genes regulating CD4+ T cell HIV-1 reservoir size in women with HIV

“…Our results, derived from the largest sample size reported to date, reveal specific methylation Consistent with previous findings 15 , we found that the majority of the integrated DNA proviruses were defective. Recent studies have reported that both intact and defective integrated HIV-1 DNA proviruses remain transcriptionally active under suppressive ART, contributing to prolonged immune activation [33][34][35] and greater comorbidity among PWH. Epigenetic regulation of host factors plays a critical role in HIV-1 transcriptome activation and silencing.…”

Age at ART initiation and proviral reservoir size in perinatal HIV-1 infection: considerations for ART-free remission

“…Studies in adults living with HIV-1 have demonstrated the heightened decay of cells harboring replication-competent intact proviruses and potentially replication-competent over those harboring defective proviruses [46,47]. In both adult and pediatric populations, intact proviruses levels positively correlate with total HIV-1 cpm CD4 þ T cells [46,48]. The advent of newer multiplex HIV-1 DNA assays optimized for different HIV-1 subtypes will be instrumental for identifying the composition of the proviral pool capable of eliciting rebound after ATI.…”