Background:
Understanding factors that affect timing of viral rebound after antiretroviral treatment (ART) interruption will accelerate efforts toward inducing sustained HIV remission. Here, we evaluated whether HIV DNA size, activity, and molecular diversity as well as peripheral T cell phenotypes prior to treatment interruption predict time to HIV rebound in individuals interrupting ART initiated during primary infection.
Methods:
The Zurich Primary HIV Infection Cohort (ZPHI) enrolled people with HIV (PWH) who started ART during primary infection and interrupted therapy after a median of 18 months of viral suppression. We selected stored cross-sectional samples (pre-ART interruption) from 70 ZPHI participants for this study. Using flow cytometry, we evaluated frequencies of T cell maturation subsets, levels of T cell activation (HLA-DR+CD38+), exhaustion (PD-1+, TIGIT+), proliferation (Ki67+) degranulation/cytotoxicity (CD107a+) and regulatory CD4+ T Cells (CD25+FoxP3+). On a subset of 38 individuals, we measured levels of cellular total HIV DNA (gag), HIV RNA (spliced and multiple spliced encoding tatrev) by digital droplet PCR, and molecular diversity by deep sequencing of HIV DNA (full length envelope). We evaluated associations between time to rebound (i.e., reaching 1,000 cps/ml) and each virologic and immunologic factors using univariate Cox proportional hazard models for interval censored outcomes without adjusting for multiple comparisons.
Results:
Main cohort characteristics were 14% female, 70% Caucasians, median age 39, median Nadir CD4+ 289 cells/ml. Lower molecular diversity of HIV DNA envelope pre-ART interruption was significantly associated with longer time to rebound (p=0.048), but not the size (HIV DNA) or activity (HIV RNA) of the HIV reservoir. Among immunological factors, lower percentage of effector and terminally differentiated CD4+ and CD8+ T cells expressing markers of activation and degranulation/cytotoxicity were consistently associated with longer time to rebound (all P< 0.05, see Table 1).
Conclusions:
We found viral and immune factors associated with delayed rebound of HIV RNA after ART interruption in PWH starting ART during early infection. Our results suggest that a combination approach will be necessary to boost viral control, including early ART start to limit viral diversity and additional interventions to reduce or reverse T cell activation and degranulation/cytotoxicity.
Table 1: Factors significantly predictive of time to viral rebound 