Background:
Antiretroviral therapy (ART) suppresses HIV replication in people living with HIV (PLWH), but is not curative. Upon interruption of ART, viral typically rebounds within a period of several weeks, although prolonged time-to-rebound occurs in some individuals through unclear mechanisms. In this study, we used CyTOF to identify phenotypic features of T cells associated with time-to-rebound in the ACTG 5345 analytical treatment interruption (ATI) cohort, which included both individuals who initiated treatment during the acute and chronic phases of HIV infection.
Methods:
We designed a 40-parameter CyTOF T cell phenotyping panel, which included markers of T cell differentiation, activation, exhaustion, and homing. We applied the panel on pre-ATI blood specimens from 33 chronic-treated and 12 acute-treated individuals from the ACTG 5345 cohort. We then performed clustering analysis to identify associations with time-to-rebound upon ATI.
Results:
11 clusters were identified using a leave-one-out cross-validation model with a resolution of 0.2. Within the 11 clusters, 2 clusters were significantly (p< 0.01) and positively associated with longer time-to-rebound. One of these, Cluster 8, consisted of memory CD8+ T cells expressing high levels of CD49d, the integrin alpha subunit that makes up half of the α4β1 homing receptor associated with mucosal tissue homing, and that has been used as a marker of T resident memory (Trm) cells. Cluster 8 cells also expressed CD73, a hypoxia-regulated ectonucleotidase recently identified as host determinant of HIV latency. The second associated cluster, Cluster 10, were memory CD4+ T cells that expressed high levels of the co-stimulatory molecule CD28, and CD29, the beta 1 integrin chain of α4β1. Interestingly, T cells in both clusters, and not any of the other clusters, expressed high levels of CD103, a Trm marker.
Conclusions:
These data demonstrate that expression of CD103 on T cells may serve as a marker predicting longer time-to-rebound. More broadly, the findings suggest that different subsets of CD4+ and CD8+ Trm with distinct features associate with temporary ART-free HIV control. To what extent these cells play an active role in this control remains to be deciphered.