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Phenotypic signatures of immune selection in HIV-1 reservoir cells

Weiwei Sun, Ce Gao, Ciputra Adijaya Hartana, Matthew R. Osborn, Kevin B. Einkauf, Xiaodong Lian, Benjamin Bone, Nathalie Bonheur, Tae-Wook Chun, Eric S. Rosenberg, Bruce D. Walker, Xu G. Yu, Mathias Lichterfeld
Nature Jan 2023

Human immunodeficiency virus 1 (HIV-1) reservoir cells persist lifelong despite antiretroviral treatment1,2 but may be vulnerable to host immune responses that could be exploited in strategies to cure HIV-1. Here we used a single-cell, next-generation sequencing approach for the direct ex vivo phenotypic profiling of individual HIV-1-infected memory CD4+ T cells from peripheral blood and lymph nodes of people living with HIV-1 and receiving antiretroviral treatment for approximately 10 years. We demonstrate that in peripheral blood, cells harbouring genome-intact proviruses and large clones of virally infected cells frequently express ensemble signatures of surface markers conferring increased resistance to immune-mediated killing by cytotoxic T and natural killer cells, paired with elevated levels of expression of immune checkpoint markers likely to limit proviral gene transcription; this phenotypic profile might reduce HIV-1 reservoir cell exposure to and killing by cellular host immune responses. Viral reservoir cells harbouring intact HIV-1 from lymph nodes exhibited a phenotypic signature primarily characterized by upregulation of surface markers promoting cell survival, including CD44, CD28, CD127 and the IL-21 receptor. Together, these results suggest compartmentalized phenotypic signatures of immune selection in HIV-1 reservoir cells, implying that only small subsets of infected cells with optimal adaptation to their anatomical immune microenvironment are able to survive during long-term antiretroviral treatment. The identification of phenotypic markers distinguishing viral reservoir cells may inform future approaches for strategies to cure and eradicate HIV-1.



Viral Latency

Institution Type


Indication / Modality

HIV Viral Latency

Goal of Study

Viral Characterization

PAD Project


Analytes Assessed

Near Full-length Viral Genome

Sample Type

Patient Material

Tissue / Organ

Lymph Nodes