Characterizing ART-free NK cell-mediated control of HIV infection in people living with HIV

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PROJECT SUMMARY People living with HIV (PLWH) can be treated effectively with antiretroviral therapy (ART) but for most, as soon as ART is stopped, HIV quickly rebounds within weeks. However, in rare individuals, called post-treatment controllers (PTCs), HIV is controlled by immune-mediated mechanisms and viral rebound is suppressed. How this occurs remains poorly understood. One type of immune cell in PTCs that has been implicated in viral control during ART interruption is Natural Killer (NK) cells. These cells can rapidly respond to and kill infected cells as part of a classical innate immune response, but more recently has also been suggested to be capable of harboring “memory” against prior infection including that by HIV. This “memory” is thought to be in part mediated through epigenetic mechanisms. The types and features of NK cells in PTCs, and whether they differ from those in non-controllers (NCs), is not known. A better understanding of these cells is the first step towards understanding how they can control HIV and be harnessed for therapy. The objective of this proposal is to deeply characterize the features and effector functions of NK cells in PTCs and non-controllers (NCs), and to identify biomarkers on NK cells prior to analytical treatment interruption (ATI) that predict HIV remission. We hypothesize that NK cells, including memory NK cell subsets, help to control HIV after ART is removed in PTCs. We will use longitudinal samples from clinically-matched PTCs and NCs from the CHAMP study, sampled ATI, and at early (within 12 weeks) and late (after 24 weeks) timepoints after ATI. In Aim 1, we will use mass cytometry (CyTOF) to determine the phenotypes and effector functions of NK cell subsets from PTCs and NCs before and after ATI. In Aim 2, we will use multiplexed single-cell RNAseq and single-cell ATACseq to identify transcriptional and epigenetic signatures of memory and non-memory NK cells from PTCs vs. NCs after treatment interruption. Understanding immune responses capable of mediating HIV remission provides an avenue for development of novel therapeutics to cure HIV. Equally essential are non-invasive biomarker(s) that predict HIV remission for safer treatment interruption trials. This proposal addresses both these aspects focusing specifically on NK cells, powerful immune effectors that are much understudied with regards to their potential to mediate HIV remission.