Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Homeostatic proliferation, in particular that mediated by IL7, is an important driver of HIV persistence in CD4+ T cells. We recently established that CD127, the alpha chain of the IL7 receptor, is expressed on a subset of tissue-derived, long-lived memory CD4+ T cells preferentially prone to latent infection by HIV. These latently- infected cells, however, harbor incomplete HIV transcripts, and hence belong to a category of latent cells termed transcriptionally-active reservoir cells. These active reservoir cells are important targets for HIV cure, as they can be rebound-competent and can drive chronic inflammation in antiretroviral therapy (ART)-suppressed people with HIV (PWH). We postulate that given the role of IL7-driven homeostatic proliferation in reservoir maintenance, the IL7-CD127 axis serves as a good target for HIV cure. Here, we leverage a safe and potent chimeric CD127 monoclonal antibody called 4A10, developed for T-ALL cancer therapy, to simultaneously target IL7 signaling and CD127+ reservoir cells as a novel approach for HIV cure. We postulate that by both inhibiting IL7-mediated signaling through CD127 and potentiating innate immune effector functions (ADCC, ADCP) to deplete CD127-expressing cells, 4A10 can reduce the HIV reservoir and potentially lead to HIV remission. In Aim 1, we use an ex vivo tissue model of HIV persistence to test the direct IL7 antagonism effects of 4A10, as well as its ability to mediate ADCC and ADCP, against HIV reservoir cells expressing CD127. In Aim 2, we use a recently-developed humanized mouse model suitable for ADCC and ADCP studies to interrogate the effects of 4A10 on HIV persistence. These studies will administer 4A10 to mice already stably suppressed on ART, as well as those about to initiate ART. The latter will be done to in order to implement intervention at a period of time where reservoir cells are stabilized and homeostatic proliferation is proceeding in the context of immune reconstitution. Treatment interruption studies will assess the ability of 4A10 to lead to ART-free HIV remission. In both aims, multi-omics single-cell sequencing approaches will be used to assess the effects of intervention on HIV and host gene expression, and on clonal expansion of HIV reservoir cells. Collectively, our study will characterize mechanisms of homeostatic proliferation-driven HIV persistence, and directly test the potential of 4A10 as a novel cure strategy. Should the latter prove promising, rapid translation to the clinic can occur as 4A10 has an excellent safety profile and is soon entering patients in the context of cancer therapy trials.
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