Antigen stimulation drives clonal expansion of latent CD4+ T cells using a full-length HIV latency reporter

Abstract

HIV persistence despite years of ART suppression poses a major barrier to cure. Using a full-length latency reporter to generate HIV-infected, transcriptionally silent CD4+ T cells in vitro, we show that cognate DC:T cell interactions drive clonal expansion of latent T cells in an antigen dependent manner and that a pro-survival state within proliferating cells is reinforced through IL-7 signaling. Interestingly, we describe a dominant role for CD28 co-stimulation in regulating robust latent T cell proliferation which was partially reversed by PD-1 blockade. Our studies show that a gradual reduction in antigenic stimulation was sufficient to induce proliferative responses without measurable proviral reactivation. Thus, the magnitude of TCR/co-stimulatory signals during cognate APC:T cell interactions are key regulators of the underlying proliferative and survival programs maintaining the latent reservoir under ART suppression. Significance StatementViral replication can be effectively suppressed by antiretroviral therapy (ART) but is not curative due to persistence of latent virus in a stable reservoir in resting CD4+ T cells. We show that antigen recognition through cell-cell interactions is an important driver of latent T cell proliferation, and that modulating TCR stimulatory signaling independently regulates proliferative, survival and proviral reactivation potential in infected T cells. Our observations show that latent T cells retain their ability to engage other immune cells to support their long-term survival under ART suppression, similar to uninfected T cells. These characteristics of latent T cell pools represent an additional hurdle to eradicating the reservoir.