Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure

Abstract

Recent studies demonstrate that the stable HIV-1 reservoir in resting CD4⁺ T cells is mostly formed from viruses circulating when combination antiretroviral therapy (ART) is initiated. Here we explore the immunological basis for these observations. Untreated HIV-1 infection is characterized by a progressive depletion of memory CD4⁺ T cells which mostly express CD127, the α chain of the IL-7 receptor (IL-7R). Depletion results from both direct infection and bystander loss of memory CD4⁺ T cells in part attributed to dysregulated IL-7/IL-7R signaling. While IL-7/IL7R signaling is not essential for the generation of effector CD4⁺ T cells from naïve cells, it is essential for the further transition of effectors to memory CD4⁺ T cells and their subsequent homeostatic maintenance. HIV-1 infection therefore limits the transition of CD4⁺ T cells from an effector to long-lived memory state. With the onset of ART, virus load (VL) levels rapidly decrease and the frequency of CD127⁺ CD4⁺ memory T cells increases, indicating restoration of effector to memory transition in CD4⁺ T cells. Collectively these data suggest that following ART initiation, HIV-1 infected effector CD4⁺ T cells transition to long-lived, CD127⁺ CD4⁺ T cells forming the majority of the stable HIV-1 reservoir. We propose that combining ART initiation with inhibition of IL-7/IL-7R signaling to block CD4⁺ T cell memory formation will limit the generation of long-lived HIV-infected CD4⁺ T cells and reduce the overall size of the stable HIV-1 reservoir.

Keywords: CD127; CD4+ T cell; HIV-1; IL-7; latency; memory; reservoir.

Figure 1

CD4⁺ T cell lineage differentiation is impaired following HIV-1 infection. IL-7, that is mostly produced by stromal cells, binds the IL-7 receptor (IL-7R) comprising CD132 and IL-7Rα (CD127) initiating signaling pathways including as Jak/STAT5 signaling and expression of anti-apoptopic genes, including Bcl-2. Naïve CD4⁺ T cells, selected against self-antigens, express the IL-7R. IL-7/IL-7R signaling is necessary for homeostatic turnover of naïve T cells (curved blue arrow). Following priming by foreign antigens, CD4⁺ T cells undergo significant transcriptional and phenotypic changes, including downmodulation of the IL-7R. These effector CD4⁺ T cells express activation markers (not shown), undergo rapid division and exit the lymph node to home to the site of infection. Most effector CD4⁺ T cells undergo apoptopic death; a subset however re-express the IL-7R and induce expression of anti-apoptopic genes. These memory cells are long-lived, undergoing slow mitotic division/homeostatic proliferation. HIV-1 infection drives ongoing expansion of effector CD4⁺ T cells. In addition, dysregulated IL-7/IL-7R signaling resulting from HIV-induced immune activation impairs several stages of CD4⁺ T cell lineage—naïve CD4⁺ T cell survival, generation of long-lived memory CD4⁺ T cells and homeostatic proliferation of naïve and memory CD4⁺ T cells. Other cytokines, notably IL-2 and IL-15, contribute to CD4⁺ T cell differentiation and homeostasis [not illustrated, reviewed in (11)].

Figure 2

Blockade of IL7/IL-7R signaling at the time of ART initiation may limit the size of the stable HIV-1 reservoir. (A) HIV-1 infection is characterized by extensive viral replication (red line) and virus evolution (colored virions). Virus-driven immune activation (purple dotted line) is observed throughout untreated infection. ART rapidly reduces plasma virus levels. Immune activation is also significantly reduced but not fully abrogated. (B) HIV-1 infection impairs CD4⁺ T cell effector to memory transition (black dotted line), which is restored on ART. Abrahams et al. (2) showed that on average, 80% of the replication-competent virus in CD4⁺ T cells from durably ART-suppressed individuals is derived from virus present in plasma in the year prior to ART initiation. Viruses that were circulating earlier in untreated infection comprise a minority of the latent reservoir. (C) Blocking IL-7/IL-7R signaling at the time of ART initiation, aimed at delaying ART-mediated restoration of CD4⁺ T cell effector to memory transition, may limit the entry of viruses circulating immediately prior to ART into the HIV reservoir.