The forces driving clonal expansion of the HIV-1 latent reservoir

Abstract

Despite antiretroviral therapy (ART) which halts HIV-1 replication and reduces plasma viral load to clinically undetectable levels, viral rebound inevitably occurs once ART is interrupted. HIV-1-infected cells can undergo clonal expansion, and these clonally expanded cells increase over time. Over 50% of latent reservoirs are maintained through clonal expansion. The clonally expanding HIV-1-infected cells, both in the blood and in the lymphoid tissues, contribute to viral rebound. The major drivers of clonal expansion of HIV-1-infected cells include antigen-driven proliferation, homeostatic proliferation and HIV-1 integration site-dependent proliferation. Here, we reviewed how viral, immunologic and genomic factors contribute to clonal expansion of HIV-1-infected cells, and how clonal expansion shapes the HIV-1 latent reservoir. Antigen-specific CD4⁺ T cells specific for different pathogens have different clonal expansion dynamics, depending on antigen exposure, cytokine profiles and exhaustion phenotypes. Homeostatic proliferation replenishes the HIV-1 latent reservoir without inducing viral expression and immune clearance. Integration site-dependent proliferation, a mechanism also deployed by other retroviruses, leads to slow but steady increase of HIV-1-infected cells harboring HIV-1 proviruses integrated in the same orientation at specific sites of certain cancer-related genes. Targeting clonally expanding HIV-1 latent reservoir without disrupting CD4⁺ T cell function is a top priority for HIV-1 eradication.

Keywords: Aberrant proliferation; Antigen-driven proliferation; Chromatin accessibility; Clonal expansion; Defective HIV-1 proviruses; HIV-1 cure; HIV-1 integration site; HIV-1 latent reservoir; HIV-1 proviral landscape; Homeostatic proliferation.

Fig. 1

Expansion dynamics of HIV-1-infected CD4⁺ T cells during HIV-1 infection. a The landscape of HIV-1-infected cells is shaped by viral cytopathic effect, immune clearance and clonal expansion of the HIV-1-infected cells. The major drives of clonal expansion of HIV-1-infected cells include antigen-driven proliferation, homeostatic proliferation, and integration site-driven proliferation. HIV-1-infected antigen-specific cells surge as antigen stimulation peaks and wane as the antigen-specific response subsides. Homeostatic proliferation driven by cytokines such as IL-7 and IL-15 does not induce viral antigen expression and evades immune clearance. These two mechanisms are controlled by physiologic immune responses. In contrast, HIV-1 integration may drive aberrant cellular proliferation, which is not affected by host immune feedback controls. Thus, HIV-1 integration site-driven clonal expansion leads to a slow but steady increase of HIV-1-infected cells. Y axis, frequency of HIV-1-infected cells. b The clonal expansion dynamics of antigen-specific CD4⁺ T cells depends on antigen exposure, cytokine profiles and exhaustion phenotypes. HIV-1-specific CD4⁺ T cells increase during acute HIV-1 infection and decline after ART initiation as the majority of HIV-1 antigen is eliminated. Despite chronic antigen exposure, these HIV-1-specific CD4⁺ T cells are few, dysfunctional and impaired in proliferation capacity. On the other hand, TB-specific and Candida-specific CD4⁺ T cells are preferentially infected and depleted during HIV-1-infection, which can be partially restored upon ART. In contrast, CMV-specific CD4⁺ T cells are relatively protected from HIV-1 infection and remain relatively abundant and functional during HIV-1 infection

Fig. 2

Mechanisms of integration site-dependent clonal expansion of HIV-1-infected cells. HIV-1-host interactions at the integration site when HIV-1 is integrated in the same (a) or opposite (b) orientation in respect to the transcription unit. c HIV-1-driven integration site-dependent proliferation depends on the orientation, orientation and the functional consequences of the host gene in which HIV-1 is integrated in