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