CD8+ T cells in HIV control, cure and prevention

Abstract

HIV infection can be effectively treated by lifelong administration of combination antiretroviral therapy, but an effective vaccine will likely be required to end the HIV epidemic. Although the majority of current vaccine strategies focus on the induction of neutralizing antibodies, there is substantial evidence that cellular immunity mediated by CD8⁺ T cells can sustain long-term disease-free and transmission-free HIV control and may be harnessed to induce both therapeutic and preventive antiviral effects. In this Review, we discuss the increasing evidence derived from individuals who spontaneously control infection without antiretroviral therapy as well as preclinical immunization studies that provide a clear rationale for renewed efforts to develop a CD8⁺ T cell-based HIV vaccine in conjunction with B cell vaccine efforts. Further, we outline the remaining challenges in translating these findings into viable HIV prevention, treatment and cure strategies.

Fig. 1. Ex vivo CD8⁺ T cell function and phenotype are modulated by the magnitude and duration of in vivo HIV antigen exposure.

The graph illustrates correlations between in vivo antigen exposure and HIV reservoir size (x-axis), increasing levels of mutational escape and T cell exhaustion in elite controllers (EC), viraemic controllers (VC) and chronic progressors (CP), and HIV-specific CD8⁺ T cell function following ex vivo antigenic stimulation (y-axis) by different measurements, including interferon-γ (IFNγ) production in ELISPOT assays (solid blue line), immediate cytolytic capacity (dashed blue line) and proliferative capacity and cytolytic capacity of expanded T cells (red line).

Fig. 2. CD8⁺ T cell function and specificity differentiate HIV controllers and progressors.

Diagram representing CD8⁺ T cell interactions with infected cells in HIV controllers (top) and progressors (bottom). HIV controller CD8⁺ T cells recognize structurally constrained HIV peptides presented via MHC class I (pMHC-I) on infected cells via T cell receptors (TCRs), inducing proliferation and perforin/granzyme-mediated cytolysis of infected cells. Mutation of HIV epitopes presented via MHC-I in HIV progressors promotes escape from recognition by functional CD8⁺ T cells, and dysfunctional CD8⁺ T cells recognize non-escaped viral epitopes through TCR–pMHC-I interactions and secrete interferon-γ (IFNγ) but fail to proliferate or kill infected cells due to inhibitory receptor–ligand interactions, such as PD1 and PDL1. Infected cells that evade killing via escape and/or exhaustion spread infection and promote further immune dysregulation in progressors.

Fig. 3. HIV-specific CD8⁺ T cell responses in natural infection as well as following therapeutic and preventive vaccination.

Diagram representing relative HIV viral load (VL, green), relative total CD4⁺ T cell count (CD4, violet), and relative natural (nCD8) or vaccine-induced (vCD8) HIV-specific CD8⁺ T cell responses over time. In natural HIV infection (top panel), incomplete natural CD8⁺ T cell-mediated control of VL eventually leads to disease progression, marked by CD4⁺ T cell decline and uncontrolled VLs. Therapeutic vaccines that elicit effective vaccine-induced CD8⁺ T cell-mediated control of viraemia aim to protect against disease progression, lower VLs to below the transmission threshold and contain and reduce the residual HIV reservoir in the absence of antiretroviral therapy. Preventive CD8⁺ T cell-mediated vaccines aim to induce a rapid memory-recall, vaccine-induced CD8⁺ T cell response and clear the first infected cells to prevent reservoir establishment as well as to control and ideally clear residual infected cells.