Immune checkpoints and the HIV-1 reservoir: proceed with caution

Successfully identifying and targeting immune checkpoints on latently HIV-1-infected CD4 T cells could be a key component in HIV-1 eradication therapies [1,2]. Immune checkpoints are negative regulators of: (i) T cell activation; (ii) T cell proliferation; and (iii) effector functions including cytokine production [3]. Thus, inhibiting immune checkpoints could influence the resting status of latently infected cells [1,2], which are key obstacles to curing HIV-1 [4,5]. Candidate immune checkpoints in this regard include programmed cell death-1 (PD-1), T cell immunoreceptor with immunoglobulin and ITIM-domains (TIGIT), lymphocyte-activating protein-3 (LAG-3) and type-1 transmembrane immunoglobulin and mucin-3 (TIM3) [1,2,6–8]. Antibodies blocking immune checkpoints have been hypothesised to disrupt the resting status of T cells and hence have been utilised as latency-reversing agents [5,7,9] and may enhance CD8 T cell effector functions in HIV eradication trials [1,2,6–8].