HIV controllers, lessons learnt from the lymphoid tissues

The existence of HIV controllers offers the possibility of identifying specific immune-virological attributes associated with the control of HIV replication, possibly guiding the development of immunological interventions to achieve a functional cure. In the past few years, pioneering studies focused on the study of viral reservoir and immune responses in lymphoid tissues. In the present review, we propose to summarize their findings.

The mechanisms of HIV control in tissues may present peculiar features. Despite efficient viral suppression in vitro , HIV-specific CD8 T cells from lymphoid tissues express lower levels of the classical cytotoxic molecules (Granzyme B and Perforin) directly ex vivo , suggesting that alternative mechanism(s) may operate in these compartments. Interestingly, tissue-resident CD8 T cells from multiple tissues express an array of alternative granzymes, whose contribution to the control of HIV replication remains to be established. NK cells also display peculiar features in lymphoid tissues, including lower levels of classical cytotoxic molecules and increased expression of CXCR5, highlighting the complexity of tissue-specific immunity in the context of HIV.

The immunological mechanisms associated with the control of HIV replication in tissues remain to be fully identified and may involve multiple mediators acting through distinct mechanisms. Recent evidence suggests that the control of HIV replication in lymphoid tissues probably depends on an appropriate positioning of effector cells in the tissue microenvironment, and may be mediated by different mechanisms depending on the levels of viral production and the body compartment.