Figure 7. Proposed model for the differential colocalization of HIV-specific CD4⁺ and CD8⁺ T-cells into the GALT.

The control of viral replication is dependent on the in situ colocalization of excess effector versus target cells [28]. Given the results included in Figures 1– 6 of the present manuscript, we propose a model where (A) HIV replication in CD4⁺ T-cells may be controlled by CD8⁺ T-cells in certain GALT sites (e.g., lamina propria), where recruitment is dependent on integrin β7, CXCR3 and CCR5 because of an increased ratio between HIV-specific CD8⁺ and CD4⁺ T-cells. In contrast, (B) HIV-specific CD4⁺ T-cells recruited into other GALT sites via CCR6 (e.g., Peyers's Patches) may escape the CD8⁺ T-cell-mediated antiviral control due to a limited CCR6-dependent colocalization potential of CD4⁺ and CD8⁺ T-cells. This model is in line with our previous findings that CCR6⁺CD4⁺ T-cells harbor the highest levels of integrated HIV-DNA in vivo [44] and suggests that novel therapeutic strategies aimed at increasing CCR6 expression on CD8⁺ T-cells may lead to a better control of HIV replication in CCR6⁺CD4⁺ T-cells.