Fig. 5

Cartoon schematic summarizing the importance of lymphoid tissues in harboring the vast majority of the infected cellular reservoir before and during effective cART treatment. A very small fraction of potential target cells is found in the peripheral blood compared to lymphoid tissues (i.e. lymph nodes, spleen, gut). Both before and during cART, the localization of infected cells (and/or trapped virions on the FDC network) within lymphoid tissues account for a disproportionately vast majority of infected cells in the body. Modern ISH approaches have been important in understanding unique tissue compartments where infected cells reside and persist during cART, like BCFs of lymph nodes, gut, reproductive organs (like testis), and CNS. Mechanisms contributing to viral persistence within tissue compartments are likely multifactorial, and may include: variable tissue ARV drug penetration, continued virus production by infected cells, and/or homeostatic and/or antigenic clonal expansion of infected cells. Collectively, ISH approaches have made important contributions to our understanding of viral persistence in tissue compartments and to reservoir biology, and illustrate the relevant need to focus efforts on developing novel methods to explore tissue reservoirs for the assessment of ‘HIV cure’ strategies