Abstract Body

HIV-specific CTL partially, but incompletely suppress virus replication in most infected individuals. Multiple mechanisms have been invoked to explain the failure of CTL to fully suppress virus replication including numerical and functional deficiencies. Whether there is an immune privileged site that is impervious to CTL has not been fully explored. In asymptomatic disease, HIV replication is concentrated in T follicular helper cells (TFH) located within B cell follicles (F) of secondary lymphoid tissues including lymph nodes, spleen, and GALT. In lymph nodes from untreated people, HIV-specific CTL fail to accumulate within F. In the SIV-infected rhesus macaque model, virus replication during chronic, asymptomatic disease is similarly concentrated in F of all lymphoid tissues and SIV-specific CTL fail to accumulate in large numbers. Compartmentalization of virus replication within lymphoid tissues appears related to CTL distribution. Frequencies of virus-specific CTL in F and extrafollicular (EF) compartments of lymph node and spleen of SIV-infected macaques predict SIV RNA+ cells within these compartments. In simian AIDS, when CTL are often numerically deficient, the follicular concentration of virus replication is attenuated. In acute infection, prior to when CTL exert substantial effects on virus replication, as well as in chronically infected animals after CD8 depletion, SIV RNA+ cells are wide spread and not concentrated in F. Thus, EF cells are capable of replicating virus, but virus replication is efficiently suppressed in them when CTL are present. Substantial differences in perforin or granzyme B expression are not evident between F and EF CTL in chronic SIV infection. Frequencies of SIV RNA+ cells increase modestly within F after CD8 depletion, suggesting that the few CTL present in F exert antiviral activity. Few SIV-specific CTL express the follicular homing molecule CXCR5 in the absence of the extrafollicular retention molecule CCR7, which likely accounts for their failure to home to B cell follicles and suppress virus replication. Thus, B cell follicles are immune privileged sites that shield TFH from CTL killing and are exploited by HIV and SIV, and likely other infections and malignancies. Strategies to induce migration of virus-specific CTL into B cell follicles, such as CTL transduction with CXCR5, could lead to improved viral control and possibly a functional cure for HIV.