Although our data do not definitively implicate the activity of SIV-specific CD8+ T cells in the preferential localization of SIV RNA+ cells in CD4+ TFH in monkeys with cART-suppressed infection, follicular integrity is largely intact in the LNs of these monkeys (Suppl. to either evade or escape innate and adaptive immunity1,2. Indeed, the vast majority of infected individuals experience prolonged high-level viral replication that in the absence RGB-286638 of combination anti-retroviral therapy (cART) prospects to AIDS in susceptible species (humans and Asian macaques)3. However, rare individuals ( 1% for humans) are able to mount highly effective immune responses that suppress RGB-286638 viral replication to very low levels, as much as 10,000-fold lower than common HIV or SIV infections4,5. Given the ability of HIV and SIV to establish a stable latent viral reservoir early in contamination(6), and the inability of the adaptive immune system to recognize latently infected cells (e.g. cells with integrated viral genomes and no viral gene expression), it is not surprising that this highly effective immune responses developed by EC fail to completely clear HIV/SIV contamination. However, it is noteworthy that even these uniquely potent responses are not entirely effective at suppressing ongoing rounds of viral replication. Ultrasensitive analysis reveals detectable plasma computer virus in most (if not all) ECs at levels that are, on average, higher than those in individuals with contamination suppressed by optimal cART); moreover, recovery of replication qualified HIV from CD4+ T cells of EC subjects is reduced by cART, and viral sequence analysis indicates that viral replication is usually high enough to allow for viral sequence evolution7C12. EC also manifest higher levels of systemic immune activation than uninfected individuals13, and this extra immune activation can be reduced by cART14, findings that taken together provide indirect, but compelling, evidence of prolonged, low level productive contamination in these subjects. Highly effective virus-specific CD8+ T cell responses targeting functionally constrained epitopes, typically associated with protective major histocompatibility complex class I alleles, are thought to be responsible for many, if not most, instances of elite HIV and SIV control4,5,15C18. The observation that in vivo CD8+ lymphocyte depletion of monkey EC is usually associated with a rapid upsurge in SIV replication19, the paperwork of immune development in EC9,12, and the ability to isolate replication-competent HIV from human EC20 all strongly suggest that elite control typically displays continuous CD8+ T cell-mediated containment of replication-competent computer virus. If this conclusion is correct, how then does the ongoing low-level productive contamination escape the highly effective CD8+ T cell responses? RGB-286638 We recognized a possible clue to this question in a previous study of live attenuated SIV vaccines (LAV) in rhesus monkeys, in which we exhibited that SIV-specific T cell responses capable of completely protecting the LAV-vaccinated monkeys from highly pathogenic SIV challenge were continuously managed by highly restricted LAV replication within the phenotypically unique CD4+ TFH populace in secondary RGB-286638 lymphoid tissues21. Since RGB-286638 most CD8+ effector T cells, including HIV- and SIV-specific CD8+ T cells, lack the appropriate chemokine receptors for B cell follicle access and therefore are relatively excluded from B Flt1 cell follicles22C26, the implication was that the LAV-infected TFH avoided elimination by the highly effective SIV-specific T cells they themselves generated by their location in a B cell follicle sanctuary27. Indeed, it has been hypothesized that CD8+ T cell exclusion from B cell follicles provides this site with an immune privilege that, along with infection-associated growth of CD4+ TFH, accounts for preferential viral targeting of CD4+ TFH in progressive HIV/SIV contamination28C33. In this study, we used SIV contamination of Indian-origin rhesus macaques to experimentally assess whether this hypothesized B follicular immune privilege constitutes a substantial barrier to T cell-mediated suppression or clearance of productive lentiviral contamination, and might account for persistence of productive SIV contamination in elite control. Our data demonstrate that productive SIV contamination becomes progressively restricted to CD4+ TFH within B cell follicles with increasing immunologic control, and that this restriction is usually abruptly abrogated with CD8+ lymphocyte depletion, returning with CD8+ T cell recovery. We also demonstrate preferential localization of residual, productive SIV contamination in SIV+ monkeys with long-term, fully suppressive cART. Taken together, these data confirm that productive SIV contamination within resident intrafollicular CD4+ TFH is usually substantially shielded from CD8+ T cell-mediated suppression or clearance, and that the B cell follicle sanctuary this shielding implies will likely constitute a barrier to eradication or functional remedy of HIV contamination. Results Immune control restricts productive SIV contamination to TFH.