In this study, we showed that rhesus macaque infection with SIVagm results in an infection pattern that models that of elite controlled HIV infection in 100% of cases. Acute SIVagm infection of RMs was similar to pathogenic infection, being characterized by robust acute viral replication and massive mucosal CD4+ T cell depletion. However, during the chronic stage of infection, SIVagm was eventually completely controlled in all RMs in blood and tissues. Inflammation and apoptosis were resolved at mucosal sites, microbial translocation was controlled, immune activation returned to baseline levels and mucosal CD4+ T cells were completely restored in RMs infected with SIVagm. We also report that SIVagm elite controlled infection in RMs could be reverted by experimental depletion of CD8+ cells, suggesting that, similar to HIV-infected human elite controllers, cellular immune responses are involved in the control of SIVagm infection in RMs. Therefore, this new animal model of elite controlled infection may be used to model the viral and host factors involved in the achievement of long-term control of HIV replication in the absence of antiretroviral therapy, i.e., the “functional cure” of HIV infection.
The use of this new animal model for SIV infection allowed us to address some of the most important open questions of SIV/HIV pathogenesis, which may have immediate implication for the management of HIV-infected patients. First, in agreement with our previous reports 
, our model of functional cure for HIV infection demonstrates that acute mucosal CD4+
T cell depletion has no prognostic value for the chronic outcome of infection. Second, we report that residual apoptosis and immune activation in subjects with undetectable plasma VLs are due to an incomplete control of viral replication. In SIVagm-infected RMs, low levels of viral replication persisted in tissues several months after plasma VL became undetectable and prevented the control of the apoptosis, microbial translocation and immune activation, hence the immune restoration was quasi inexistent during this time. Conversely, after the achievement of the complete control of virus replication in tissues, apoptosis and immune activation were resolved and normalization of these parameters was followed complete restoration of the mucosal CD4+
T cells. These findings suggest that in human ECs, as well as in patients treated with HAART, incomplete immune restoration and persistent elevated levels of immune activation which are observed in spite of undetectable plasma VLs may be due to very low levels of residual viral replication in tissues 
, calling for a therapeutic control of viral reservoirs to restore and preserve the levels of CD4+
T cells 
. Furthermore, our model demonstrates that only the long-term normalization of immune activation and inflammation may lead to complete immune restoration in HIV-infected patients. In our study, mucosal CD4+
T cells restoration only occurred four years after the return of apoptosis and immune activation to near baseline levels. Finally, our study showed that sustained complete control of viral replication may result in seroreversion. Seroreversion was not reported in ECs, but occurred in a patient that achieved the functional cure after being treated with allogeneic CCR5Δ32/Δ32 stem cell transplantation for relapsed acute myeloid leukemia (the “Berlin patient”) 
. As for the SIVagm-infected RMs, the functional cure in this patient was characterized by lack of disease progression for 45 months in the absence of antiretroviral therapy, CD4+
T cell reconstitution to normal values in peripheral blood and at mucosal sites, undetectable HIV RNA and DNA in plasma and tissues and seroreversion 
. These striking similarities between RMs infected with SIVagm and the “Berlin patient”, which is currently the standard for the functional cure of HIV infection, reinforce the value of our new animal model.
In the currently available animal models of EC infection, control is only achieved in a fraction of monkeys or it is due to significant attenuation of the virus. Thus, viral replication of attenuated strains of SIVmac, such as Δ-nef or Δ-3 strains 
is impaired in all phases of infection by significant alterations in virus structure. This pattern is in sharp contrast with the majority of the EC infection in humans in which the viruses are replication-competent without major deletions 
. Second, suppression of viremia in pathogenic macaque infections through highly active antiretroviral treatments 
does not fulfill the definition criteria for EC infection, as the animals are ARV-treated and low levels of viral replication, immune activation and incomplete immune restoration persist under treatment 
. Third, during SIVmac infections in Chinese (Ch) RMs long-term nonprogression occurs only in a subset of monkeys 
, cannot be predicted based on in vitro
and is associated with persistent viral replication in tissues 
. Reagents are not yet fully tested in ChRMs and MHC characterization is incomplete, as opposed to IndRMs. Finally, a fraction of SIVmac239-infected Indian RMs with particular MHC profiles is defined as “elite-controlling” infection 
. Note, however, that “EC” SIVmac-infected RMs show persistent low levels of viral replication (102
. Moreover, as for ChRMs, control of infection cannot be predicted before it is achieved. The advantage of the EC model reported here over the existing models, is that in SIVagm-infected RMs, a robust acute viral replication is followed by complete control in all cases, therefore, to date, this animal model is the only one that can be used for the study of early events of SIV infection leading to EC infection and to define the biomarkers that will allow early identification of the HIV infected patients that have the potential of controlling infection and the delineation of the parameters of a successful functional cure of HIV infection (i.e., control of viral replication in tissues, normalization of apoptosis and immune activation, seroreversion etc).
One may argue that, since SIVagm infection is cross-species transmitted to RMs, the proposed model might not be relevant because control is dependent on host restriction factors. We have several lines of evidence that the role of host intrinsic immunity may be peripheral in achieving control of infection in this model: (i) SIVagm replicated at high levels in RMs during acute infection; (ii) in vitro data showed persistent high levels of SIVagm.sab replication (comparable to that of SIVmac) on RM PBMCs; (iii) the analysis of SIVagm evolution in RMs showed no evidence of hypermutation that might have been the result of a partial host restriction through the deaminase system; (iv) the high ds/dn ratios observed in RMs suggest that SIVagm was under purifying selection in the postacute phase of SIVagm.sab infection; finally, (v) Trim5 genotypes of the infected monkeys were not associated with particular viral replication profiles; (vi) CD8 depletion experiments in controllers resulted in rebounds of VL, thus pointing to an immune control of viral replication.
Another critique to this new animal system may be that it only models a fraction of controlled HIV infections. LTNPs are a heterogeneous group of patients, in which different mechanisms may lead to various levels of viral control 
. Thus, viremic controllers have residual levels of viral replication. Elite controllers, on the other hand, control viral replication to undetectable levels of plasma viral load, but the majority of ECs have persistent levels of increased immune activation 
, inflammation-associated vascular dysfunction 
and declining CD4 counts over time 
. Only a fraction of EC patients (the “super-elites”), achieve control of immune activation close to baseline levels, in addition to the control of viral replication. These patients sustain CD4+
T cell counts and preserved CD8+
T cell function [Landay, unpublished] and are probably the best examples of functional cure of HIV infection. Even if these patients represent a minority of the HIV infected patients, understanding the mechanisms through which the functional cure of HIV infection occurs in the absence of antiretroviral therapy is probably the most important information that can be derived from the study of controlled HIV/SIV infections for both vaccine development and HIV eradication efforts. Our new animal system models these super-elite controllers, which are the most difficult to model in animal systems and therefore it is a major achievement in the field, as it can be used to identify the factors driving the infection to elite controlled status overcoming the most important limitation to the study of the functional cure, which is that control cannot be predicted at the time when the virus actively replicate during the early stages of infection.
We conclude that SIVagm infected RMs represent a valuable model of super elite controlled infection which can be used to: (i) examine virologic and immunologic changes during early infection that may lead to the infection control; (ii) perform invasive studies facilitating concomitant investigations in a large array of tissues collected at critical time points of infection; (iii) perform in vivo manipulation of SIV pathogenesis by selective depletion of different cellular subsets, or experimental modulation of immune activation to assess their contribution to the control of VL. Such experiments have not been and cannot be pursued in studies of human HIV-1 ECs and thus, this new model addresses an immediate need in AIDS research: deciphering the mechanisms and biomarkers of durable and effective control of SIV replication.