Background:  Understanding the mechanism of infection control in elite controllers (EC) may shed light on the correlates of control of disease progression in HIV infection. However, research on human EC is limited to studies at late time points in infection, after control is achieved, on limited samples collected at random time points and limited access to tissues. These limitations have prevented development of a clear understanding of the mechanisms of EC HIV infection. In the existing animal models of EC infection, control is not achieved in all cases, which prevents the study of early events that may drive EC infection. We developed an animal model for EC HIV infection.

Methods:  We infected 5 rhesus macaques with SIV_agm. Viral loads in blood and tissues, viral evolution, dynamics of major immune cell populations and subsets, and immune responses were followed as long as 6 years. CD8 cells were depleted using cM-T807.

Results:  Acute SIV_agm infection in rhesus macaques is characterized by:  high levels of viral replication and dramatic mucosal CD4⁺ T cell depletion, both similar to pathogenic HIV-1/SIV infections of humans and rhesus macaques, followed by complete control of SIV_agm replication, defined as:  undetectable viral loads beginning 72 to 90 days postinoculation and continuing through at least 6 years; negative polymerase chain reactions for multiple SIV_agm genes in peripheral blood mononuclear cells, lymph nodes, and intestine; seroreversion; progressive recovery of mucosal CD4⁺ T cells, with complete recovery by 4 years postinoculation; normal levels of T cell immune activation, proliferation, and apoptosis; and no disease progression. We also showed that control is independent of MHC types, partial APOBEC restriction is not involved in SIV_agm control in rhesus macaques and experimental CD8 cell depletion in controlled SIV_agm infections of rhesus macaques resulted in transient rebounds of viral loads.

Conclusions:  All SIV_agm-infected rhesus macaques demonstrated durable control of SIV_agm infection. This control was independent of MHC types and was most probably due to effective cellular immune responses. SIV_agm-infected rhesus macaques can be used as an animal model of EC lentiviral infection, for studies that cannot be done in HIV-infected patients: examine early events of infection in blood and tissues, before the defining characteristics of EC are evident; determine if viral persistence in a given host is due to low levels of viral replication or latency; and selectively deplete different cellular subsets to assess their contribution to the control of viral load.