In both HIV and SIV infections, it has been shown that the most rapid and extensive loss of CD4 T cells occurs in the gut. As a consequence, a theory has emerged positing that gut CD4 T-cell depletion plays a central causative role in driving HIV pathogenesis; the proposed mechanism is that gut wall integrity becomes compromised, leading to the leakage of normally friendly bacteria from the digestive tract and into systemic circulation, which in turn contributes to persistent immune activation and, ultimately, progression to AIDS. However, some scientists have remained skeptical of this theory, suggesting instead that gut CD4 T-cell depletion is an effect of HIV infection, but not necessarily the primary cause of disease progression. The skeptics have gained some support from studies showing that severe gut CD4 T-cell depletion occurs during acute SIV infection in monkey species that experience no apparent ill effects from the virus (sooty mangabeys and African green monkeys). A paper published recently in the Journal of Virology now shows that the opposite phenomenon is also possible: a modified SIV that does not cause loss of gut CD4 T cells nevertheless causes persistent immune activation and progression to simian AIDS in rhesus macaques.
Published ahead of print, 14 November 2012, doi: 10.1128/JVI.01928-12
Matthew W. Breed1, Andrea P.O. Jordan2, Pyone P. Aye1, Cornelis F. Lichtveld1, Cecily Midkiff1, Faith Schiro1, Beth S. Haggarty2, Chie Sugimoto1, Xavier Alvarez1, Netanya G. Sandler3, Daniel C. Douek3, Marcelo J. Kuroda1, Bapi Pahar1, Michael Piatak Jr4, Jeffrey D. Lifson4, Brandon F. Keele4, James A. Hoxie2 and Andrew A. Lackner1 1 Tulane National Primate Research Center, Covington, LA, USA 2 University of Pennsylvania, Philadelphia, PA, USA 3 Human Immunology Section, Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA 4 SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA
A hallmark of pathogenic SIV and HIV infection is the rapid and near complete depletion of mucosal CD4+ T-lymphocytes from the gastrointestinal tract. Loss of these cells and disruption of epithelial barrier function are associated with microbial translocation, which has been proposed to drive chronic systemic immune activation and disease progression. Here we evaluate in rhesus macaques, a novel attenuated variant of pathogenic SIVmac239, termed ΔGY, which contains a deletion of a Tyr and a proximal Gly from a highly conserved YxxØ trafficking motif in the envelope cytoplasmic tail. Compared to SIVmac239, ΔGY established a comparable acute peak of viremia, but only transiently infected lamina propria and caused little or no acute depletion of mucosal CD4+ T-cells and no detectable microbial translocation. Nonetheless, these animals developed T-cell activation, declining peripheral blood CD4+ T-cells and ultimately progressed with clinical or pathological features of AIDS. ΔGY-infected animals also showed no infection of macrophages or CNS tissues even in late stage disease. Although the ΔGY mutation persisted, novel mutations evolved including the formation of new YxxØ motifs in two of four animals. These findings indicate that disruption of this trafficking motif by the ΔGY mutation leads to a striking alteration in anatomic distribution of virus with sparing of lamina propria and a lack of microbial translocation. Because these animals exhibited wildtype levels of acute viremia and immune activation, our findings indicate that these pathological events are dissociable, and that immune activation unrelated to gut damage can be sufficient for the development of AIDS.