An Animal Model for a Functional Cure for AIDS

Dr. Cristian Apetrei

A very small proportion of HIV-infected people experience long-term control of viral growth and disease progression in the absence of any antiretroviral therapy. And a fraction of these fortunate individuals, known as "super-elite controllers," also lack the chronic immune system activation that is typical of an HIV infection, whether treated or not. Such activation is thought responsible for the accelerated aging of heart, bones, etc. that accompanies HIV disease. If one could uncover the mechanisms by which these very few "super-elites" spontaneously control their infection, we might be able to induce control in others. amfAR grantee Dr. Cristian Apetrei and colleagues have discovered a new animal model enabling this research.

Writing in the August issue of PLoS Pathogens, a prestigious online journal, Apetrei and colleagues from Tulane University, the University of Pittsburgh, Duke University, Frederick, Inc., and the Los Alamos National Laboratory describe a functional cure of SIV, the simian counterpart of HIV, in rhesus monkeys. A functional cure controls the virus at extremely low levels in the body while a sterilizing cure entirely eliminates the virus from the body. Rhesus monkeys experimentally infected with the virus all displayed very high viral loads -- from 10 million to a billion copies -- accompanied by the loss of CD4+ T cells in blood and tissues, just as occurs in most humans with HIV. But in some of these monkeys, this was followed by complete and durable control of the virus.

Viral loads were undetectable in the blood and tissues of all animals within three months of infection. This continued for the four-year observation period, despite lack of any antiretroviral treatment. Within that four-year interval the monkeys remained healthy, with complete resolution of initial signs of abnormal immune activation. They also seroreverted, meaning their formerly positive SIV antibody tests became negative. The researchers determined this was a functional cure, rather than a sterilizing one, because when immunity was experimentally suppressed, by depletion of the monkeys' CD8+ "killer" T cells, virus growth resumed.

Several critical pieces of the HIV disease puzzle have been addressed by this study. First, it shows that the immune system, through the CD8+ "killer" T cell, contributes to the control of an HIV-like infection. Second, it suggests that the chronic immune activation characteristic of HIV infection, even in those patients whose virus is seemingly well-controlled with drugs, is the result of incomplete suppression of virus. And unless such low levels of continuous virus growth can be blocked, it may preclude restoration of normal immunity. As Apetrei and associates appropriately conclude, their model provides the opportunity for further investigation into the phenomenon of "super-elites," which should enable "design of new approaches for controlling HIV infection" and help make a functional cure a reality.

Dr. Laurence is amfAR's senior scientific consultant.