CD4 cell loss not enough to cause AIDS in some monkeys

Sooty mangabeys infected with the monkey immunodeficiency virus from which HIV is descended (SIV) do not develop AIDS despite the massive loss of CD4 cells seen in humans. US researchers now believe that it is immune activation, missing in sooty mangebeys, that challenges immune function so extensively that AIDS is the result in humans.

Their views are outlined in three papers published in the September edition of the Journal of Immunology, and the authors agree that alongside antiretroviral therapy, treatment approaches that can switch off HIV-related immune activation need to be investigated.

The researchers, who include some of the leading figures investigating how HIV causes disease, come from three separate research groups, but all arrived at broadly similar conclusions in the course of observing the course of SIV infection in soory mangebeys, the natural host of the virus, and rhesus macaques.

Sooty mangebeys typically live with SIV and suffer no ill effects, and have probably done so for hundreds of thousands of years, but experimental infection with SIV in the laboratory did result in severe CD4 cell loss in the gut in a pair of mangebeys housed at Tulane Primate Research Center.

However, neither animal suffered any illness as a result of this CD4 cell loss, nor did they lose CD4 cells in the bloodstream, in contrast with other species, where massive CD4 cell loss eventually results in increasingly severe opportunistic infections.

And, when the monkeys were given antiretroviral drugs, they experienced a prompt restoration of the CD4 cell population in the gut, a phenomenon that occurs much more slowly in humans.

What made these animals different, the researchers believe, is the lack of immune activation that accompanied this CD4 cell loss. Immune activation occurs when the immune system encounters foreign or infectious agents, and is a normal but low-level part of the human body's functioning.

Immune activation becomes problematic when it is constant, high level, and leads to an inflammatory state in which some health conditions worsen. It also exhausts some subsets of the immune system eventually, and for this reason is damaging to the long-term ability of the immune system to control infections.

Their investigations also showed that bacterial translocation across the gut wall, believed to be an important cause of immune activation in humans with HIV, does not occur in sooty mangabeys beyond the early weeks of infection.

Evolution has helped sooty mangebeys to adapt to SIV by maintaining immune surveillance despite the massive loss of CD4 cells and by limiting immune activation, they conclude. In contrast, rhesus macaques do suffer disease after SIV infection.

Closer examination of the immune systems of the two sooty mangebeys by a second group, led by Daniel Sodora of the Seattle Biomedical Research Institute, and comparison with the range of immune system changes seen in humans with HIV, led the group to conclude that various other forms of immune dysfunction are the critical determinants of AIDS in people who have already suffered an early and massive loss of CD4 cells in the gut, which is home to 85% of the human CD4 cell population.

The sooty mangebeys experienced no damage to the structure of their lymphoid tissue, unlike humans with HIV, and this may be one factor that allows other immune responses to function normally.

Nevertheless, it is immune activation that has the most disruptive effect on immune responses that could control HIV and opportunistic infections, and this should be target for future therapeutic research.

Ultimately, a treatment approach that could dampen immune activation caused by HIV might allow people to stop daily antiretroviral therapy once they had experienced a sustained period of immune restoration. Instead individuals might receive treatment that would limit immune activation, preventing depletion of the CD4 cells restored by long-term antiretroviral treatment.