Our immune systems offer a very rapid, non-specific first line of defense against invading viruses. These innate pathways lack the specificity and memory characteristic of our more mature immune defenses, which can take weeks to evolve, but they are essential in the control of many infectious diseases. Writing in the June issue of The Journal of Infectious Diseases, amfAR-funded scientist Dr. R. Keith Reeves and colleagues from Harvard Medical School and the New England Primate Research Center dissect the role of one of these early defenses in the control of HIV.
Using a monkey model for AIDS -- SIV infection in the macaque -- Reeves and associates examined CD4+ plasmacytoid dendritic cells (pDCs), a potent source of interferon-alpha. By bringing interferon to sites of viral invasion and growth, pDCs can inactivate many viruses before they have a chance to replicate and spread. They can also amplify the killing effects of another form of innate immunity against viruses, natural killer cells. The importance of pDCs is emphasized by the fact that they are present at high levels in elite controllers of HIV infection, but are depleted in most humans, and monkeys, soon after infection occurs. They rise again after the introduction of antiretroviral therapy.
But how much of a trade-off does this innate, interferon-based defense present in the context of HIV? It is a key concern because too much interferon leads to inflammation in the gut and other tissues. As regular readers of these updates will recognize, inflammation contributes to HIV growth, and to premature aging of the heart, kidney, and bones in HIV-positive individuals.
Reeves and colleagues discovered that the production of interferon by pDCs occurred too late to control acute SIV infection. Additionally, pDCs failed to migrate to and accumulate in the gut -- a major source of early SIV and HIV growth -- until after virus levels were well established in the blood. And they may also be pathologic, contributing to ongoing immune activation. Whether this system should be modulated as part of strategies to enhance the control, and eventual cure, of HIV requires further investigation.
Dr. Laurence is amfAR's senior scientific consultant.