HIV control: Is getting there the same as staying there?

Abstract

In this brief review and perspective, we address the question of whether the immune responses that bring about immune control of acute HIV infection are the same as, or distinct from, those that maintain long-term viral suppression once control of viremia has been achieved. To this end, we describe the natural history of elite and post-treatment control, noting the lack of data regarding what happens acutely. We review the evidence suggesting that the two clinical phenotypes may differ in terms of the mechanisms required to achieve and maintain control, as well as the level of inflammation that persists once a steady state is achieved. We then describe the evidence from longitudinal studies of controllers who fail and studies of biologic sex (male versus female), age (children versus adults), and simian immunodeficiency virus (SIV) (pathogenic/experimental versus nonpathogenic/natural infection). Collectively, these studies demonstrate that the battle between the inflammatory and anti-inflammatory pathways during acute infection has long-term consequences, both for the degree to which control is maintained and the health of the individual. Potent and stringent control of HIV may be required acutely, but once control is established, the chronic inflammatory response can be detrimental. Interventional approaches designed to bring about HIV cure and/or remission should be nuanced accordingly.

Fig 1. The time ART is initiated may prove to be critical determinant of post-treatment control.

Treatment of “hyperacute” HIV infection (Fiebig 1) may prevent the development of an effective immune response. During a subsequent treatment interruption, the virus will rebound rapidly, and there will be limited chance for post-treatment control. In contrast, a delay in treatment for too long will result in a generation of escape mutants, a large and difficult-to-control reservoir, and a damaged immune system. ART, antiretroviral therapy; CTL, cytotoxic T lymphocyte.

Fig 2. Favorable immune responses in order to achieve control of viremia in acute infection and in order to maintain control once achieved as in post-treatment control.

(A) Favorable immune responses to achieve control in acute infection. (B) Favorable immune responses to maintain virus control once achieved. SIV, simian immunodeficiency virus.