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.

Pre-existing resistant proviruses can compromise maintenance of remission by VRC01 in chronic HIV-1 infection

“…Next, we created a virtual patient population to mimic inter-patient variations expected in clinical trials. A number of host factors, including HLA types, are known to affect the ability of individuals to control viremia 60 . Similarly, viral factors have also been argued to determine the level of viremia in chronic infection 61 .…”

“…A convolution of host and viral factors is expected to determine clinical outcomes. The specific factors involved and how they vary across individuals, however, is not fully established 46,60 . Here, we employed a parsimonious approach where we let two parameters, one reflective of variations in host factors and the other viral factors, define the inter-patient variations.…”

“…The simulations tended to over-predict the clinical data for long remission times (>40 d). We attributed this to the presence of individuals with strong immune responses and/or small latent cell populations, including post-treatment controllers 60 , who may not be seen in the small population of 12 individuals in the A5340 trial. Secondly, after the effect of VRC01 wanes, failure may also occur due to the reactivation of wild-type virus.…”

“…An important question in HIV cure research is how early should ART be initiated to maximize post-treatment control 60 . While starting early would restrict the reservoir size and improve the chances of post-treatment control, starting it too early would not allow enough time for the development of an immune response, compromising post-treatment control.…”

“…We therefore did not consider the effect of NNRTIs in our study. A number of host 60 and viral 61 factors are thought to be involved in determining disease progression and treatment outcomes. Our model subsumed inter-patient variations in these factors into variations in two factors, the latent pool size and the viral production rate.…”