New insights into elite control of HIV and a possible case of virus clearance
Richard Jefferys, TAG
Several media outlets are reporting on a newly published study of elite controllers, a rare subset of people with HIV who suppress viral load to low or undetectable levels without treatment. 
A major impetus for the interest is a finding that one long-term elite controller, Loreen Willenberg, may have cleared all the intact HIV from her body. The study was published today in the journal Nature (paired with an open access commentary by Nicolas Chomont) , and Apoorva Mandavilli covered the research in a story for the New York Times.  Jon Cohen has authored an excellent explanatory article for Science. 
The study results offer potentially important clues about how HIV may be cured in some circumstances, but unfortunately do not directly help design interventions that might produce similar outcomes in the majority of people living with the virus (who are not elite controllers).
The crux of the new paper is that elite controllers appear to preferentially deplete the HIV-infected cells from their bodies that contain virus capable of replicating, likely due to potent anti-HIV immune responses (particularly HIV-specific CD8 and CD4 T cells). The HIV-infected cells that are left behind preferentially harbor viral DNA in regions of the cell’s genetic code that are inactive, essentially entombing the virus and preventing its reemergence. In some cases, the HIV DNA is not intact, which also prevents further replication. For Loreen Willenberg, analyses of huge numbers of cells from both the blood and gut could not find any intact HIV, leading to the suggestion that all virus capable of replicating (referred to as replication-competent HIV) has been eliminated over time.
In the New York Times article, scientist Steve Deeks notes that a somewhat similar phenomenon may occur in people with HIV on long term antiretroviral therapy (ART), raising the possibility that over a period of decades cells containing replication-competent virus might be eliminated. Deeks intends to investigate this scenario in people on very long-term ART. However, it’s important to note that the evidence is very thin—the most detailed paper indicating the phenomenon might be occurring involves only three individuals on ART. 
Furthermore, the Nature paper compares elite controllers with people on ART, finding that the entombment of HIV in cells is far more common in the former group than the latter. Given the significant uncertainty, people on long-term ART shouldn’t attempt to interrupt treatment outside of research studies.
Another way researchers are attempting to translate the knowledge gleaned from elite controllers is by testing approaches that may be able to enhance immune responses against HIV. Examples include therapeutic vaccines, broadly neutralising antibodies, toll-like receptor agonists and gene therapies (see TAG’s Research Toward a Cure clinical trials listing and 2020 Pipeline Report). [6, 7]
Success to date has been limited, and part of the challenge may be that elite controllers tend to possess particular genetic traits associated with superior HIV-specific immunity.
While the Nature paper was published today, the content was partially known to people who follow HIV research. Xu Yu described some of the data, including the case of Loreen Willenberg, at the IAS 2019 conference. 
Loreen was subsequently profiled in an article for Leapsmag by Bob Roehr.  In a tour-de-force plenary talk on cure research at CROI 2020 earlier this year, Sharon Lewin highlighted the need to consider how much of the HIV reservoir that persists on ART is replication-competent and able to reemerge if treatment is interrupted. Lewin cited the work of the Nature paper’s lead author Chenyang Jiang, who also presented during the conference. 
Jefferys R. TAG Basic Science Project. (26 August 2020).
- Jiang C et al. Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Nature (2020).
- Chomont N et al. HIV enters deep sleep in people who naturally control the virus. Nature. Comment. (26 August 2000).
- Mandevilli A. A woman may have been cured of HIV without medical treatment. New York Times. (26 August 2020).
- Cohen J. How ‘elite controllers’ tame HIV without drugs. Science. (26 August 2020).
- Einkauf KB. Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapy. JCI. DOI: 10.1172/JCI124291. (28 January 2019).
- TAG. Research Toward a Cure Trials.
- TAG Pipeline Report 2020. Research Toward a Cure and Immune-Based Therapies.
- Jefferys R. Promising approaches to HIV remission and cure. (19 November 2019).
- Roehr B. The World’s First Known Person Who Naturally Beat HIV Goes Public. (16 October 2019).
- Lewin S. HIV cure from bench to bedside. CROI 2020. Plenary PL-01.
- Jiang C et al. Distinct chromosomal integration site configuration in HIV-1 elite controllers. CROI 2020, Oral abstract OL-06.
This report was first published online on 28 August 2020.