An anonymous woman from Argentina has become only the second person known to ever show no detectable traces of an HIV infection without receiving a stem cell transplantation treatment to cure it. The so-called ‘Esperanza patient’, named after her hometown in Argentina, was first diagnosed with HIV-1 in 2013 – but after eight years of follow-up checks and a total of 10 commercial viral load tests, there appears to be no sign of active viral infection in her body, nor any evidence of HIV-1-associated disease. While the woman’s case recalls some other famous patients who made headlines for seemingly beating the infection – notably the ‘Berlin patient’ (aka Timothy Ray Brown, diagnosed in 1995) and the ‘London patient’ (diagnosed in 2003) – both those cases involved stem cell transplants to treat different kinds of cancer. In the case of the Berlin patient, his transplant unexpectedly ‘cured him’ of the virus – or rather, put the virus into such a level of sustained remission that it could no longer be detected, even in the absence of antiretroviral (ART) drugs. Several years later, the London patient’s experience shared many similarities, suggesting that Brown’s case was not entirely unique, and that stem cell transplants could provide an effective, albeit rare form of sterilization of the virus. Since those discoveries, scientists have progressively been learning more about how some people’s bodies seem to sometimes find natural ways of countering the virus, including the extremely rare ‘elite controllers’, who appear to somehow tame the virus without the aid of drugs or transplants. Amongst this elite, the Esperanza patient is particularly notable, because even ‘elite controllers’ sometimes show detectable signs of the virus, depending on how hard you go looking for it. “In a small subgroup of persons living with HIV-1 who are frequently termed ‘elite controllers’ or ‘natural suppressors’, HIV-1 plasma viremia remains durably undetectable by commercial polymerase chain reaction (PCR) assays in the absence of antiretroviral therapy,” an international team of researchers explains in a new study, led by co-first authors Gabriela Turk and Kyra Seiger. “However, genome-intact proviral DNA and replication-competent viruses can readily be isolated in these persons by using in vitro laboratory assays, indicating that drug-free viral control in these persons results from host-dependent inhibition of viral replication and does not reflect elimination of all virally infected cells.” Whatever’s going on with the Esperanza patient is on a different level, the researchers say, with the woman appearing to have achieved “complete clearance of all replication-competent HIV-1 proviruses during natural infection”. During the patient’s eight years of follow-up after her initial March 2013 diagnosis, she only took antiretroviral drugs (ART) for one point (when she was pregnant in between 2019–2020). After delivering her healthy (and HIV-1-negative) baby, she stopped ART, and a comprehensive round of tests showed no signs of active virus. “What distinguishes her from all other described elite controllers and post-treatment controllers is the absence of detectable intact HIV-1 proviruses and replication-competent HIV-1 viral particles in large numbers of cells,” the researchers write. A similar case has been identified before, in a Californian patient called Loreen Willenberg, who has shown decades of drug-free remission, and no signs of intact virus in peripheral blood mononuclear cells (PBMCs) analysis. Despite the remarkable and hugely promising leads these case studies demonstrate in terms of HIV research, however, the scientists are very careful to distinguish what they are (and are not) claiming here. “Does this imply that our patient has developed a sterilizing cure during natural infection? We believe this is likely, but it cannot be proved,” the researchers explain. “Scientific concepts can never be proved through empirical data collection; they can only be disproved. In the context of HIV-1 research, this means that it will be impossible to empirically prove that anybody has achieved a sterilizing cure.” Despite not being able to call this seemingly natural phenomenon a ‘proof’, though, our inability to detect any sign of ongoing intact viral infection – despite comprehensive searching – is a huge win, and it’s something that could help us to reframe the boundaries of HIV research. “Collectively, our results raise the possibility that a sterilizing cure of HIV-1 infection, defined by the absence of detectable intact HIV-1 proviruses, is an extremely rare but possible clinical outcome,” the team writes. “It means there must be more people like this out there,” senior author and HIV researcher Natalia Laufer from Universidad de Buenos Aires told the media when initial results of the case were shared earlier in the year. “This is a significant leap forward in the world of HIV cure research. Upon diagnosis, her tests surprised us all. Her HIV antibody test showed she was HIV positive, but the level of virus was undetectable and continued so, over time. This is highly unusual.” The findings are reported in Annals of Internal Medicine.