A cure for HIV: how would we know?
Authors: Jennifer M Zerbato, Sharon R Lewin
Journal: The Lancet HIV (2020)

With the need for lifelong treatment of HIV with antiretroviral therapy (ART), and the associated costs, adverse events, and stigma, there is a growing need and a global scientific effort to find a cure, with many interventions being currently assessed in animal models and clinical trials.1Ndung'u T McCune JM Deeks SG Why and where an HIV cure is needed and how it might be achieved.Nature. 2019; 576: 397-405Crossref PubMed Scopus (33) Google Scholar But what does a cure for HIV mean and how can scientists really know that someone is indeed cured? In The Lancet HIV, Ravindra Kumar Gupta and colleagues describe follow-up with extensive tissue and blood sampling2Gupta RK Peppa D Hill AL et al.Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report.Lancet HIV. 2020; (published online March 10.)https://doi.org/10.1016/S2352-3018(20)30069-2Summary Full Text Full Text PDF PubMed Scopus (42) Google Scholar of an individual (referred to as the London patient) whose case was originally reported 12 months ago.3Gupta RK Abdul-Jawad S McCoy LE et al.HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation.Nature. 2019; 568: 244-248Crossref PubMed Scopus (210) Google Scholar The London patient is a man living with HIV who was diagnosed with Hodgkin disease and who received a stem-cell transplant from a donor who carried a mutation in the CCR5 gene (CCR5∆32/∆32). CCR5 is a key receptor for most strains of HIV and, therefore, T cells or macrophages that do not express CCR5 are protected from infection with strains of HIV that use this receptor. After transplantation and cessation of ART, Gupta and colleagues report that the London patient's plasma HIV RNA has remained undetectable for 30 months.2Gupta RK Peppa D Hill AL et al.Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report.Lancet HIV. 2020; (published online March 10.)https://doi.org/10.1016/S2352-3018(20)30069-2Summary Full Text Full Text PDF PubMed Scopus (42) Google Scholar This period is indeed a very long time to remain aviraemic off ART, considering the median time to viral rebound after cessation of ART is 2–3 weeks. The investigators also assessed semen and cerebrospinal fluid, and samples of gut, lymph node, and rectal tissue. Low levels of HIV DNA were found in lymph node tissue and in blood CD4+ T cells, whereas all other samples were negative for HIV DNA. Importantly, the low levels of HIV DNA that were found were not intact, consistent with archived viral fragments that cannot replicate. Finally, Gupta and colleagues developed a mathematical model to predict the chance of viral rebound after stopping ART, based on the number of infected cells (the size of the reservoir) and the number of susceptible target cells, estimated by the degree of chimerism or the proportion of donor cells relative to recipient cells.2Gupta RK Peppa D Hill AL et al.Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report.Lancet HIV. 2020; (published online March 10.)https://doi.org/10.1016/S2352-3018(20)30069-2Summary Full Text Full Text PDF PubMed Scopus (42) Google Scholar Based on the London patient having greater than 90% chimerism in circulating T cells, they concluded that the chance of future viral rebound while off ART is negligible. With more prolonged follow-up and now tissue sampling, is the London patient really cured? One difficulty in quantifying persistent virus in an individual on ART is that the ability to detect an infected cell is dependent on the total number of cells tested, which has an upper limit, particularly when sampling tissue sites. A second individual (Timothy Brown, sometimes referred to as the Berlin patient) received a stem-cell transplant from a CCR5∆32/∆32 donor and has been off ART for more than 13 years with undetectable plasma HIV RNA. This patient also had extensive blood and tissue sampling to find infected cells,4Hutter G Nowak D Mossner M et al.Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation.N Engl J Med. 2009; 360: 692-698Crossref PubMed Scopus (1210) Google Scholar and no virus was detected in almost all samples except for some blood samples and one sample from rectal tissue, in which traces of HIV were detected. At the time of testing, this finding was thought to represent low-level contamination of the assay.5Yukl SA Boritz E Busch M et al.Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient.PLoS Pathog. 2013; 9e1003347Crossref PubMed Scopus (186) Google Scholar We now know that most virus that persists on ART is defective and unable to replicate, and we are able to better quantify intact and defective virus with either near full-length sequencing6Bruner KM Murray AJ Pollack RA et al.Defective proviruses rapidly accumulate during acute HIV-1 infection.Nat Med. 2016; 22: 1043-1049Crossref PubMed Scopus (342) Google Scholar or PCR-based assays.7Bruner KM Wang Z Simonetti FR et al.A quantitative approach for measuring the reservoir of latent HIV-1 proviruses.Nature. 2019; 566: 120-125Crossref PubMed Scopus (159) Google Scholar Therefore, a cure for HIV might be better defined as no intact virus, rather than no detectable virus. What about the immune response to the virus? Could this be a helpful strategy to define a cure? Previous work has suggested that less HIV antigen means less stimulation of antibody production. Therefore, a lower frequency of infected cells on ART has been associated with lower concentration and avidity of anti-HIV antibodies and fewer specific bands on an HIV-specific western blot assay.8Burbelo PD Bayat A Rhodes CS et al.HIV antibody characterization as a method to quantify reservoir size during curative interventions.J Infect Dis. 2014; 209: 1613-1617Crossref PubMed Scopus (35) Google Scholar In both the London patient and Timothy Brown, detection of antibodies to HIV proteins diminished after transplantation and gradually declined over time, but these antibodies still persisted.3Gupta RK Abdul-Jawad S McCoy LE et al.HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation.Nature. 2019; 568: 244-248Crossref PubMed Scopus (210) Google Scholar, 5Yukl SA Boritz E Busch M et al.Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient.PLoS Pathog. 2013; 9e1003347Crossref PubMed Scopus (186) Google Scholar A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV? Prolonged clinical observation and follow-up is required, with regular testing of plasma HIV RNA. But if, over time, the chance of viral rebound becomes less likely, could the frequency of testing be reduced and one day even stopped? Reduced frequency of monitoring for disease relapse over time is a common practise in follow-up of many malignant diseases. However, the duration and frequency of follow-up in such as setting is based on very large cohorts with a deep understanding of the natural history of the specific malignant disease. We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication. The finding of no intact virus in both blood and tissue can be reassuring for a patient who might face great anxiety and uncertainty about whether and when viral rebound off ART might occur, which in other settings has been completely unpredictable.9Henrich TJ Hanhauser E Marty FM et al.Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases.Ann Intern Med. 2014; 161: 319-327Crossref PubMed Scopus (287) Google Scholar, 10Henrich TJ Hatano H Bacon O et al.HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: an observational study.PLoS Med. 2017; 14e1002417Crossref PubMed Scopus (106) Google Scholar In view of the many cells sampled in this case, and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow-up case report is certainly exciting and encouraging but, in the end, only time will tell. SRL reports grants from the National Health and Medical Research Council of Australia, the National Institutes of Health, the American Foundation for AIDS Research, Gilead Sciences, Merck, ViiV Healthcare, Leidos, the Wellcome Trust, the Australian Centre for HIV and Hepatitis Virology Research, and the Melbourne HIV Cure Consortium, outside the area of work commented on here. JMZ reports grants from the Melbourne HIV Cure Consortium, outside the area of work commented on here. Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case reportThe London patient has been in HIV-1 remission for 30 months with no detectable replication-competent virus in blood, CSF, intestinal tissue, or lymphoid tissue. Donor chimerism has been maintained at 99% in peripheral T cells. We propose that these findings represent HIV-1 cure. Full-Text PDF Open Access