Thirty months following treatment interruption, a patient known as the “London patient” has continued to remain in sustained remission of human immunodeficiency virus (HIV) status.1 The patient had no detectable HIV type 1 (HIV-1) in plasma, cerebrospinal fluid (CSF), intestinal tissue, or lymphoid tissue, following HIV treatment interruption. The findings were presented at the virtual Conference on Retroviruses and Opportunistic Infections (CROI) and simultaneously published in The Lancet HIV.1,2
The elusive HIV cure is demonstrated by the extended periods without antiretroviral therapy (ART), showing negative results on the test for HIV nucleic acid and loss of adaptive immune responses. Only one such case of HIV cure, referred to as the Berlin patient, has been identified.3 This individual underwent two rounds of total body irradiation and allogeneic haemopoietic stem-cell transplantation (allo-HSCT) with donor cells that did not express CCR5 for the treatment of acute myelogenous leukemia. The London patient underwent allo-HSCT with cells that did not express CCR5 (CCR5Δ32/Δ32) for the treatment of refractory Hodgkin lymphoma (stage IVb), and reported remission after analytical treatment interruption (ATI).1
As of March 4, 2020, the London patient has been in HIV remission for 30 months, with plasma negative for HIV-1 RNA (<1 copy per mL) and semen negative at 21 months. However, HIV-1 replication can occur in the central nervous system (CNS) even during suppressive ART and is frequently associated with symptoms and magnetic resonance imaging (MRI) abnormalities.1 Most importantly, no detectable HIV-1 load was recorded in the CSF of this patient. Similarly, intestinal lymphoid tissue, an important HIV reservoir, was devoid of HIV-1 DNA in gut biopsy samples. HIV-1 DNA assessed by digital polymerase chain reaction (ddCR) was also negative in the rectum, cecum, sigmoid colon, and terminal ileum tissue samples at 22 months.1
Additionally, HIV-1-specific CD4 and CD8 T-cell responses also remained below detection levels. The patient’s CD4 count was 430 cells/μL (23.5% of total T-cells) at 28 months. The viral load in semen was undetectable in both plasma and cells at 21 months.1 The researchers also reported declining responses in HIV-1 specific antibodies up to 27 months after ATI using detuned (low-sensitive) and low-avidity assays. Western blot results showed similar appearances at 27 months compared with 18 months after ATI, with only glycoprotein 160 antibodies (HIV envelope marker) remaining. These results are consistent with the positive HIV-1 and related markers reported previously in the Berlin patient.1
Furthermore, like the Berlin patient, highly sensitive tests showed very low levels of so-called fossilized HIV-1 DNA in some tissue samples from the London patient.1 Residual HIV-1 DNA in axillary lymph node tissue could represent a defective clone that expanded during hyperplasia within the sampled lymph node. Moreover, the researchers believe that persistent HIV-1 envelope-specific plasma cells could have survived allo-HSCT, and the low level HIV-1 DNA depicted in lymph node polymerase chain reaction (PCR) signal could be related to this observation.1
Therefore, more work needs to be done to assess the role of detuned and low-avidity antibody assays in defining cure for HIV patients.1 The slow recovery in CD4 count observed in the London patient could be the result of the lengthy duration of untreated HIV infection between 2003 and 2013 or to the effects of alemtuzumab (anti-CD52 monoclonal antibody used for lymphodepletion in the setting of allo-HSCT). Notably, the reactivation of Epstein-Barr virus that was observed at 21 months after ATI could have been related to this continued relative immunosuppression. However no cytomegalovirus reactivation or opportunistic infections were reported at that time.1 Most importantly, the London patient did not receive any cytotoxic agents or prophylaxis of graft versus host disease (GvHD) beyond 6 months after allo-HSCT.1
When asked about whether this patient is truly cured, the researchers responded with “Only time will tell”.2 However, these findings probably represent the second recorded HIV cure after CCR5 allo-HSCT, with evidence of residual low-level HIV-1 DNA. These cases demonstrated that CCR5-directed approaches can lead to long-term remission of HIV-1, but several barriers, such as gene editing efficiency and robust safety data remain to be overcome.
1. Gupta RK et al. Evidence for HIV-1 cure after CCR5Δ32/Δ32 allogeneic haemopoietic stem-cell transplantation 30 months post analytical treatment interruption: a case report. The Lancet HIV. 2020;0(0). https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(20)30069-2/abstract. Accessed March 31, 2020.
2. After 30 Months, “London Patient” Still in HIV Remission. https://www.medpagetoday.com/meetingcoverage/croi/85346. Published March 10, 2020. Accessed March 31, 2020.
3. Hütter G et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360(7):692-698.