A 66-year-old man, diagnosed with HIV in 1988, has been in remission for more that 17 months after stopping antiretroviral therapy (ART) for the disease following a stem-cell transplant from an unrelated donor for leukaemia.
And a fifth possible success is on the cards, with Spanish researchers saying a woman who received an immune-boosting regimen in 2006 is in viral remission, meaning she still harbours viable HIV but her immune system has controlled the virus’s replication for over 15 years.
Both cases were presented at the AIDS 2022 Conference (29 July-2 August).
The first case was presented by Dr Jana Dickter, associate clinical professor in the Division of Infectious Diseases at City of Hope, one of the largest cancer research and treatment organisations in the US. The caucasian patient, who received the transplant at City of Hope, is the fourth known person to go into HIV remission.
Data presented at the conference showed that the man, diagnosed with HIV in 1988, received chemotherapy and an allogeneic haematopoietic stem-cell transplant (aHCT) after developing acute myelogenous leukaemia in 2018. Previously, he had an undetectable HIV-1 viral load on ART for many years.
The transplant recipient continued ART for 25 months after aHCT and his ART levels remained undetectable 12 months post-analytic treatment interruption.
As of 14 months after stopping treatment and 39 months post-transplantation, there is no evidence of HIV RNA rebound and no detectable HIV DNA.
Declining HIV-1 specific humoral and no detectable HIV-specific cellular immune response was observed. The man’s CD8-depleted peripheral blood mononuclear cells remained uninfected after an ex vivo challenge with HIV R5 strains. Immunological studies 37 months after the aHCT and 12 months post-analytic treatment interruption showed a robust response to cytomegalovirus stimulation and no response to HIV CD4 and CD8 T cells.
“The patient received his blood stem cell transplant in early 2019 for acute myelogenous leukaemia from an unrelated donor, who has a rare genetic mutation, homozygous CCR5 Delta 32. That mutation makes people who have it resistant to acquiring HIV. CCR5 is a receptor on CD4+ immune cells, and HIV uses that receptor to enter and attack the immune system. But the CCR5 mutation blocks that pathway, which stops HIV from replicating,” said Dickter.
She said he stopped taking ART for HIV in March 2021. “He might have been able to stop the therapies sooner but wanted to wait until he was vaccinated against COVID-19.”
“We were thrilled to let him know that his HIV is in remission and he no longer needs to take antiretroviral therapy that he had been on for more than 30 years,” Dickter added. “His case, if the right donor can be identified, may open up the opportunity for more older patients living with HIV and blood cancers to receive a stem cell transplant and go into remission for both diseases.”
In the case of the Spanish woman (59), she had sexually-acquired HIV and was enrolled in the “Immune-mediated PHI trial”: she maintained an undetectable viral load for more than 15 years without ART.
Núria Climent, researcher at Hospital Clínic-IDIBAPS/University of Barcelona, said after receiving antiretroviral and immunomodulatory treatment, including eight weeks of cyclosporine, during primary HIV infection, the woman has maintained undetectable viral load in plasma for more than 15 years without ART. A pronounced and progressive fall of the viral reservoir was observed in total HIV-DNA (from 4,573.50 to 95.33 copies/106 CD4+ T-cells) and integrated proviral DNA (from 85.37 to 5.25 copies/106 CD4+ T-cells).
The authors noted that study results showed that replication-competent HIV-1 could be isolated by qVOA. They also reported that NKG2C+-memory-like NK-cells and Yd+CD8+ T-cells could contribute to the control of viral replication and functional cure observed.
Making history, previously, as the first two patients to be cured of HIV were Adam Castillejo, of Dutch/Spanish descent, who was raised in Venezuela but settled in London in 2002 and discovered he was HIV positive in 2003 at 23. He became known as the London Patient, the second patient to be cured of HIV, and continues to advocate for a widely applicable HIV cure.
The very first person to be cured of HIV, who died in 2020 of cancer, was Timothy Ray Brown. Brown, initially known as the Berlin Patient, had lived with HIV for years before being diagnosed with blood cancer: acute myeloid leukaemia in his case, and Hodgkin lymphoma in Castillejo’s case.
Both underwent treatment with chemotherapy before undergoing a bone marrow transplant from a donor with a rare genetic mutation known as CCR5-delta32, which blocks HIV from entering T cells. The treatments – Castillejo’s in 2016, Brown’s nearly a decade earlier – cured both men of HIV by replacing their immune cells with resistant cells carrying the mutation.
In 2019, Brown discovered that his cancer had returned. In 2020, he announced that he was terminally ill. He died in hospice care in September that year.
The third case, reported WebMD in February this year, was a woman who has been in remission from HIV for 14 months after being treated for leukaemia with transplants of adult stem cells and umbilical cord blood. If she remains off treatment without any hint of HIV, she would be only the third person in the world – and the first woman – to be cured through a transplant.
“Her own virus could not infect her cells,” said Dr Yvonne Bryson, chief of paediatric infectious diseases at the UCLA School of Medicine.
This approach may be available to a more diverse pool of people living with HIV. The New York woman, who is biracial, was diagnosed with HIV in 2013. She started treatment right away and quickly developed an undetectable viral load, which not only prevents someone from transmitting HIV to others, but also gives the virus less time to enter cells, where it can hide.
But in 2017, she was diagnosed with leukaemia. As a last resort to cure her of the cancer, she received a combination of adult stem cells from a relative’s blood and umbilical cord blood obtained from a cord-blood bank. That sample of cord blood was selected because it contained a genetic mutation that makes the immune system resistant to HIV.
The two previous HIV cures, in Brown of Berlin and Castillejo of London, also used stem cell transplantation with the same mutation. But they had bone marrow transplants. Those transplants are more difficult than cord blood transplants, which are commonly used to treat cancer in children.
In this case, the doctors treating her used both.
Study 1 details
The 'City of Hope’ Patient: prolonged HIV-1 remission without antiretrovirals (ART) after allogeneic hematopoietic stem cell transplantation (aHCT) of CCR5-Δ32/Δ32 donor cells for acute myelogenous leukemia (AML)
J. Dickter, S. Weibel, A. Cardoso, S. Li, K. Gendzekhadze, Y. Feng, S. Dadwal, R. Taplitz, J. Ross, A. Aribi, R. Stan, T. Kidambi, L. Lai, S. Chang, A. Chaillon, M. Al Malki, J. Alvarnas, S. Forman, J. Zaia.
HIV-1 remission has been described post aHCT. We report a 66-year-old Caucasian male, diagnosed with HIV-1 in 1988 (CD4 nadir <100 cells/uL), undetectable HIV-1 viral load on ART since 1990s. In 2018, he developed AML, treated with chemotherapy followed by aHCT from unrelated HLA-matched CCR5-Î?32 homozygous donor. He continued emtricitabine/tenofovir alafenamide/dolutegravir 25 months (m) post-aHCT. After analytic treatment interruption (ATI), he remains in HIV-1 remission.
3/2019-current, City of Hope.
Pre-aHCT: HIV-1 DNA quantification, sequencing of genotypic tropism. Post-aHCT: blood, intestinal biopsies were obtained for cellular HIV DNA, RNA (by droplet digital PCR); compartmental testing for donor cells; ART levels; HIV-1 antibody quantification; peripheral blood mononuclear cells (PBMC) challenged with HIV-1; HIV, CMV T-cell responses.
Pre-aHCT: 80 HIV-1 DNA copies/million PBMC, majority R5 tropic virus (10% false-positive rate). Post-aHCT, 14m post-ATI: 100% donor chimerism.
Study 2 details
Exceptional post-treatment control associated with strong NK and Ï?É? cytotoxic T cells
N. Climent, J. Ambrosioni, T. González, M. Casadellà, M. Noguera, R. Paredes, M. Plana, J. Mallolas, J. Alcamí, S. Sánchez-Palomino, J.M. Miró
Although ART is effective in suppressing viral replication, HIV persists in reservoirs and rebounds after stopping therapy. However, there are few patients, such as post-treatment controllers (PTC), who are able to maintain viral loads below detection limits without ART, being a realistic model for the HIV-functional-cure. We describe the mechanisms of control of an exceptional PTC (>15 years).
A 59-year woman with sexually-acquired acute HIV-infection was included in the Immune-mediated PHI trial involving several interventions: short course of low doses of CsA, IL-2, GM-CSF and Peg-a-IFN followed by analytical STI. Virological studies were performed: total and integrated HIV-1 DNA in CD4+ T-cells and rectal tissue, viral outgrowth assay (qVOA), HIV-1 infectivity in PBMC and CD4+ T-cells cultures and viral inhibitory activity (VIA) of autologous CD4+T-cells with NK and CD8+ T-cells. NK and T-cell phenotype was determined by flow-cytometry.HLA class I, Î?32CCR5 and NKG2C alleles were genotyped.
After antiretroviral and immunomodulatory treatment, the patient maintained undetectable viral load in plasma for 15 years. HIV-1 subtype was CFR_02AG, R5-tropic. We found a pronounced and progressive fall of the viral reservoir (VR): total HIV-DNA (from 4573.50 to 95.33 copies/106 CD4+T-cells) and integrated proviral DNA (from 85.37 to 5.25 copies/106 CD4+T-cells).VR in rectal biopsy was 3 HIV DNA total copies/106 cells and qVOA detected 1.61 UIMP at year 9. VIA assay showed strong inhibition of in vitro replication in co-cultures with autologous NK-cells or CD8+T-cells at 1:2 ratio (75% and 62%, respectively). Co-cultures with NK and CD8+T-cells resulted in 93% inhibition of HIV-replication. Higher levels of both NKG2C+-memory-like NK-cells and NKG2C+Ï?É?+T-cells than referenced data from untreated normal HIV-infected progressors were detected (46.2% versus 24.0% and 64.9% versus 19.7%, respectively). The patient has A*29:01/A*29:01, B*44:03/B*44:03, C*16:01/C*16:01 HLA-I, wt/wt CCR5 and wt/wt NKG2C alleles.
We describe the case of functional cure in a 59-years-old woman treated during PHI that has maintained undetectable viral load for 15 years without ART. Replication-competent HIV-1 could be isolated by qVOA. NKG2C+-memory-like NK-cells and Ï?É?+CD8+T-cells contribute to the control of viral-replication and functional-cure observed. Strategies able to expand these cells could help to achieve HIV-functional-cure.
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