Stem cells in HIV infection

At the crossroad of virology and oncology stem cells constitute an interesting means for cure of HIV infection in a subset of patients. There are two ways of HIV cure: Functional cure refers to a state of sustained viral suppression in the absence of antiretroviral treatment (ART); sterilizing cure aims to completely eliminate replication-competent proviruses from the body which can usually be found in several reservoirs such as follicular dendritic cells, macrophages, resting CD4+ T-cells in the gut-associated lymphoid tissue (GALT), other lymph nodes, cerebrospinal fluid and CNS as well as the urogenital tract. It is estimated that approximately 1 per million resting CD4+ T cells harbor a latent provirus. The CCR5 chemokine receptor on the surface of CD4+ T-cells acts as a co-receptor for HIV-1 viral entry. The Delta32 mutation at the CCR5 locus is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Delta32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells [1]. In the serious case of required stem cell transplantation in HIV-infected patients it seems therefore sensible to look for donors harboring the CCR5 Delta32 mutation to curtail viral entry into the “new” CD4+ T cells thereby potentially preventing HIV reservoirs and enabling cure.

So far, 4 cases of HIV cure have been reported in patients from Berlin, London, Düsseldorf and most recently New York.

The first reported patient, the Berlin patient was an HIV-infected Caucasian male who was diagnosed with an acute myeloid leukemia (AML) and as a result of refractory leukemia received adult donor CCR5 Delta32/Delta32 bone marrow cells (10/10 human leukocyte antigen (HLA) match) in 2009. In addition to successful treatment of AML his HIV-1 infection went into remission for >12 years [2]. Unfortunately, the patient subsequently died due to a reemergence of his cancer in 2020.

The second HIV-infected patient, the London patient, a Latino male suffered from Hodgkin lymphoma shortly after starting ART in 2012 and received adult donor CCR5 Delta32/Delta32 homozygous peripheral blood mononuclear cells (PBMCs; 9/10 HLA match) after failing to respond to either first line chemotherapy or several salvage combinations. ART was maintained throughout and continued for 16 months post-transplant. Fortunately, his HIV-1 infection has been in remission since then [3].

The third HIV-infected patient was treated in Germany [4]. He was a Caucasian male diagnosed with HIV-1 infection in October 2010 and subsequently started on antiretroviral therapy (ART) as was the case in the other two patients. He received a diagnosis of AML in January 2011 and subsequently had to be treated with human stem cell transplantation (HSCT) from a 10/10 HLA matched female CCR5 Delta32/Delta32 donor in February 2013. The follow-up in terms of the leukemia was clinically complicated with graft vs. host disease (GvHD) and a relapse which was successfully treated with 8 cycles of 5-Azacytidine and 4 donor-lymphocyte-infusions (DLI). Regarding his HIV-infection the clinicians went to great length to detect virus in various compartments including Serum, PBMCs, ileum, rectum and lymph node biopsies. 9 years after the HSCT and after being off ART for more than 39 months all blood samples were tested negative for HIV.

The fourth HIV-infected patient undergoing SCT and achieving HIV-1 remission was reported at the Conference of Retrovirus and Opportunistic Infections (CROI) 2022 [5]. Interestingly, it is the first woman to achieve HIV-1 remission after SCT. She was diagnosed with an acute HIV-1 infection in 2013 and subsequently with a high-risk AML in 2017. After induction chemotherapy the patient underwent CCR5 Delta32/Delta32 cord/haploidentical transplant (5/8 HLA match cord blood units) and PBMCs from a relative in 2017. Following the novel treatment approach ART was interrupted 36 months after transplantation. After additional 14 months of ART-free follow-up no viral rebound was seen nor a relapse of AML. There was no detectable replication competent latent reservoir nor HIV-1 specific cellular immune responses accompanied by HIV-1 antibody negativity. Using umbilical cord blood cells has distinct advantages: they are archived in cord blood stem cell banks and hence easily accessible for screening and require a less strict HLA matching limiting chances of GvHD.

In conclusion, these four cases illustrate that SCT remains an option for cure of HIV in only few cases. Long-term follow-up data on viral shedding of reservoirs are still needed. So far, interruption of ART is the only way to validate long-term HIV remission.