World’s First Reported Spontaneous Clearance of HIV, Without Treatment
News Jun 13, 2019
Image credit: Pixabay
In 1981, a patient from Sydney was transfused with a weakened form of HIV-1 when he received a blood transfusion following a motorbike accident. After controlling his infection for more than 30 years, he appears to have cleared his infection altogether – without therapy.
Remarkably, a 73-year old man in Sydney with a unique combination of genetic and immunological characteristics appears to have spontaneously cleared his HIV infection. The details of his viral burden and immunological responses have been published in the Journal of Virus Eradication.
John Zaunders, Senior Hospital Scientist at St Vincent’s Hospital, Sydney, comments on the finding: “The patient belongs to a small group of HIV+ patients who were first recognized as unusually asymptomatic in 1992, and all found to be infected by transfusion products from a single donor, who was also asymptomatic. At that time they had been infected, prior to the availability of the HIV antibody test, for more than 10 years with no apparent decrease in CD4 cell count. They were one of the first groups of HIV controllers to be described.”
The patient (referred to here as the “Sydney Patient”) was the last recipient to be identified, 15 years after his original transfusion. Along with the eight other recipients, he was unaware of any possible HIV infection, until the Red Cross Blood Service went back to test recipients who may have received infectious transfusion products, including from the index asymptomatic blood donor.
Subsequently, it was recognized that they were all infected, including the donor, with a particular strain of HIV-1 that had a nef gene deletion, in the region in which the nef gene and the long terminal repeat overlap. Nef-deleted strains of HIV, and of simian immunodeficiency virus (SIV), are associated with virus attenuation, or weakening, and the nef gene deletion was discovered in this cohort by researchers at the Burnet Institute in 1995. At the time, it was thought to be a possible vaccine candidate, and was published in Science. While the approach led to an effective SIV vaccine in non-human primates, there were significant safety concerns for use of nef-deleted HIV in humans.
The Sydney Patient is distinct by several measures; the most unique observation is that he had detectable HIV DNA in blood samples (peripheral blood mononuclear cells, PBMCs) taken around 15 years after infection, but has had subsequent negative samples across a range of tests. Negative results were confirmed in samples taken from PBMCs, purified memory CD4 T cells, and lymph node and gut biopsy samples.
Of note, the Sydney Patient possesses genetic variants of the major histocompatibility complex gene group, HLA-B57 and HLA-DR13, that are associated with lower HIV-1 viral loads. These variants are also much more common in patients that control their HIV-1 infection than in the general population.
As is commonly found in HIV controllers, the Sydney Patient showed a clear CD8 T cell immune response to HIV-1 Gag, a protein necessary for virus assembly and virion structure. Furthermore, he had a CD4 response to the same protein, which appeared to augment his CD8 T cell response.
Of the tens of millions of people living with HIV globally, there have only been two documented cases of apparent clearance of HIV-1; the Berlin Patient and the recent London Patient, both of which received bone marrow transplants from donors whose cells lacked the HIV coreceptor CCR5 (due to being homozygous for the ∆32 mutation of ccr5).
Finally, the Sydney Patient is also heterozygous for the ∆32 mutation ccr5 and his T cells had demonstrably lower cell surface expression levels of CCR5.
At present, the function of the Nef peptide remains unknown, and a therapeutic approach to block the nef gene is unclear. However, future studies of nef deletion are justified, as it appears to be the best described association with HIV (or SIV) attenuation in vivo. The authors believe that Nef inhibition may be a critical component of possible HIV cures via T cell control of the HIV-1 reservoir.
The genetic and immunological factors possessed by the Sydney Patient in combination with the nef-deleted strain has never been described before, which may be why spontaneous clearance has also never been described, until now.
The authors note that this probable case of clearance of HIV-1 infection in a single individual “provides some hope that a similar combination of favorable pressures can be more generally applied to HIV-1 infection with a similar outcome”.
Zaunders, J., Dyer, W.B., Churchill, M., et al. (2019). Possible clearance of transfusion-acquired nef/LTR-deleted attenuated HIV-1 infection by an elite controller with CCR5 Δ32 heterozygous and HLA-B57 genotype. Journal of Virus Eradication 5:73-82
nb: an amendment has been made to this press release, to update the age of the patient. He is now 73 years old, not 60.