By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: In a 30-year-old woman with human immunodeficiency virus (HIV) not on antiretroviral therapy (the “Esperanza patient”), an analysis of 1.188 billion peripheral blood mononuclear cells and 503 million mononuclear cells from placental tissue found no genome-intact or replication-competent HIV-1 proviruses. This indicates a sterilizing cure of HIV-1 infection.
SOURCE: Turk G, Seiger K, Lian X, et al. A possible sterilizing cure of HIV-1 infection without stem cell transplantation. Ann Intern Med 2022;175:95-100.
The development of antiretroviral therapy (ART) is a miracle of medical science that has allowed people infected with human immunodeficiency virus (HIV) to live normal lives. However, ART cannot eradicate HIV infection because the virus becomes latent in CD4+ T cells. Two individuals with HIV and leukemia who underwent allogeneic hematopoietic stem cell transplantation achieved what is widely regarded as sterilizing cures. Very rarely, some individuals, known as elite controllers, can achieve long-term suppression of viremia without ART, but genome-intact proviral deoxyribonucleic acid (DNA) and replication-competent viruses still can be detected. Turk and colleagues described an HIV-infected individual who achieved complete clearance of all replication-competent HIV-1, suggesting a natural sterilizing cure of HIV-1 infection.
The individual is a 30-year-old woman who initially was diagnosed with HIV-1 by serologic testing in March 2013. She had previously tested negative in 2011. Her partner was HIV-positive with a plasma viral load of 186,000 copies/mL in February 2013 and died from acquired immunodeficiency syndrome (AIDS) complications in July 2017. In the following eight years after the individual’s initial positive test, 10 viral load assays were below the level of detection. She became pregnant in 2019 and took ART for six months during the second and third trimesters. The baby was given four weeks of zidovudine and tested negative for HIV on multiple occasions. The patient stopped ART after delivery, and all follow-up HIV-1 viral loads remained undetectable. Testing for hepatitis B and C viruses, along with other sexually transmitted diseases, was negative.
To assess persistent HIV-1 reservoir cells, the investigators used peripheral blood samples from the patient collected between October 2017 and August 2019 and placental tissue collected in March 2020 after vaginal delivery of a healthy infant. They analyzed 1.188 billion peripheral blood mononuclear cells (PBMCs) and 503 million mononuclear cells from the placenta using single-genome amplification of HIV-1 DNA. They found seven defective proviral HIV-1 DNA specimens from the PBMCs and none from the placenta, indicating previous HIV-1 infection in which active replication occurred. Of the 150 million CD4+ T cells, none had a single replication-competent viral particle. Moreover, ultrasensitivity analysis of HIV-1 ribonucleic acid (RNA) from plasma did not detect any viral RNA copies. The patient’s CCR5 gene was homozygous for the wild-type allele. Immunologic assays found positive responses of CD4+ T cells against HIV-1 p24, and an HIV-1 Western blot was positive for gp160/120 and p24 bands. Plasma testing for 18 antiretroviral drugs was negative in 2019. Finally, her CD4+ T cells expressed the CCR5 and CXCR4 receptors and were able to support HIV-1 replication in vitro with R5 and X4-tropic viral isolates.
COMMENTARY
The patient reported in this study is only the second individual to be infected with HIV-1 and yet to have the complete absence of detectable intact HIV-1 proviruses and replication-competent viral particles in a large number of cells without receiving a stem cell transplant. This has been reported only one time previously, which was in a 67-year-old woman who had not taken ART in 28 years and had no intact proviral sequences after 1.5 billion PBMCs were analyzed. These two cases are similar to the so-called Berlin patient, who underwent hematopoietic stem cell transplantation with CCR5Δ32-encoding cells that enabled cell-intrinsic resistance to HIV-1 infection. In the Berlin patient, no replication-competent HIV-1 proviruses were detected in 1.4 billion CD4+ T cells.
The mechanism by which the 30-year-old woman in the present report cleared her HIV infection is unknown. The investigators hypothesized that innate immune cells, HIV-1 specific T-cell or B-cell responses, or cell-intrinsic restriction of viral replication steps may have been responsible. It is notable that both individuals who developed a sterilizing cure during natural infection were female. However, because the sample size is so small, it is difficult to draw any conclusions about this finding. The hypermutated sequence that was discovered did not contain any nef deletions, which are associated with drug-free HIV suppression in elite controllers. These are individuals with HIV-1 who have undetectable HIV viral loads in the absence of ART. The lack of nef deletions implies that the described patient was not infected with an attenuated viral strain.
The patient originally lived in the city of Esperanza in Argentina, and the investigators have chosen to refer to her as the “Esperanza patient.” The results of the study raise hope that a sterilizing cure for HIV-1 might be possible for other infected individuals. For this to happen will require a deep understanding of the mechanism(s) that resulted in her body’s remarkable ability to eradicate HIV-1 infection. These insights also might help guide further investigation on HIV vaccine development and, ultimately, end the HIV epidemic.
In a 30-year-old woman with HIV not on antiretroviral therapy (the “Esperanza patient”), an analysis of 1.188 billion peripheral blood mononuclear cells and 503 million mononuclear cells from placental tissue revealed no genome-intact or replication-competent HIV-1 proviruses. This indicates a sterilizing cure of HIV-1 infection.
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