A Possible Sterilizing Cure of HIV-1 Infection Without Stem Cell Transplantation

Abstract

Background: A sterilizing cure of HIV-1 infection has been reported in 2 persons living with HIV-1 who underwent allogeneic hematopoietic stem cell transplantations from donors who were homozygous for the CCR5Δ32 gene polymorphism. However, this has been considered elusive during natural infection.

Objective: To evaluate persistent HIV-1 reservoir cells in an elite controller with undetectable HIV-1 viremia for more than 8 years in the absence of antiretroviral therapy.

Design: Detailed investigation of virologic and immunologic characteristics.

Setting: Tertiary care centers in Buenos Aires, Argentina, and Boston, Massachusetts.

Patient: A patient with HIV-1 infection and durable drug-free suppression of HIV-1 replication.

Measurements: Analysis of genome-intact and replication-competent HIV-1 using near-full-length individual proviral sequencing and viral outgrowth assays, respectively; analysis of HIV-1 plasma RNA by ultrasensitive HIV-1 viral load testing.

Results: No genome-intact HIV-1 proviruses were detected in analysis of a total of 1.188 billion peripheral blood mononuclear cells and 503 million mononuclear cells from placental tissues. Seven defective proviruses, some of them derived from clonally expanded cells, were detected. A viral outgrowth assay failed to retrieve replication-competent HIV-1 from 150 million resting CD4⁺ T cells. No HIV-1 RNA was detected in 4.5 mL of plasma.

Limitations: Absence of evidence for intact HIV-1 proviruses in large numbers of cells is not evidence of absence of intact HIV-1 proviruses. A sterilizing cure of HIV-1 can never be empirically proved.

Conclusion: Genome-intact and replication-competent HIV-1 were not detected in an elite controller despite analysis of massive numbers of cells from blood and tissues, suggesting that this patient may have naturally achieved a sterilizing cure of HIV-1 infection. These observations raise the possibility that a sterilizing cure may be an extremely rare but possible outcome of HIV-1 infection.

Primary funding source: National Institutes of Health and Bill & Melinda Gates Foundation.

Figure.

Clinical and virologic characteristics of the Esperanza patient. ART = antiretroviral therapy; LTR = long terminal repeat; PBMC = peripheral blood mononuclear cell. A. Longitudinal CD4⁺ T-cell counts (cells/mL), CD4–CD8 ratios, and HIV-1 viral loads in the Esperanza patient. The recorded diagnosis date of HIV-1 infection is shown as the first date on the x-axis. The detection threshold for each viral load test is represented by a diamond (50 RNA copies/mL), a square (40 RNA copies/mL), or a circle (20 RNA copies/mL). B. Virogram indicating proviral HIV-1 DNA sequences isolated from a total of 1.188 billion PBMCs in the Esperanza patient. Sequences with hypermutations and large deletions are indicated by different colors; sequence-identical (clonal) sequences are boxed. C. Linear maximum-likelihood phylogenetic tree of HIV-1 proviral sequences detected in the Esperanza patient, relative to HXB2. The clonal cluster of proviral sequences with a large deletion was detected in PBMCs collected in 2018 and 2020 and is highlighted by the box.