Dramatic HIV DNA degradation associated with spontaneous HIV suppression and disease-free outcome in a young seropositive woman following her infection

Philippe Colson,Didier Raoult,Jeremy Delerce,Catherine Dhiver,Olga O. Glazunova,Maxime Gaudin,Catherine Tamalet,Anthony Levasseur

doi:10.1038/s41598-020-58969-6

Abstract

Strategies to cure HIV-infected patients by virus-targeting drugs have failed to date. We identified a HIV-1-seropositive woman who spontaneously suppressed HIV replication and had normal CD4-cell counts, no HIV-disease, no replication-competent virus and no cell HIV DNA detected with a routine assay. We suspected that dramatic HIV DNA degradation occurred post-infection. We performed multiple nested-PCRs followed by Sanger sequencing and applied a multiplex-PCR approach. Furthermore, we implemented a new technique based on two hybridization steps on beads prior to next-generation sequencing that removed human DNA then retrieved integrated HIV sequences with HIV-specific probes. We assembled ≈45% of the HIV genome and further analyzed the G-to-A mutations putatively generated by cellular APOBEC3 enzymes that can change tryptophan codons into stop codons. We found more G-to-A mutations in the HIV DNA from the woman than in that of her transmitting partner. Moreover, 74% of the tryptophan codons were changed to stop codons (25%) or were deleted as a possible consequence of gene inactivation. Finally, we found that this woman’s cells remained HIV-susceptible in vitro. Our findings show that she does not exhibit innate HIV-resistance but may have been cured of it by extrinsic factors, a plausible candidate for which is the gut microbiota.

Highlights

Strategies to cure HIV-infected patients by virus-targeting drugs have failed to date
Replication-competent HIV was retrieved by co-culture on two occasions, including using peripheral blood mononuclear cell (PBMC) collected in 2019 as determined by HIV-1 RNA or DNA undetectability after 28 days of culture, whereas the same culture procedure allowed growing the virus from the PBMCs of the transmitting partner
The woman PBMCs were found to be susceptible to the HIV-1 NL4-3 strain and to the HIV strain cultured from the PBMCs of her transmitting partner

Summary

Introduction

Strategies to cure HIV-infected patients by virus-targeting drugs have failed to date. Most integrated retrovirus sequences were inactivated by substantial degradation, and only remain as relics of ancient retrovirus epidemics[2,3] This general biological phenomenon that consists in the cannibalism of the DNA from viral invaders has been revealed to be on-going in koalas with retroviruses causing an AIDS-like syndrome[4]. It was recently shown that a patient experienced a dramatic decrease in peripheral blood mononuclear cell (PBMC) HIV-1 DNA load in response to a release of immunity by monoclonal antibodies targeting PD-112, whose activity is known to be modulated by the gut microbiota[13,14]. We previously described two HIV-1-seropositive patients who we believe might have been spontaneously cured of HIV15,16 They never received antiretrovirals, they persistently have a suppressed HIV replication, normal CD4 T cell counts, and no HIV-related disease for more than 10 years (one was HIV-diagnosed in 1985). While searching for other index cases to understand if it is possible to be cured spontaneously of HIV, we investigated a third case

Methods

Results

Conclusion