Plasma-Derived HIV-1 Virions Contain Considerable Levels of Defective Genomes

Fisher, Katie; Wang, Xiao Qian; Lee, Ashley; Morcilla, Vincent; Vries, Anneke de; Lee, Eunok; Eden, John‐Sebastian; Deeks, Steven G.; Kelleher, Anthony D.; Palmer, Sarah

doi:10.1128/jvi.02011-21

Cited by 21 publications

(17 citation statements)

References 120 publications

(201 reference statements)

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“…Some defective proviruses can express HIV-1 RNA and produce viral proteins (25)(26)(27)(28)(29)(30). A recent study suggested that a fraction of viruses found in plasma before ART was defective due to small deletions and frameshifts (31). Some defective proviruses have small deletions in the 5'-Leader (5'-L) upstream of gag (23,32,33).…”

Section: Introductionmentioning

confidence: 99%

Clonally expanded HIV-1 proviruses with 5′-leader defects can give rise to nonsuppressible residual viremia

White¹,

Wu²,

Yasin³

et al. 2023

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

Clonally expanded HIV-1 proviruses with 5′-leader defects can give rise to nonsuppressible residual viremia

White¹,

Wu²,

Yasin³

et al. 2023

Journal of Clinical Investigation

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“…Though the sequence recovered from BC-001's lowlevel viremia dated to the year before ART, those recovered from BC-002 and BC-004's on-ART viremia indicated that proviruses capable of reactivating to produce viremia can be genetically heterogeneous, and can originate from very ancestral proviruses, which may in some cases be defective. The existence of genetically defective virions is supported by their presence during untreated infection 76 (though recently-infected, rather than reservoir cells, would be the likely source during that time), and the recent discovery that low-level viremia can originate from defective proviruses 51,72 . By contrast, HIV RNA rebounding in plasma after ART interruption dated to the years just prior to ART (BC-001), consistent with its origin from intact proviruses dating to that same period.…”

Section: Discussionmentioning

confidence: 99%

HIV reservoirs are dominated by genetically younger and clonally enriched proviruses

Kinloch

Shahid

Dong

et al. 2023

Preprint

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In order to cure HIV, we need to better understand the within-host evolutionary origins of the small reservoir of genome-intact proviruses that persists within infected cells during antiretroviral therapy (ART). Most prior studies on reservoir evolutionary dynamics however did not discriminate genome-intact proviruses from the vast background of defective ones. We reconstructed within-host pre-ART HIV evolutionary histories in six individuals and leveraged this information to infer the ages of intact and defective proviruses sampled after an average >9 years on ART, along with the ages of rebound and low-level/isolated viremia occurring during this time. We observed that the longest-lived proviruses persisting on ART were exclusively defective, usually due to large deletions. In contrast, intact proviruses and rebound HIV exclusively dated to the years immediately preceding ART. These observations are consistent with genome-intact proviruses having shorter lifespans, likely due to the cumulative risk of elimination following viral reactivation and protein production. Consistent with this, intact proviruses (and those with packaging signal defects) were three times more likely to be genetically identical compared to other proviral types, highlighting clonal expansion as particularly important in ensuring their survival. By contrast, low-level/isolated viremia sequences were genetically heterogeneous and sometimes ancestral, where viremia may have originated from defective proviruses. Results reveal that the HIV reservoir is dominated by clonally-enriched and genetically younger sequences that date to the untreated infection period when viral populations had been under within-host selection pressures for the longest duration. Knowledge of these qualities may help focus strategies for reservoir elimination.

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“…The first method used a previouslydesigned custom workflow in CLC Genomics (Qiagen) (10). The second method is a custom pipeline for contig de novo assembly (34,35), and can be found at https://github.com/jsede/virus_assembly. Briefly, the generated reads are QC trimmed using BBDuk v 37.98 (https://sourceforge.net/projects/bbmap/).…”

Section: Dna Extraction and Full-length Individual Proviral Sequencingmentioning

confidence: 99%

Unequal distribution of genetically-intact HIV-1 proviruses in cells expressing the immune checkpoint markers PD-1 and/or CTLA-4

et al. 2023

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IntroductionHIV-1 persists in resting CD4+ T-cells despite antiretroviral therapy (ART). Determining the cell surface markers that enrich for genetically-intact HIV-1 genomes is vital in developing targeted curative strategies. Previous studies have found that HIV-1 proviral DNA is enriched in CD4+ T-cells expressing the immune checkpoint markers programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocyte associated protein-4 (CTLA-4). There has also been some success in blocking these markers in an effort to reverse HIV-1 latency. However, it remains unclear whether cells expressing PD-1 and/or CTLA-4 are enriched for genetically-intact, and potentially replication-competent, HIV-1 genomes. MethodsWe obtained peripheral blood from 16 HIV-1-infected participants, and paired lymph node from four of these participants, during effective ART. Memory CD4+ T-cells from either site were sorted into four populations: PD-1-CTLA-4- (double negative, DN), PD-1+CTLA-4- (PD-1+), PD-1-CTLA-4+ (CTLA-4+) and PD-1+CTLA-4+ (double positive, DP). We performed an exploratory study using the full-length individual proviral sequencing (FLIPS) assay to identify genetically-intact and defective genomes from each subset, as well as HIV-1 genomes with specific intact open reading frames (ORFs). Results and DiscussionIn peripheral blood, we observed that proviruses found within PD-1+ cells are more likely to have intact ORFs for genes such as tat, rev and nef compared to DN, CTLA-4+ and DP cells, all of which may contribute to HIV-1 persistence. Conversely, we observed that CTLA-4 expression is a marker for cells harbouring HIV-1 provirus that is more likely to be defective, containing low levels of these intact ORFs. In the lymph node, we found evidence that CTLA-4+ cells contain lower levels of HIV-1 provirus compared to the other cell subsets. Importantly, however, we observed significant participant variation in the enrichment of HIV-1 proviruses with intact genomes or specific intact ORFs across these memory CD4+ T-cell subsets, and therefore consideration of additional cellular markers will likely be needed to consistently identify cells harbouring latent, and potentially replication-competent, HIV-1.

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Plasma-Derived HIV-1 Virions Contain Considerable Levels of Defective Genomes

Cited by 21 publications

References 120 publications

Clonally expanded HIV-1 proviruses with 5′-leader defects can give rise to nonsuppressible residual viremia

Clonally expanded HIV-1 proviruses with 5′-leader defects can give rise to nonsuppressible residual viremia

HIV reservoirs are dominated by genetically younger and clonally enriched proviruses

Unequal distribution of genetically-intact HIV-1 proviruses in cells expressing the immune checkpoint markers PD-1 and/or CTLA-4

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