Recommendations for measuring HIV reservoir size in cure-directed clinical trials

Abdel‐Mohsen, Mohamed; Richman, Douglas D.; Siliciano, Robert F.; Nussenzweig, Michel C.; Howell, Bonnie J.; Martínez-Picado, Javier; Chomont, Nicolas; Bar, Katharine J.; Yu, Xu G.; Lichterfeld, Mathias; Alcamí, José; Hazuda, Daria J.; Bushman, Frederic D.; Siliciano, Janet D.; Betts, Michael R.; Spivak, Adam M.; Planelles, Vicente; Hahn, Beatrice H.; Smith, Davey M; Ho, Ya-Chi; Buzón, María J.; Gaebler, Christian; Paiardini, Mirko; Li, Qingsheng; Estes, Jacob D.; Hope, Thomas J.; Kostman, Jay R.; Mounzer, Karam; Caskey, Marina; Fox, Lawrence; Frank, Ian; Riley, James L.; Tebas, Pablo; Montaner, Luis J.

doi:10.1038/s41591-020-1022-1

“…More recently, NFL provirus sequencing and ISA were combined into a single assay, allowing the study of the relationship between proviral integration site (IS) and genome structure 33,34 . However, because these assays are usually performed on bulk CD4 T cell DNA, they mainly identify defective proviruses, as it has been estimated that only 2-5% of the total proviruses are genome-intact 28,35–37 . As such, they do not focus on proviruses that could lead to viral rebound upon TI.…”

Section: Introductionmentioning

confidence: 99%

In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia

Cole

¹

,

Lambrechts

²

,

Gantner

³

et al. 2021

Preprint

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Clonal expansion of HIV-infected cells contributes to the long-term persistence of the HIV reservoir in ART-suppressed individuals. However, the contribution to plasma viremia from cell clones that harbor inducible proviruses is poorly understood. Here, we describe a single-cell approach to simultaneously sequence the TCR, integration sites and proviral genomes from translation-competent reservoir cells, called STIP-Seq. By applying this approach to blood samples from eight participants, we showed that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5-prime-end of the genome, often involving the major splice donor site. TCR and integration site sequencing revealed that antigen-responsive cells can harbor inducible proviruses integrated into cancer-related genes. Furthermore, we found several matches between proviruses retrieved with STIP-Seq and plasma viruses obtained during ART and upon treatment interruption, showing that STIP-Seq can capture clones that are responsible for low-level viremia or viral rebound.

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“…The likelihood of viral rebound and viral remission after ART cessation is likely a function of both the size of the inducible replicationcompetent HIV reservoir and the host environment that in uences in ammatory and immunological responses. 55 The on-going efforts by many groups to understand the quantitative and qualitative nature of the HIV reservoir are critical to understanding the virological basis of viral rebound. [56][57][58] However, complementary studies are also needed to understand host determinants of in ammatory and immunological states that also may impact post-treatment control of HIV.…”

Section: Discussionmentioning

confidence: 99%

“…Because current technologies are unable to measure the impact of interventions on the total body burden of HIV, HIV cure-focused clinical trials rely on the inclusion of an analytic treatment interruption (ATI) as the only de nitive approach to evaluate the effectiveness of interventions. 2 However, this approach is costly, cumbersome, and poses some risk to both study participants and the community. These realities highlight the urgent need for biomarkers that can accurately predict time-to-viral-rebound after treatment interruption and can be leveraged to guide clinical decision making.…”

Section: Introductionmentioning

confidence: 99%

Non-Invasive Plasma Glycomic and Metabolic Biomarkers of Post-treatment Control of HIV

Giron

¹

,

Palmer

²

,

Liu

³

et al. 2021

Preprint

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0

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Non-invasive biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are urgently needed. Such biomarkers can improve the safety of analytic treatment interruption (ATI) and provide mechanistic insights into the pathways involved in post-ART HIV control. We identified plasma glycomic and metabolic signatures of time-to-viral-rebound and probability-of-viral-rebound using samples from two independent cohorts. These samples include a large number of post-treatment controllers, a rare population demonstrating sustained virologic suppression after ART-cessation. The signatures remained significant after adjusting for key demographic and clinical confounders. We also confirmed a mechanistic link between biomarkers and HIV latency reactivation and myeloid inflammation in vitro. Finally, machine learning algorithms selected sets of biomarkers that predict time-to-viral-rebound with 74-76% capacity and probability-of-viral-rebound with 97.5% capacity. In summary, we fill a major gap in HIV cure research by identifying non-invasive biomarkers, with potential functional significance, that predict duration and probability of viral remission after treatment interruption.

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“…The likelihood of viral rebound and viral remission after ART cessation is likely a function of both the size of the inducible replication-competent HIV reservoir and the host environment that influences inflammatory and immunological responses. 55 The on-going efforts by many groups to understand the quantitative and qualitative nature of the HIV reservoir are critical to understanding the virological basis of viral rebound. 56-58 However, complementary studies are also needed to understand host determinants of inflammatory and immunological states that also may impact post-treatment control of HIV.…”

Section: Discussionmentioning

confidence: 99%

Non-Invasive Plasma Glycomic and Metabolic Biomarkers of Post-treatment Control of HIV

Giron

¹

,

Palmer

²

,

Yin

³

et al. 2020

Preprint

Self Cite

0

View full text Add to dashboard Cite

Non-invasive biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are urgently needed. Such biomarkers can improve the safety of analytic treatment interruption (ATI) and provide mechanistic insights into the pathways involved in post-ART HIV control. We identified plasma glycomic and metabolic signatures of time-to-viral-rebound and probability-of-viral-rebound using samples from two independent cohorts. These samples include a large number of post-treatment controllers, a rare population demonstrating sustained virologic suppression after ART-cessation. The signatures remained significant after adjusting for key demographic and clinical confounders. We also confirmed a mechanistic link between biomarkers and HIV latency reactivation and myeloid inflammation in vitro. Finally, machine learning algorithms selected sets of biomarkers that predict time-to-viral-rebound with 74-76% capacity and probability-of-viral-rebound with 97.5% capacity. In summary, we fill a major gap in HIV cure research by identifying non-invasive biomarkers, with potential functional significance, that predict duration and probability of viral remission after treatment interruption.

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Recommendations for measuring HIV reservoir size in cure-directed clinical trials

Cited by 100 publications

References 119 publications

In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia

In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia

Non-Invasive Plasma Glycomic and Metabolic Biomarkers of Post-treatment Control of HIV

Non-Invasive Plasma Glycomic and Metabolic Biomarkers of Post-treatment Control of HIV

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