Extensive characterization of HIV-1 reservoirs reveals links to plasma viremia before and during analytical treatment interruption

Cole, Basiel; Lambrechts, Laurens; Boyer, Zoe; Noppe, Ytse; Scheerder, Marie‐Angélique De; Eden, John‐Sebastian; Vrancken, Bram; Schlub, Timothy E.; McLaughlin, Sherry; Frenkel, Lisa M.; Palmer, Sarah; Vandekerckhove, Linos

doi:10.1016/j.celrep.2022.110739

Cited by 21 publications

(16 citation statements)

References 58 publications

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“…More intriguingly, it was not significantly different from the HIV sequence rank abundance slope (p=0.2, Figure 3E ), suggesting that the clonality of the most highly-expanded, ‘observed’ HIV proviruses may be driven by the same biological factors that drive the clonality of the most highly expanded rmCD4 clonotypes, e.g. antigen-specificity, effector ratio, lack of exhaustion 21,23,24,74 . The magnitude of the first slope indicates there are still large relative differences in clonal abundances; for example, the larger TCRβ clone slope of α 1 ∼0.8 implies the 10 th largest clone is less than 1/6 the size of the largest clone.…”

Section: Resultsmentioning

confidence: 92%

Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells

Reeves,

Rigau,

Romero

et al. 2024

Preprint

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The latent reservoir of HIV persists for decades in people living with HIV (PWH) on antiretroviral therapy (ART). To determine if persistence arises from the natural dynamics of memory CD4+ T cells harboring HIV, we compared the clonal dynamics of HIV proviruses to that of memory CD4+ T cell receptors (TCRβ) from the same PWH and from HIV-seronegative people. We show that clonal dominance of HIV proviruses and antigen-specific CD4+ T cells are similar but that the field's understanding of the persistence of the less clonally dominant reservoir is significantly limited by undersampling. We demonstrate that increasing reservoir clonality over time and differential decay of intact and defective proviruses cannot be explained by mCD4+ T cell kinetics alone. Finally, we develop a stochastic model of TCRβ and proviruses that recapitulates experimental observations and suggests that HIV-specific negative selection mediates approximately 6% of intact and 2% of defective proviral clearance. Thus, HIV persistence is mostly, but not entirely, driven by natural mCD4+ T cell kinetics.

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Section: Resultsmentioning

confidence: 92%

Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells

Reeves,

Rigau,

Romero

et al. 2024

Preprint

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show abstract

“…Latency has also been proposed to result from the integration of HIV-1 proviruses into regions of heterochromatin, resulting in epigenetic silencing 41 . Yet analysis of individual latent HIV-1 integration sites in patients has shown that most of the intact full-length HIV-1 proviruses are integrated into actively transcribed genes 42 – 46 . Overall, the mechanism(s) underlying the establishment of HIV-1 latency have remained elusive and cellular factors that promote viral latency largely undefined.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency

2022

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After viral entry and reverse transcription, HIV-1 proviruses that fail to integrate are epigenetically silenced, but the underlying mechanism has remained unclear. Using a genome-wide CRISPR/Cas9 knockout screen, we identified the host SMC5/6 complex as essential for this epigenetic silencing. We show that SMC5/6 binds to and then SUMOylates unintegrated chromatinized HIV-1 DNA. Inhibition of SUMOylation, either by point mutagenesis of the SMC5/6 component NSMCE2—a SUMO E3 ligase—or using the SUMOylation inhibitor TAK-981, prevents epigenetic silencing, enables transcription from unintegrated HIV-1 DNA and rescues the replication of integrase-deficient HIV-1. Finally, we show that blocking SMC5/6 complex expression, or inhibiting its SUMOylation activity, suppresses the establishment of latent HIV-1 infections in both CD4+ T cell lines and primary human T cells. Collectively, our data show that the SMC5/6 complex plays a direct role in mediating the establishment of HIV-1 latency by epigenetically silencing integration-competent HIV-1 proviruses before integration.

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“…Taken together, these observations suggested the possibility of infection of a progenitor cell, clonal proliferation followed by the dissemination of proliferating clones within the two compartments. Recently developed assays including - simultaneous detection of matched integration site analysis and near-full-length proviral sequencing assays (MIP-Seq) [40] and/or microfluidic method to sequence entire proviruses in their native integration site (SIP-seq) [41] may further provide an in-depth characterization of the integrated viral reservoir that is necessary to address the contribution of clonal expansion to HIV persistence and viral rebound [42]. These initial observations also point to alternate mechanisms such as the epigenetic landscape of Tfh cells that could be associated with the higher inducibility of replication-competent virus within Tfh cells in viral outgrowth assays, that remains to be determined in future studies.…”

Section: Maintenance Of the Lymph Node Reservoir By Clonal Proliferationmentioning

confidence: 99%

HIV persistence in lymph nodes

Banga

Munoz

Perreau

2021

Current Opinion in HIV and AIDS

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Purpose of reviewHIV persists in distinct cellular and anatomical compartments in the body including blood, Central nervous system, and lymphoid tissues (spleen, lymph nodes [LNs], gut-associated lymphoid tissue) by diverse mechanisms despite antiretroviral therapy. Within LNs, human and animal studies have highlighted that a specific CD4 T cell subset - called T follicular helper cells locating in B cell follicles is enriched in cells containing replication-competent HIV as compared to extra-follicular CD4 T cells. Therefore, the objective of the present review is to focus on the potential mechanisms allowing HIV to persist within LN microenvironment.Recent findingsThe combination of factors that might be involved in the regulation of HIV persistence within LNs remain to be fully identified but may include - the level of activation, antiretroviral drug concentrations, presence of cytolytic mechanisms and/or regulatory cells, in addition to cell survival and proliferation propensity which would ultimately determine the fate of HIV-infected cells within LN tissue areas.SummaryHIV persistence in blood and distinct body compartments despite long-standing and potent therapy is one of the major barriers to a cure. Given that the HIV reservoir is established early and is highly complex based on composition, viral diversity, distribution, replication competence, migration dynamics across the human body and possible compartmentalization in specific tissues, combinatorial therapeutic approaches are needed that may synergize to target multiple viral reservoirs to achieve a cure for HIV infection.

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Extensive characterization of HIV-1 reservoirs reveals links to plasma viremia before and during analytical treatment interruption

Cited by 21 publications

References 58 publications

Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells

Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells

Epigenetic silencing by the SMC5/6 complex mediates HIV-1 latency

HIV persistence in lymph nodes

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