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Peripheral V?9V?2 T Cells Are a Novel Reservoir of Latent HIV Infection.

ABSTRACT: Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection. Despite low or lack of CD4 receptor expression on V?2 T cells, infection of these cells has previously been reported. We found that upregulation of the CD4 receptor may render primary V?2 cells target for HIV infection in vitro and we propose that HIV-induced immune activation may allow infection of ?? T cells in vivo. We assessed the presence of latent HIV infection by measurements of DNA and outgrowth assays within V?2 cells in 18 aviremic patients on long-standing antiretroviral therapy. In 14 patients we recovered latent but replication-competent HIV from highly purified V?2 cells demonstrating that peripheral V?2 T cells are a previously unrecognized reservoir in which latent HIV infection is unexpectedly frequent.

SUBMITTER: Soriano-Sarabia N

PROVIDER: S-EPMC4608739 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Peripheral Vγ9Vδ2 T Cells Are a Novel Reservoir of Latent HIV Infection.

Soriano-Sarabia Natalia N Archin Nancie M NM Bateson Rosalie R Dahl Noelle P NP Crooks Amanda M AM Kuruc JoAnn D JD Garrido Carolina C Margolis David M DM

PLoS pathogens 20151016 10

Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection. Despite low or lack of CD4 receptor expression on Vδ2 T cells, infection of these cells has previously been reported. We found that upregulation of the CD4 receptor may render primary Vδ2 cells target for HIV infection in vitro and we propose that HIV-induced immune activation may allow infection of γδ T cells in vivo. We assessed the presence of latent HIV infection by measureme ...[more]

PMID: 26473478

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Project description:Passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 appears a promising strategy for eliciting long-term HIV-1 remission. When administered concomitantly with the cessation of antiretroviral therapy (ART) to patients with established viremic control, bNAb therapy is expected to prolong remission. Surprisingly, in clinical trials on chronic HIV-1 patients, the bNAb VRC01 failed to prolong remission substantially. Identifying the cause of this failure is important for improving VRC01-based therapies and unraveling potential vulnerabilities of other bNAbs. In the trials, viremia resurged rapidly in most patients despite suppressive VRC01 concentrations in circulation, suggesting that VRC01 resistance was the likely cause of failure. ART swiftly halts viral replication, precluding the development of resistance during ART. If resistance were to emerge post ART, virological breakthrough would have taken longer than without VRC01 therapy. We hypothesized therefore that VRC01-resistant strains must have been formed before ART initiation, survived ART in latently infected cells, and been activated during VRC01 therapy, causing treatment failure. Current assays preclude testing this hypothesis experimentally. We developed a mathematical model based on the hypothesis and challenged it with available clinical data. The model integrated within-host HIV-1 evolution, stochastic latency reactivation, and viral dynamics with multiple-dose VRC01 pharmacokinetics. The model predicted that single but not higher VRC01-resistant mutants would pre-exist in the latent reservoir. We constructed a virtual patient population that parsimoniously recapitulated inter-patient variations. Model predictions with this population quantitatively captured data of VRC01 failure from clinical trials, presenting strong evidence supporting the hypothesis. We attributed VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral recrudescence, particularly when VRC01 was at trough levels. Pre-existing resistant proviruses in the latent reservoir may similarly compromise other bNAbs. Our study provides a framework for designing bNAb-based therapeutic protocols that would avert such failure and maximize HIV-1 remission.

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Peripheral V?9V?2 T Cells Are a Novel Reservoir of Latent HIV Infection.

Publications

Peripheral Vγ9Vδ2 T Cells Are a Novel Reservoir of Latent HIV Infection.

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