Dataset Information

Adoptive lymphocyte transfer to an HIV-infected progressor from an elite controller.

ABSTRACT: BACKGROUNDHIV-infected patients with poor virologic control and multidrug-resistant virus have limited therapeutic options. The current study was undertaken to evaluate the safety, immunologic effects, and antiviral activity of peripheral lymphocytes transferred from an elite controller, whose immune system is able to control viral replication without antiretroviral medications, to an HLA-B*2705-matched progressor.METHODSApproximately 22 billion cells were collected from an elite controller by lymphapheresis and infused within 6 hours into a recipient with a preinfusion CD4+ T cell count of 10 cells/?L (1%) and HIV plasma viral load of 114,993 copies/mL.RESULTSDonor cells were cleared from the recipient's peripheral blood by day 8. A transient decrease in viral load to 58,421 (day 3) was followed by a rebound to 702,972 (day 6) before returning to baseline values by day 8. The decreased viral load was temporally associated with peak levels of donor T cells, including CD8+ T cells that had high levels of expression of Ki67, perforin, and granzyme B. Notably, recipient CD8+ T cells also showed increased expression of these markers, especially in HIV-specific tetramer-positive cells.CONCLUSIONThese results suggest that the adoptive transfer of lymphocytes from an HIV-infected elite controller to an HIV-infected patient with progressive disease may be able to perturb the immune system of the recipient in both positive and negative ways.TRIAL REGISTRATIONClinicalTrials.gov NCT00559416.FUNDINGIntramural Research Programs of the US NIH Clinical Center and the National Institute of Allergy and Infectious Diseases (NIAID); the National Cancer Institute.

SUBMITTER: Migueles SA

PROVIDER: S-EPMC6795294 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Adoptive lymphocyte transfer to an HIV-infected progressor from an elite controller.

Migueles Stephen A SA Chairez Cheryl C Lin Siying S Gavil Noah V NV Rosenthal Danielle M DM Pooran Milad M Natarajan Ven V Rupert Adam A Dewar Robin R Rehman Tauseef T Sherman Brad T BT Adelsberger Joseph J Leitman Susan F SF Stroncek David D Morse Caryn G CG Connors Mark M Lane H Clifford HC Kovacs Joseph A JA

JCI insight 20190919 18

BACKGROUNDHIV-infected patients with poor virologic control and multidrug-resistant virus have limited therapeutic options. The current study was undertaken to evaluate the safety, immunologic effects, and antiviral activity of peripheral lymphocytes transferred from an elite controller, whose immune system is able to control viral replication without antiretroviral medications, to an HLA-B*2705-matched progressor.METHODSApproximately 22 billion cells were collected from an elite controller by l ...[more]

PMID: 31415245

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Project description:Background:Elite controller refers to a patient with human immunodeficiency virus infection with an undetected viral load in the absence of highly active antiretroviral therapy. Studies on gene expression and regulation in these individuals are limited but significant, and have helped researchers and clinicians to understand the interrelationships between HIV and its host. Methods:We collected CD4 T-cell samples from two elite controllers (ECs), two HIV-positive infected patients (HPs), and two healthy controls (HCs) to perform second-generation transcriptome sequencing. Using the Cufflinks software, we calculated the Fragments Per Kilobase of transcript per Million fragments mapped (FPKM) and identified differentially expressed (DE) mRNAs and long non-coding RNAs (lncRNAs), with corrected P value < 0.05 (based on a false discovery rate (FDR) < 0.05). We then constructed a protein-protein interaction network using cytoHubba and a long non-coding RNA-mRNA co-expression network based on the Pearson correlation coefficient. Results:In total, 1109 linear correlations of DE lncRNAs targeting DE mRNAs were found and several interesting interactions were identified as being associated with viral infections and immune responses within the networks based on these correlations. Among these lncRNA-mRNA relationships, hub mRNAs including HDAC6, MAPK8, MAPK9, ATM and their corresponding annotated co-expressed lncRNAs presented strong correlations with the MAPK-NF-kappa B pathway, which plays a role in the reactivation and replication of the virus. Conclusions:Using RNA-sequencing, we systematically analyzed the expression profiles of lncRNAs and mRNAs from CD4+ T cells from ECs, HPs, and HCs, and constructed a co-expression network based on the relationships among DE transcripts and database annotations. This was the first study to examine gene transcription in elite controllers and to study their functional relationships. Our results provide a reference for subsequent functional verification at the molecular or cellular level.

Project description:HIV elite controllers represent a remarkable minority of patients who maintain normal CD4+ T-cell counts and low or undetectable viral loads for decades in the absence of antiretroviral therapy. To examine the possible contribution of virus attenuation to elite control, we obtained a primary HIV-1 isolate from an elite controller who had been infected for 19 years, the last 10 of which were in the absence of antiretroviral therapy. Full-length sequencing of this isolate revealed a highly unusual V1 domain in Envelope (Env). The V1 domain in this HIV-1 strain was 49 amino acids, placing it in the top 1% of lengths among the 6,112 Env sequences in the Los Alamos National Laboratory online database. Furthermore, it included two additional N-glycosylation sites and a pair of cysteines suggestive of an extra disulfide loop. Virus with this Env retained good infectivity and replicative capacity; however, analysis of recombinant viruses suggested that other sequences in Env were adapted to accommodate the unusual V1 domain. While the long V1 domain did not confer resistance to neutralization by monoclonal antibodies of the V1/V2-glycan-dependent class, it did confer resistance to neutralization by monoclonal antibodies of the V3-glycan-dependent class. Our findings support results in the literature that suggest a role for long V1 regions in shielding HIV-1 from recognition by V3-directed broadly neutralizing antibodies. In the case of the elite controller described here, it seems likely that selective pressures from the humoral immune system were responsible for driving the highly unusual polymorphisms present in this HIV-1 Envelope.IMPORTANCE Elite controllers have long provided an avenue for researchers to reveal mechanisms underlying control of HIV-1. While the role of host genetic factors in facilitating elite control is well known, the possibility of infection by attenuated strains of HIV-1 has been much less studied. Here we describe an unusual viral feature found in an elite controller of HIV-1 infection and demonstrate its role in conferring escape from monoclonal antibodies of the V3-glycan class. Our results suggest that extreme variation may be needed by HIV-1 to escape neutralization by some antibody specificities.

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Adoptive lymphocyte transfer to an HIV-infected progressor from an elite controller.

Publications

Adoptive lymphocyte transfer to an HIV-infected progressor from an elite controller.

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