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J Virol. 2017 Dec 6. pii: JVI.01805-17. doi: 10.1128/JVI.01805-17. [Epub ahead of print]

Factors Leading to the Loss of Natural Elite Control of HIV-1 Infection.

Author information

1
Virologia Molecular Unit. Laboratory of Research and Reference in Retrovirus. Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid.
2
Laboratory of Immunovirology, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville.
3
Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain.
4
AIDS Research Institute-IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
5
AIDS Immunopathology Unit. Laboratory of Research and Reference in Retrovirus. Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid.
6
Hospital Clinic-Fundació Clinic, IDIBAPS, HIVACAT, Universidad de Barcelona, Barcelona.
7
Centro Sanitario Sandoval, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
8
IIS-Fundación Jiménez Diaz, UAM, Madrid. Hospital Universitario Rey Juan Carlos, Móstoles, Spain.
9
Unidad Enfermedades Infecciosas, Hospital Gral Universitario Santa Lucía, Cartagena, Spain.
10
Servicio de Enfermedades Infecciosas, Hospital General de Castellón, Castellón, Spain.
11
Servicio de Enfermedades Infecciosas, Hospital Universitario Donostia, San Sebastián, Spain.
12
Laboratory of Molecular Immuno-Biology, Hospital General Universitario Gregorio Marañón, IiSGM, CIBER BBN, Spanish HIV HGM BioBank, Madrid, Spain.
13
Laboratory of Immunovirology, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville. ezequiel.ruizmateos@gmail.com.

Abstract

HIV-1 elite controllers (EC) maintain undetectable viral load (VL) in the absence of antiretroviral treatment. However, these subjects have heterogeneous clinical outcomes including a proportion loosing HIV-1 control over time. In this work we compared, in a longitudinal design, transient EC, analyzed before and after the loss of virological control, versus persistent EC. The aim was to identify factors leading to the loss of natural virological control of HIV-1-infection with a longitudinal retrospective study design. Gag-specific T-cell response was assessed by in vitro intracellular poly-cytokine production quantified by flow cytometry. Viral diversity and sequence-dating were performed in proviral DNA by PCR amplification at limiting dilution in env and gag genes. The expression profile of 70 serum cytokines and chemokines was assessed by multiplex immunoassays. We identified transient EC as subjects with low Gag-specific T-cell polyfunctionality, high viral diversity and high proinflammatory cytokines levels before the loss of control. Gag-specific T-cell polyfunctionality was inversely associated with viral diversity in transient controllers before the loss of control (r=-0.8; p=0.02). RANTES was a potential biomarker of transient control. This study identified, virological and immunological factors including inflammatory biomarkers associated with two different phenotypes within EC. These results may allow a more accurate definition of EC, which could help in a better clinical management of these individuals and in the development of future curative approaches.IMPORTANCE There is a rare group of HIV-infected patients who have the extraordinary capacity to maintain undetectable viral load levels in the absence of antiretroviral treatment, the so called HIV-1 elite controllers (EC). However, there is a proportion within these subjects that eventually loses this capability. In this work we found differences in virological and immune factors including soluble inflammatory biomarkers between subjects with persistent control of viral replication and EC that will loss the virological control. The identification of these factors could be a key point for a right medical care of those EC who are going to lose the natural control of viral replication, and for the design of future immunotherapeutic strategies using as a model the natural persistent control of HIV-infection.

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