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Long-term Persistent Elite HIV-controllers: The Right Model of Functional Cure

2018; Elsevier BV; Volume: 28; Linguagem: Inglês

10.1016/j.ebiom.2018.01.013

2352-3964

Laura Tarancón‐Díez, Beatriz Domínguez-Molina, Pompeyo Viciana, Luís F. López‐Cortés, Ezequiel Ruiz‐Mateos,

HIV/AIDS drug development and treatment

The understanding of the mechanisms associated to the natural control of HIV-infection is essential to achieve HIV-long-term remission or new insights in HIV cure strategies. Despite the enormous advances in the last 15 years showing that the presence of protective genetic factors, as protective HLA alleles and the associated cytotoxic T-lymphocytes (CTL) response, are capital for the spontaneous control of HIV-infection (Pereyra et al., 2010Pereyra F. et al.The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.Science. 2010; 330: 1551-1557Crossref PubMed Scopus (896) Google Scholar), the detailed nature of the mechanisms associated with this phenomenon are not completely clear. In the study by Bendenoun et al., 2018Bendenoun et al.What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSM.EBioMedicine. 2018; 27: 51-60Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar in EBioMedicine, the authors describe the case report of the spontaneous control of HIV-1 for ten years in a homosexual man after transmission by his unique couple, who was not able to naturally control the virus. Similar reports had been previously published (Bailey et al., 2008Bailey J.R. O'Connell K. Yang H.C. Han Y. Xu J. Jilek B. Williams T.M. Ray S.C. Siliciano R.F. Blankson J.N. Transmission of human immunodeficiency virus type 1 from a patient who developed AIDS to an elite suppressor.J. Virol. 2008; 82: 7395-7410Crossref PubMed Scopus (86) Google Scholar, Buckheit III et al., 2012Buckheit III, R.W. Allen T.G. Alme A. Salgado M. O'Connell K.A. Huculak S. Falade-Nwulia O. Williams T.M. Gallant J.E. Siliciano R.F. Blankson J.N. Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs.Nat. Commun. 2012; 3: 716Crossref PubMed Scopus (52) Google Scholar) but in this case, in contrast to previous works, both individuals had no protective HLA-alleles. How this individual was able to persistently control de virus is not well understood. The clues to answer this question come from the fact that in a comprehensive analysis the authors found incomplete western blot against HIV-1 during 10 years of follow up, extremely low HIV-1 reservoir in peripheral blood and tissues, no blips of viral load, high polyfunctional CTL response and enhance capacity of antibody-dependent cell cytotoxicity (ADCC) in NK cells compared to his couple. These features associated to persistent control of HIV-infection are very similar to those found in the extreme phenotypes of elite HIV-controllers found in a French cohort (Canouï et al., 2017Canouï E. Lécuroux C. Avettand-Fenoël V. Gousset M. Rouzioux C. Saez-Cirion A. Meyer L. Boufassa F. Lambotte O. Noël N. ANRS CO21 CODEX Study Group A subset of extreme human immunodeficiency virus (HIV) controllers is characterized by a small HIV blood reservoir and a weak T-cell activation level.Open Forum Infect. Dis. 2017; 4: ofx064Crossref PubMed Scopus (33) Google Scholar) with the exception that these individuals had weak HIV-specific CD8+ T-cell response measured by the ability to suppress HIV-1 infection of autologous CD4+ T cells ex vivo. The results by Bendenoun et al., 2018Bendenoun et al.What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSM.EBioMedicine. 2018; 27: 51-60Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar are also in accordance with the low reservoir and high polyfunctional HIV-specific T-cell response measured by intracellular cytokine staining recently found in a similar phenotype of individuals that persistently controlled the virus compared to patients that transiently controlled HIV-1 (Pernas et al., 2017Pernas M. Tarancón-Diez L. Rodríguez-Gallego E. Gómez J. Prado J.G. Casado C. Dominguez-Molina B. Olivares I. Coiras M. León A. Rodriguez C. Benito J.M. Rallón N. Plana M. Martinez-Madrid O. Dapena M. Iribarren J.A. Del Romero J. García F. Alcamí J. Muñoz-Fernández M.Á. Vidal F. Leal M. Lopez-Galindez C. Ruiz-Mateos E. ECRIS integrated in the Spanish AIDS Research Network Factors leading to the loss of natural elite control of HIV-1 infection.J. Virol. 2017; (pii: JVI.01805-17)Crossref PubMed Google Scholar). As discussed by the authors the individual of the case report may be one of these examples of extreme phenotype with persistent long-term elite control of HIV-infection. This is important, because it is everyday clearer that the HIV-controllers scenario is quite heterogeneous in terms of definitions and immunologic and virological characteristics related to disease progression (Leon et al., 2016Leon A. Perez I. Ruiz-Mateos E. Benito J.M. Leal M. Lopez-Galindez C. Rallon N. Alcami J. Lopez-Aldeguer J. Viciana P. Rodriguez C. Grau E. Iribarren J. Gatell J.M. Garcia F. EC and Immune Pathogenesis Working group of the Spanish AIDS Research Network Rate and predictors of progression in elite and viremic HIV-1 controllers.AIDS. 2016; 30: 1209-1220Crossref PubMed Scopus (53) Google Scholar). The delineation of the right model of "persistent" elite HIV-controller phenotype is essential for two main reasons. First, it is unclear in the current treatment guidelines whether elite HIV-controllers must be treated with antiretrovirals. Elite HIV-controllers who lose their capability at the mid-short term might be benefited of combined antiretroviral treatment thanks to the identification of predictive biomarkers (Pernas et al., 2017Pernas M. Tarancón-Diez L. Rodríguez-Gallego E. Gómez J. Prado J.G. Casado C. Dominguez-Molina B. Olivares I. Coiras M. León A. Rodriguez C. Benito J.M. Rallón N. Plana M. Martinez-Madrid O. Dapena M. Iribarren J.A. Del Romero J. García F. Alcamí J. Muñoz-Fernández M.Á. Vidal F. Leal M. Lopez-Galindez C. Ruiz-Mateos E. ECRIS integrated in the Spanish AIDS Research Network Factors leading to the loss of natural elite control of HIV-1 infection.J. Virol. 2017; (pii: JVI.01805-17)Crossref PubMed Google Scholar). Second, individuals who persistently control the virus for even more than 25 years since infection with no viral "blips", high CD4+ T-cell counts, extremely low reservoir and low levels of activation comparable to non-HIV infected subjects, might be considered as a right model of functional cure that will undoubtedly help for the development of future HIV-cure strategies. An indiscriminate treatment of these patients will eliminate this model. The implementation of large cohorts of elite HIV-controllers will help for the identification of this extreme phenotype with the aim to refine the immune correlates of persistent natural HIV-control. In this sense, protective HLA-alleles are for sure to go on playing a major role, as it has been recently shown in a cohort of long term non progressor HIV-controllers enriched in this persistent elite HIV-controller phenotype (Dominguez-Molina et al., 2017Dominguez-Molina B. Tarancon-Diez L. Hua S. Abad-Molina C. Rodriguez-Gallego E. Machmach K. Vidal F. Tural C. Moreno S. Goñi J.M. Ramírez de Arellano E. Del Val M. Gonzalez-Escribano M.F. Del Romero J. Rodriguez C. Capa L. Viciana P. Alcamí J. Yu X.G. Walker B.D. Leal M. Lichterfeld M. Ruiz-Mateos E. ECRIS integrated in the Spanish AIDS Research Network HLA-B*57 and IFNL4-related polymorphisms are associated with protection against HIV-1 disease progression in controllers.Clin. Infect. Dis. 2017; 64: 621-628PubMed Google Scholar). However, like in the case report presented herein and other works, no association was found between spontaneous control and protective HLA alleles (Tsai et al., 2016Tsai M.H. Muenchhoff M. Adland E. Carlqvist A. Roider J. Cole D.K. Sewell A.K. Carlson J. Ndung'u T. Goulder P.J. Paediatric non-progression following grandmother-to-child HIV transmission.Retrovirology. 2016; 13: 65Crossref PubMed Scopus (6) Google Scholar). Interestingly, other factors like certain KIR ligands, ADCC-mediated response, dendritic cell mechanisms (Machmach et al., 2012Machmach K. Leal M. Gras C. Viciana P. Genebat M. Franco E. Boufassa F. Lambotte O. Herbeuval J.P. Ruiz-Mateos E. Plasmacytoid dendritic cells reduce HIV production in elite controllers.J.Virol. 2012; 86: 4245-4252Crossref PubMed Scopus (56) Google Scholar) and others yet undefined are likely to be associated with persistent control of HIV-1 infection. Despite that the host factors seem to be essential in the persistent control of the virus in this case report (Bendenoun et al., 2018Bendenoun et al.What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSM.EBioMedicine. 2018; 27: 51-60Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar), the fact that both individuals were heterozygous for CCR5∆32, does not clarify if this "bottleneck" could render a lower virus fitness that enabled the spontaneous virus control. It remains also unknown at what date during the follow up occurred the transmission. This is important because there was a period of time where the input of virus was potentially small due to the low viral load levels. In any case, persistent elite HIV-controllers must be considered as a model of functional cure. Studies like the one presented by Bendenoun et al., 2018Bendenoun et al.What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSM.EBioMedicine. 2018; 27: 51-60Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar show that spontaneous long-term control of HIV-infection is possible even in the absence of protective HLA-alleles. Future efforts are necessary to identify this very scarce proportion of individuals that are able to persistently control the virus and use them as the right model of functional cure to redefine immune correlates of long-term remission that will help to new designs of HIV-cure strategies. The authors declared no conflicts of interest. What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSMThis thorough description of the natural history of an individual controlling HIV-1 in various compartments for ten years despite lack of protective alleles, and of his partner, may have implications for strategies to cure HIV-1 infection. Full-Text PDF Open Access