Permanent control of HIV-1 pathogenesis in exceptional elite controllers: a model of spontaneous cure

The understanding of HIV-1 pathogenesis and clinical progression is incomplete because of the variable contribution of host, immune and viral factors. The involvement of viral factors has been investigated in extreme clinical phenotypes from rapid progressors to long-term non-progressors (LTNPs). Among HIV-1 proteins, the envelope glycoprotein complex (Env) has concentrated many studies for its important role in the immune response and in the first steps of viral replication. In this study, we analyzed the contribution of 41 Envs from 24 patients with different clinical progression rates and viral loads (VLs), LTNP-Elite Controllers (LTNP-ECs); Viremic LTNPs (vLTNPs), and non-controller’s individuals contemporary to LTNPs or recent, named Old and Modern progressors. We analyzed the Env expression, the fusion and cell-to-cell transfer capacities as well as viral infectivity. The sequence and phylogenetic analysis of Envs were also performed. In every functional characteristic, the Envs from subjects with viral control (LTNP-ECs and vLTNPs) showed significant lower performance compared to those from the progressor individuals (Old and Modern). Regarding sequence analysis, the variable loops of the gp120 subunit of the Env (i.e., V2, V4 and mainly V5) of the progressor individuals showed longer and more glycosylated sequences than controller subjects. Therefore, HIV-1 Envs presenting poor viral functions and shorter sequences were associated with viremic control and the non-progressor clinical phenotype, whereas functional Envs were associated with the lack of virological control and progressor clinical phenotypes. These correlations support the central role of Env genotypic and phenotypic characteristics in the in vivo HIV-1 infection and pathogenesis.

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Reduced Replication Capacity of NL4-3 Recombinant Viruses Encoding Reverse Transcriptase–Integrase Sequences From HIV-1 Elite Controllers

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0b013e3181fe9450 ◽

2011 ◽

Vol 56 (2) ◽

pp. 100-108 ◽

Cited By ~ 51

Author(s):

Zabrina L Brumme ◽

Chun Li ◽

Toshiyuki Miura ◽

Jennifer Sela ◽

Pamela C Rosato ◽

...

Keyword(s):

Reverse Transcriptase ◽

Replication Capacity ◽

Elite Controllers ◽

Recombinant Viruses ◽

Hiv 1

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Viral Characteristics Associated with the Clinical Nonprogressor Phenotype Are Inherited by Viruses from a Cluster of HIV-1 Elite Controllers

mBio ◽

10.1128/mbio.02338-17 ◽

2018 ◽

Vol 9 (2) ◽

Cited By ~ 16

Author(s):

Concepción Casado ◽

Sara Marrero-Hernández ◽

Daniel Márquez-Arce ◽

María Pernas ◽

Sílvia Marfil ◽

...

Keyword(s):

Viral Replication ◽

Clinical Phenotype ◽

Functional Characterization ◽

Viral Fitness ◽

Elite Controller ◽

Replication Capacity ◽

Viral Fusion ◽

Elite Controllers ◽

Hiv 1

ABSTRACTA small group of HIV-1-infected individuals, called long-term nonprogressors (LTNPs), and in particular a subgroup of LTNPs, elite controllers (LTNP-ECs), display permanent control of viral replication and lack of clinical progression. This control is the result of a complex interaction of host, immune, and viral factors. We identified, by phylogenetic analysis, a cluster of LTNP-ECs infected with very similar low-replication HIV-1 viruses, suggesting the contribution of common viral features to the clinical LTNP-EC phenotype. HIV-1 envelope (Env) glycoprotein mediates signaling and promotes HIV-1 fusion, entry, and infection, being a key factor of viral fitnessin vitro, cytopathicity, and infection progressionin vivo. Therefore, we isolated full-lengthenvgenes from viruses of these patients and from chronically infected control individuals. Functional characterization of the initial events of the viral infection showed that Envs from the LTNP-ECs were ineffective in the binding to CD4 and in the key triggering of actin/tubulin-cytoskeleton modifications compared to Envs from chronic patients. The viral properties of the cluster viruses result in a defective viral fusion, entry, and infection, and these properties were inherited by every virus of the cluster. Therefore, inefficient HIV-1 Env functions and signaling defects may contribute to the low viral replication capacity and transmissibility of the cluster viruses, suggesting a direct role in the LTNP-EC phenotype of these individuals. These results highlight the important role of viral characteristics in the LTNP-EC clinical phenotype. These Env viral properties were common to all the cluster viruses and thus support the heritability of the viral characteristics.IMPORTANCEHIV-1 long-term nonprogressor elite controller patients, due to their permanent control of viral replication, have been the object of numerous studies to identify the factors responsible for this clinical phenotype. In this work, we analyzed the viral characteristics of the envelopes of viruses from a phylogenetic cluster of LTNP-EC patients. These envelopes showed ineffective binding to CD4 and the subsequent signaling activity to modify actin/tubulin cytoskeletons, which result in low fusion and deficient entry and infection capacities. These Env viral characteristics could explain the nonprogressor clinical phenotype of these patients. In addition, these inefficientenvviral properties were present in all viruses of the cluster, supporting the heritability of the viral phenotype.

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HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells

PLoS ONE ◽

10.1371/journal.pone.0228745 ◽

2020 ◽

Vol 15 (2) ◽

pp. e0228745 ◽

Cited By ~ 1

Author(s):

Diogo G. Caetano ◽

Hury H. S. de Paula ◽

Gonzalo Bello ◽

Brenda Hoagland ◽

Larissa M. Villela ◽

...

Keyword(s):

High Frequency ◽

Th17 Cells ◽

Elite Controllers ◽

Hiv 1

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Galectin-9 Is Rapidly Released During Acute HIV-1 Infection and Remains Sustained at High Levels Despite Viral Suppression Even in Elite Controllers

AIDS Research and Human Retroviruses ◽

10.1089/aid.2014.0004 ◽

2014 ◽

Vol 30 (7) ◽

pp. 654-664 ◽

Cited By ~ 33

Author(s):

Ravi Tandon ◽

Glen M. Chew ◽

Mary M. Byron ◽

Persephone Borrow ◽

Toshiro Niki ◽

...

Keyword(s):

Viral Suppression ◽

Elite Controllers ◽

Acute Hiv ◽

Hiv 1

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Altered T-cell subsets in HIV-1 natural viral suppressors (elite controllers) with hepatitis C infection

AIDS ◽

10.1097/qad.0b013e328362dea4 ◽

2013 ◽

Vol 27 (12) ◽

pp. 1989-1992 ◽

Cited By ~ 6

Author(s):

Mohammad M. Sajadi ◽

Robert R. Redfield ◽

Rohit Talwani

Keyword(s):

Hepatitis C ◽

T Cell ◽

T Cell Subsets ◽

Elite Controllers ◽

Hepatitis C Infection ◽

Viral Suppressors ◽

Hiv 1

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Plasmatic Levels of IL-18, IP-10, and Activated CD8+ T Cells Are Potential Biomarkers to Identify HIV-1 Elite Controllers With a True Functional Cure Profile

Frontiers in Immunology ◽

10.3389/fimmu.2018.01576 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 11

Author(s):

Fernanda H. Côrtes ◽

Hury H. S. de Paula ◽

Gonzalo Bello ◽

Marcelo Ribeiro-Alves ◽

Suwellen S. D. de Azevedo ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Elite Controllers ◽

Functional Cure ◽

Hiv 1 ◽

Potential Biomarkers

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Differential Ability of Primary HIV-1 Nef Isolates To Downregulate HIV-1 Entry Receptors

Journal of Virology ◽

10.1128/jvi.01548-15 ◽

2015 ◽

Vol 89 (18) ◽

pp. 9639-9652 ◽

Cited By ~ 18

Author(s):

Mako Toyoda ◽

Yoko Ogata ◽

Macdonald Mahiti ◽

Yosuke Maeda ◽

Xiaomei T. Kuang ◽

...

Keyword(s):

Viral Replication ◽

Viral Entry ◽

Immune Escape ◽

Elite Controllers ◽

Functional Impairments ◽

Disease Phenotypes ◽

Infected Cells ◽

Entry Receptor ◽

Hiv 1

ABSTRACTHIV-1 Nef downregulates the viral entry receptor CD4 as well as the coreceptors CCR5 and CXCR4 from the surface of HIV-infected cells, and this leads to promotion of viral replication through superinfection resistance and other mechanisms. Nef sequence motifs that modulate these functions have been identified viain vitromutagenesis with laboratory HIV-1 strains. However, it remains unclear whether the same motifs contribute to Nef activity in patient-derived sequences and whether these motifs may differ in Nef sequences isolated at different infection stages and/or from patients with different disease phenotypes. Here,nefclones from 45 elite controllers (EC), 46 chronic progressors (CP), and 43 acute progressors (AP) were examined for their CD4, CCR5, and CXCR4 downregulation functions. Nef clones from EC exhibited statistically significantly impaired CD4 and CCR5 downregulation ability and modestly impaired CXCR4 downregulation activity compared to those from CP and AP. Nef's ability to downregulate CD4 and CCR5 correlated positively in all cohorts, suggesting that they are functionally linkedin vivo. Moreover, impairments in Nef's receptor downregulation functions increased the susceptibility of Nef-expressing cells to HIV-1 infection. Mutagenesis studies on three functionally impaired EC Nef clones revealed that multiple residues, including those at novel sites, were involved in the alteration of Nef functions and steady-state protein levels. Specifically, polymorphisms at highly conserved tryptophan residues (e.g., Trp-57 and Trp-183) and immune escape-associated sites were responsible for reduced Nef functions in these clones. Our results suggest that the functional modulation of primary Nef sequences is mediated by complex polymorphism networks.IMPORTANCEHIV-1 Nef, a key factor for viral pathogenesis, downregulates functionally important molecules from the surface of infected cells, including the viral entry receptor CD4 and coreceptors CCR5 and CXCR4. This activity enhances viral replication by protecting infected cells from cytotoxicity associated with superinfection and may also serve as an immune evasion strategy. However, how these activities are maintained under selective pressurein vivoremains elusive. We addressed this question by analyzing functions of primary Nef clones isolated from patients at various infection stages and with different disease phenotypes, including elite controllers, who spontaneously control HIV-1 viremia to undetectable levels. The results indicated that downregulation of HIV-1 entry receptors, particularly CCR5, is impaired in Nef clones from elite controllers. These functional impairments were driven by rare Nef polymorphisms and adaptations associated with cellular immune responses, underscoring the complex molecular pathways responsible for maintaining and attenuating viral protein functionin vivo.

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