scholarly journals Rapid Escape from Preserved Cross-Reactive Neutralizing Humoral Immunity without Loss of Viral Fitness in HIV-1-Infected Progressors and Long-Term Nonprogressors

2010 ◽  
Vol 84 (7) ◽  
pp. 3576-3585 ◽  
Author(s):  
Marit J. van Gils ◽  
Evelien M. Bunnik ◽  
Judith A. Burger ◽  
Yodit Jacob ◽  
Becky Schweighardt ◽  
...  
Keyword(s):  
Humoral Immunity ◽  
Clinical Course ◽  
Viral Envelope ◽  
Viral Fitness ◽  
Viral Escape ◽  
Autologous Serum ◽  
Variable Regions ◽  
Neutralizing Activity ◽  
Hiv 1

ABSTRACT A substantial proportion of human immunodeficiency virus type 1 (HIV-1)-infected individuals has cross-reactive neutralizing activity in serum, with a similar prevalence in progressors and long-term nonprogressors (LTNP). We studied whether disease progression in the face of cross-reactive neutralizing serum activity is due to fading neutralizing humoral immunity over time or to viral escape. In three LTNP and three progressors, high-titer cross-reactive HIV-1-specific neutralizing activity in serum against a multiclade pseudovirus panel was preserved during the entire clinical course of infection, even after AIDS diagnosis in progressors. However, while early HIV-1 variants from all six individuals could be neutralized by autologous serum, the autologous neutralizing activity declined during chronic infection. This could be attributed to viral escape and the apparent inability of the host to elicit neutralizing antibodies to the newly emerging viral escape variants. Escape from autologous neutralizing activity was not associated with a reduction in the viral replication rate in vitro. Escape from autologous serum with cross-reactive neutralizing activity coincided with an increase in the length of the variable loops and in the number of potential N-linked glycosylation sites in the viral envelope. Positive selection pressure was observed in the variable regions in envelope, suggesting that, at least in these individuals, these regions are targeted by humoral immunity with cross-reactive potential. Our results may imply that the ability of HIV-1 to rapidly escape cross-reactive autologous neutralizing antibody responses without the loss of viral fitness is the underlying explanation for the absent effect of potent cross-reactive neutralizing humoral immunity on the clinical course of infection.

scholarly journals Reduced Susceptibility to VIRIP-Based HIV-1 Entry Inhibitors Has a High Genetic Barrier and Severe Fitness Costs

2018 ◽  
Vol 92 (17) ◽  
Author(s):  
Janis A. Müller ◽  
Anna Glöckle ◽  
Ali Gawanbacht ◽  
Matthias Geyer ◽  
Jan Münch ◽  
...  
Keyword(s):  
Cell Culture ◽  
Fusion Peptide ◽  
Viral Fitness ◽  
Genetic Barrier ◽  
Viral Susceptibility ◽  
Culture Passage ◽  
Cell Culture Passage ◽  
Replication Fitness ◽  
Hiv 1

ABSTRACTVIRIP has been identified as natural HIV-1 inhibitor targeting the gp41 fusion peptide. An optimized analogue (VIR-576) was effective in a phase I/II clinical trial and initial studies showed that HIV-1 resistance to VIRIP-based inhibitors has a high genetic barrier. Partially resistant CXCR4 (X4)-tropic HIV-1 NL4-3 variants could be obtained, however, after more than 15 months of passaging in MT-4 cells in the presence of another derivative (VIR-353). Sequence analyses identified the accumulation of seven mutations across the HIV-1 envelope glycoprotein but outside the gp41 fusion peptide. The authors suggested that the three initial alterations conferred resistance, while subsequent changes restored viral fitness. Here, we introduced these mutations individually and in combination into X4- and CCR5 (R5)-tropic HIV-1 constructs and determined their impact on VIR-353 and VIR-576 susceptibility, viral infectivity, replication fitness, and fusogenicity. We found that essentially all seven mutations contribute to reduced susceptibility to VIRIP-based inhibitors. HIV-1 constructs containing ≥4 changes were substantially more resistant to both VIRIP-based inhibitors and the VRC34.01 antibody targeting the fusion peptide. However, they were also much less infectious and fusogenic than those harboring only the three initial alterations. Furthermore, the additional changes attenuated rather than rescued HIV-1 replication in primary human cells. Thus, the genetic barrier to HIV-1 resistance against VIRIP-based inhibitors is higher than previously suggested, and mutations reducing viral susceptibility come at a severe fitness cost that was not rescued during long-term cell culture passage.IMPORTANCEMany viral pathogens are critically dependent on fusion peptides (FPs) that are inserted into the cellular membrane for infection. Initially, it was thought that FPs cannot be targeted for therapy because they are hardly accessible. However, an optimized derivative (VIR-576) of an endogenous fragment of α1-antitrypsin, named VIRIP, targeting the gp41 FP reduced viral loads in HIV-1-infected individuals. Characterization of HIV-1 variants selected during long-term cell-culture passage in the presence of a VIRIP derivative suggested that just three mutations in the HIV-1 Env protein might be sufficient for VIRIP resistance and that four subsequent changes restored viral fitness. Here, we show that all seven mutations contribute to reduced viral susceptibility to VIRIP-based inhibitors and demonstrate that the additional changes strongly impair rather than rescue HIV-1 infectivity, fusogenicity, and replication fitness. High genetic barrier to resistance and severe fitness cost support further clinical development of this class of antiviral agents.

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

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
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.

scholarly journals Assessment of COVID-19 clinical course in patients vaccinated with Spitnik V, SARS-CoV-2 S protein RBD domain variation and serum virus neutralizing activity

2021 ◽  
Author(s):  
LV Kolobukhina ◽  
OA Burgasova ◽  
IS Kruzhkova ◽  
VV Bakalin ◽  
LV Generalova ◽  
...  
Keyword(s):  
Viral Load ◽  
Humoral Immunity ◽  
Comparison Group ◽  
Clinical Course ◽  
S Protein ◽  
Neutralizing Activity ◽  
Domain Variation

The COVID-19-associated mortality remains high. Studying the features of the COVID-19 course in vaccinated patients, who have got ill on different dates after vaccination, compared to unvaccinated individuals is relevant. The study was aimed to assess clinical and immunological features of the COVID-19 course, as well as to assess humoral immunity (virus neutralizing activity, VNA) and SARS-CoV-2 S protein RBD domain variation in the groups of patients, previously vaccinated with Sputnik V, and unvaccinated patients. A total of 251 patients with confirmed diagnosis of COVID-19 were enrolled, of them 116 individuals were previously vaccinated with one or two Sputnik V vaccine components, and 135 patients were not vaccinated (comparison group). Individuals over 50 years of age prevailed (82.8%). The patients, who received two vaccine components, had mild to moderate COVID-19 (92.1%). In the group of unvaccinated patients, 11 individuals received treatment in the ICU, 10 of them died. The viral load was significantly lower in vaccinated patients. Mutations of SARS-CoV-2, such as S477N, S477N+A522S, E484K and E484K+S494P, were identified both in vaccinated and unvaccinated patients. Assessment of the neutralizing activity of sera revealed no significant differences in VNA against different variants of SARS-CoV-2 mutations. The data obtained demonstrate that the lack of vaccination is an aggravating factor and is capable of increasing the risk of severe course and death in patients with COVID-19.

scholarly journals Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells

2020 ◽  
Vol 117 (31) ◽  
pp. 18719-18728 ◽  
Author(s):  
Magnus A. G. Hoffmann ◽  
Yotam Bar-On ◽  
Zhi Yang ◽  
Harry B. Gristick ◽  
Priyanthi N. P. Gnanapragasam ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Neutralizing Antibody ◽  
Viral Fitness ◽  
Viral Escape ◽  
Target Cells ◽  
High Avidity ◽  
Viral Control ◽  
Cd4 Binding Site ◽  
Hiv 1

CD4-based decoy approaches against HIV-1 are attractive options for long-term viral control, but initial designs, including soluble CD4 (sCD4) and CD4-Ig, were ineffective. To evaluate a therapeutic that more accurately mimics HIV-1 target cells compared with monomeric sCD4 and dimeric CD4-Ig, we generated virus-like nanoparticles that present clusters of membrane-associated CD4 (CD4-VLPs) to permit high-avidity binding of trimeric HIV-1 envelope spikes. In neutralization assays, CD4-VLPs were >12,000-fold more potent than sCD4 and CD4-Ig and >100-fold more potent than the broadly neutralizing antibody (bNAb) 3BNC117, with >12,000-fold improvements against strains poorly neutralized by 3BNC117. CD4-VLPs also neutralized patient-derived viral isolates that were resistant to 3BNC117 and other bNAbs. Intraperitoneal injections of CD4-CCR5-VLP produced only subneutralizing plasma concentrations in HIV-1–infected humanized mice but elicited CD4-binding site mutations that reduced viral fitness. All mutant viruses showed reduced sensitivity to sCD4 and CD4-Ig but remained sensitive to neutralization by CD4-VLPs in vitro. In vitro evolution studies demonstrated that CD4-VLPs effectively controlled HIV-1 replication at neutralizing concentrations, and viral escape was not observed. Moreover, CD4-VLPs potently neutralized viral swarms that were completely resistant to CD4-Ig, suggesting that escape pathways that confer resistance against conventional CD4-based inhibitors are ineffective against CD4-VLPs. These findings suggest that therapeutics that mimic HIV-1 target cells could prevent viral escape by exposing a universal vulnerability of HIV-1: the requirement to bind CD4 on a target cell. We propose that therapeutic and delivery strategies that ensure durable bioavailability need to be developed to translate this concept into a clinically feasible functional cure therapy.

SOSIP trimer-specific antibodies isolated from a SHIV-infected monkey with versus without a pre-blocking step with gp41

2021 ◽  
Author(s):  
Natasha N. Duggan ◽  
Kim L. Weisgrau ◽  
Diogo M. Magnani ◽  
Eva G. Rakasz ◽  
Ronald C. Desrosiers ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Mononuclear Cells ◽  
Broadly Neutralizing Antibodies ◽  
Peripheral Blood Mononuclear ◽  
Specific Antibodies ◽  
Neutralizing Activity ◽  
Infected Monkey ◽  
External Domain ◽  
Hiv 1

BG505 SOSIP.664 (hereafter referred to as SOSIP), a stabilized trimeric mimic of the HIV-1 envelope spike resembling the native viral spike, is a useful tool for isolating anti-HIV-1 neutralizing antibodies. We screened long-term SHIV-AD8 infected rhesus monkeys for potency and breadth of serum neutralizing activity against autologous and heterologous viruses: SHIV-AD8, HIV-1 YU2, HIV-1 JR-CSF, and HIV-1 NL4-3. Monkey rh2436 neutralized all viruses tested and showed strong reactivity to the SOSIP trimer, suggesting this was a promising candidate for attempts at monoclonal antibody (mAb) isolation. Monoclonal antibodies were isolated by performing single B-cell sorts from peripheral blood mononuclear cells (PBMC) by FACS using the SOSIP trimer as a probe. An initial round of sorted cells revealed the majority of isolated mAbs were directed to the gp41 external domain portion of the SOSIP trimer and were mostly non-neutralizing against tested isolates. A second sort was performed, introducing a gp41 blocking step prior to PBMC staining and FACS sorting. These isolated mAbs bound SOSIP trimer but were no longer directed to the gp41 external domain portion. A significantly higher proportion of mAbs with neutralizing activity were obtained with this strategy. Our data show this pre-blocking step with gp41 greatly increases the yield of non-gp41 reactive, SOSIP- specific mAbs and increases the likelihood of isolating mAbs with neutralizing activity. Importance Recent advancements in the field have focused on the isolation and use of broadly neutralizing antibodies for both prophylaxis and therapy. Finding a useful probe to isolate broad potent neutralizing antibodies while avoiding non-neutralizing antibodies is important. The SOSIP trimer has been shown to be a great tool for this purpose because it binds known broadly neutralizing antibodies. However, the SOSIP trimer can isolate non-neutralizing antibodies as well, including gp41-specific mAbs. Introducing a pre-blocking step with gp41 recombinant protein decreased the percent of gp41-specific antibodies isolated with SOSIP probe, as well as increased the number of neutralizing antibodies isolated. This method could be used as a tool to increase the chances of isolating neutralizing antibodies.

Long-term high-titer neutralizing activity induced by octameric synthetic HIV-1 antigen

Science ◽  
1991 ◽  
Vol 254 (5029) ◽  
pp. 285-288 ◽  
Author(s):  
C. Wang ◽  
D. Looney ◽  
M. Li ◽  
A. Walfield ◽  
J Ye ◽  
...  
Keyword(s):  
High Titer ◽  
Neutralizing Activity ◽  
Hiv 1

HIV-1 incorporates ABO histo-blood group antigens that sensitize virions to complement-mediated inactivation

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4693-4699 ◽  
Author(s):  
Stuart J. D. Neil ◽  
Áine McKnight ◽  
Kenth Gustafsson ◽  
Robin A. Weiss
Keyword(s):  
Blood Group ◽  
Envelope Protein ◽  
Viral Envelope ◽  
Autologous Serum ◽  
Blood Group Antigens ◽  
Viral Envelope Protein ◽  
Cell Surfaces ◽  
Abo Incompatibility ◽  
Hiv 1 ◽  
Active Complement

Abstract ABO histo-blood group antigens have been postulated to modify pathogen spread through the action of natural antibodies and complement. The antigens are generated by a polymorphic glycosyl-transferase encoded by 2 dominant active and a recessive inactive allele. In this study we investigated whether ABO sugars are incorporated into the envelope of HIV-1 virions. HIV vectors derived from cells expressing ABO antigens displayed sensitivity to fresh human serum analogous to ABO incompatibility, and ABO histo-blood group sugars were detected on the viral envelope protein, glycoprotein 120 (gp120). Moreover, lymphocyte-derived virus also displayed serum sensitivity, reflecting the ABO phenotype of the host when cultured in autologous serum due to adsorption of antigens to cell surfaces. Serum sensitivity required both active complement and specific anti-ABO antibodies. Thus, incorporation of ABO antigens by HIV-1 may affect transmission of virus between individuals of discordant blood groups by interaction with host natural antibody and complement. (Blood. 2005;105:4693-4699)

scholarly journals T-cell responses to sequentially emerging viral escape mutants shape long-term HIV-1 population dynamics

2020 ◽  
Vol 16 (12) ◽  
pp. e1009177
Author(s):  
Tomohiro Akahoshi ◽  
Hiroyuki Gatanaga ◽  
Nozomi Kuse ◽  
Takayuki Chikata ◽  
Madoka Koyanagi ◽  
...  
Keyword(s):  
T Cells ◽  
Population Dynamics ◽  
T Cell ◽  
Population Level ◽  
Viral Escape ◽  
Cell Responses ◽  
Escape Mutants ◽  
B 52 ◽  
Hiv 1

HIV-1 strains harboring immune escape mutations can persist in circulation, but the impact of selection by multiple HLA alleles on population HIV-1 dynamics remains unclear. In Japan, HIV-1 Reverse Transcriptase codon 135 (RT135) is under strong immune pressure by HLA-B*51:01-restricted and HLA-B*52:01-restricted T cells that target a key epitope in this region (TI8; spanning RT codons 128–135). Major population-level shifts have occurred at HIV-1 RT135 during the Japanese epidemic, which first affected hemophiliacs (via imported contaminated blood products) and subsequently non-hemophiliacs (via domestic transmission). Specifically, threonine accumulated at RT135 (RT135T) in hemophiliac and non-hemophiliac HLA-B*51:01+ individuals diagnosed before 1997, but since then RT135T has markedly declined while RT135L has increased among non-hemophiliac individuals. We demonstrated that RT135V selection by HLA-B*52:01-restricted TI8-specific T-cells led to the creation of a new HLA-C*12:02-restricted epitope TN9-8V. We further showed that TN9-8V-specific HLA-C*12:02-restricted T cells selected RT135L while TN9-8T-specific HLA-C*12:02-restricted T cells suppressed replication of the RT135T variant. Thus, population-level accumulation of the RT135L mutation over time in Japan can be explained by initial targeting of the TI8 epitope by HLA-B*52:01-restricted T-cells, followed by targeting of the resulting escape mutant by HLA-C*12:02-restricted T-cells. We further demonstrate that this phenomenon is particular to Japan, where the HLA-B*52:01-C*12:02 haplotype is common: RT135L did not accumulate over a 15-year longitudinal analysis of HIV sequences in British Columbia, Canada, where this haplotype is rare. Together, our observations reveal that T-cell responses to sequentially emerging viral escape mutants can shape long-term HIV-1 population dynamics in a host population-specific manner.

scholarly journals Autologous Neutralizing Humoral Immunity and Evolution of the Viral Envelope in the Course of Subtype B Human Immunodeficiency Virus Type 1 Infection

2008 ◽  
Vol 82 (16) ◽  
pp. 7932-7941 ◽  
Author(s):  
Evelien M. Bunnik ◽  
Linaida Pisas ◽  
Ad C. van Nuenen ◽  
Hanneke Schuitemaker
Keyword(s):  
Human Immunodeficiency Virus ◽  
Positive Selection ◽  
Humoral Immunity ◽  
Selection Pressure ◽  
High Titer ◽  
Viral Envelope ◽  
Positive Selection Pressure ◽  
Neutralizing Activity ◽  
Immunodeficiency Virus

ABSTRACT Most human immunodeficiency virus type 1 (HIV-1)-infected individuals develop an HIV-specific neutralizing antibody (NAb) response that selects for escape variants of the virus. Here, we studied autologous NAb responses in five typical CCR5-using progressors in relation to viral NAb escape and molecular changes in the viral envelope (Env) in the period from seroconversion until after AIDS diagnosis. In sera from three patients, high-titer neutralizing activity was observed against the earliest autologous virus variants, followed by declining humoral immune responses against subsequent viral escape variants. Autologous neutralizing activity was undetectable in sera from two patients. Patients with high-titer neutralizing activity in serum showed the strongest positive selection pressure on Env early in infection. In the initial phase of infection, gp160 length and the number of potential N-linked glycosylation sites (PNGS) increased in viruses from all patients. Over the course of infection, positive selection pressure declined as the NAb response subsided, coinciding with reversions of changes in gp160 length and the number of PNGS. A number of identical amino acid changes were observed over the course of infection in the viral quasispecies of different patients. Our results indicate that although neutralizing autologous humoral immunity may have a limited effect on the disease course, it is an important selection pressure in virus evolution early in infection, while declining HIV-specific humoral immunity in later stages may coincide with reversion of NAb-driven changes in Env.

scholarly journals Nonneutralizing Antibodies Induced by the HIV-1 gp41 NHR Domain Gain Neutralizing Activity in the Presence of the HIV Fusion Inhibitor Enfuvirtide: a Potential Therapeutic Vaccine Strategy

2015 ◽  
Vol 89 (13) ◽  
pp. 6960-6964 ◽  
Author(s):  
Qian Wang ◽  
Wenwen Bi ◽  
Xiaojie Zhu ◽  
Haoyang Li ◽  
Qianqian Qi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Therapeutic Vaccine ◽  
Viral Envelope ◽  
Heptad Repeat ◽  
Fusion Inhibitor ◽  
Vaccine Strategy ◽  
Therapeutic Vaccines ◽  
Neutralizing Activity ◽  
Key Barrier ◽  
Hiv 1

A key barrier against developing preventive and therapeutic human immunodeficiency virus (HIV) vaccines is the inability of viral envelope glycoproteins to elicit broad and potent neutralizing antibodies. However, in the presence of fusion inhibitor enfuvirtide, we show that the nonneutralizing antibodies induced by the HIV type 1 (HIV-1) gp41 N-terminal heptad repeat (NHR) domain (N63) exhibit potent and broad neutralizing activity against laboratory-adapted HIV-1 strains, including the drug-resistant variants, and primary HIV-1 isolates with different subtypes, suggesting the potential of developing gp41-targeted HIV therapeutic vaccines.

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