scholarly journals Continuous HIV-1 Escape from Autologous Neutralization and Development of Cross-Reactive Antibody Responses Characterizes Slow Disease Progression of Children

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 260
Author(s):  
Stefania Dispinseri ◽  
Mariangela Cavarelli ◽  
Monica Tolazzi ◽  
Anna Maria Plebani ◽  
Marianne Jansson ◽  
...  
Keyword(s):  
Disease Progression ◽  
Antibody Responses ◽  
Viral Escape ◽  
Target Cells ◽  
Transmitted Virus ◽  
Slow Progressors ◽  
Vaccine Antigens ◽  
Kinetics Of ◽  
Hiv 1

The antibodies with different effector functions evoked by Human Immunodeficiency Virus type 1 (HIV-1) transmitted from mother to child, and their role in the pathogenesis of infected children remain unresolved. So, too, the kinetics and breadth of these responses remain to be clearly defined, compared to those developing in adults. Here, we studied the kinetics of the autologous and heterologous neutralizing antibody (Nab) responses, in addition to antibody-dependent cellular cytotoxicity (ADCC), in HIV-1 infected children with different disease progression rates followed from close after birth and five years on. Autologous and heterologous neutralization were determined by Peripheral blood mononuclear cells (PBMC)- and TZMbl-based assays, and ADCC was assessed with the GranToxiLux assay. The reactivity to an immunodominant HIV-1 gp41 epitope, and childhood vaccine antigens, was assessed by ELISA. Newborns displayed antibodies directed towards the HIV-1 gp41 epitope. However, antibodies neutralizing the transmitted virus were undetectable. Nabs directed against the transmitted virus developed usually within 12 months of age in children with slow progression, but rarely in rapid progressors. Thereafter, autologous Nabs persisted throughout the follow-up of the slow progressors and induced a continuous emergence of escape variants. Heterologous cross-Nabs were detected within two years, but their subsequent increase in potency and breadth was mainly a trait of slow progressors. Analogously, titers of antibodies mediating ADCC to gp120 BaL pulsed target cells increased in slow progressors during follow-up. The kinetics of antibody responses to the immunodominant viral antigen and the vaccine antigens were sustained and independent of disease progression. Persistent autologous Nabs triggering viral escape and an increase in the breadth and potency of cross-Nabs are exclusive to HIV-1 infected slowly progressing children.

Decline in CTL and Antibody Responses to HIV-1 p17 and p24 Antigens in HIV-1-Infected Hemophiliacs Irrespective of Disease Progression. A 5-Year Follow-up Study

1992 ◽  
Vol 8 (8) ◽  
pp. 1361-1368 ◽  
Author(s):  
CAROL M. O'TOOLE ◽  
SUSAN GRAHAM ◽  
MARK W. LOWDELL ◽  
DANIEL CHARGELEGUE ◽  
HOWARD MARSDEN ◽  
...  
Keyword(s):  
Disease Progression ◽  
Antibody Responses ◽  
Follow Up Study ◽  
Hiv 1

Long-term follow-up: no effect of therapeutic vaccination with HIV-1 p17/p24:Ty virus-like particles on HIV-1 disease progression

Vaccine ◽  
2002 ◽  
Vol 20 (17-18) ◽  
pp. 2343-2347 ◽  
Author(s):  
Catharina E.A. Lindenburg ◽  
Ineke Stolte ◽  
Miranda W. Langendam ◽  
Frank Miedema ◽  
Ian G. Williams ◽  
...  
Keyword(s):  
Disease Progression ◽  
Therapeutic Vaccination ◽  
Virus Like Particles ◽  
Long Term Follow Up ◽  
Hiv 1

scholarly journals A17 The effect of intra-host evolution of HIV-2 capsid on disease progression

2019 ◽  
Vol 5 (Supplement_1) ◽  
Author(s):  
M T Boswell ◽  
A Palm ◽  
S Karlson ◽  
F Månsson ◽  
H Norrgren ◽  
...  
Keyword(s):  
West Africa ◽  
Disease Progression ◽  
Conformational Changes ◽  
Horizontal Transmission ◽  
Evolutionary Rates ◽  
Survival Times ◽  
Infected People ◽  
Viral Loads ◽  
Hiv 1

Abstract The human immunodeficiency virus type 2 (HIV-2) is an important cause of acquired immune deficiency syndrome (AIDS) in West Africa. The virus started circulating in humans around 1938 and has spread predominantly within West Africa with an estimated 1–2 million people being infected today. Compared with the pandemic HIV-1, HIV-2 infected people have longer AIDS-free survival times, higher CD4+ counts and lower risk of vertical and horizontal transmission. Approximately 35 per cent of HIV-2 infected individuals are classified as so-called long-term non-progressors with undetectable viral loads and limited disease progression after 10 years of follow-up. It has been shown that HIV-2 is more sensitive to the host restriction factor TRIM5α when compared with HIV-1, and this has been linked to conformational changes in the retroviral capsid. TRIM5α binds at the interface between three capsid hexamers, initiates early uncoating and proteasomal degradation. TRIM5 genotype has shown only modest effects on HIV-1 disease outcomes. HIV-2 capsid sequences bearing a specific poly-proline motif have been associated with lower viral loads and presentation of protective HLA I-restricted epitopes. The major aims of this study were to (1) determine HIV-2 capsid intra-host evolutionary rates and (2) identify residues that are affected by positive selection and that can be linked to HIV-2 viral load and disease progression in conjunction with TRIM5 genotype. The Guinea-Bissau Police cohort is unique, with decades of relatively frequent follow-up. One hundred and sixty-five patients were included for genotyping of TRIM5, 62 females and 103 males. Median age at enrolment was 52.6 years (range 30–87) and 7.9 per cent of patients had a CD4 percentage < 15 per cent at enrolment. Six of these individuals were included for amplification of HIV-2 capsid from longitudinally collected samples. Viral RNA was extracted from stored blood plasma samples and capsid of the circulating viral quasispecies was amplified, cloned, and sequenced, as previously described. Bayesian analysis will be used to determine intra-host evolutionary rates, dN/dS ratios and how these parameters associate with disease progression and TRIM5 genotype.

scholarly journals ADCC-mediating non-neutralizing antibodies can exert immune pressure in early HIV-1 infection

2021 ◽  
Vol 17 (11) ◽  
pp. e1010046
Author(s):  
Dieter Mielke ◽  
Gama Bandawe ◽  
Jie Zheng ◽  
Jennifer Jones ◽  
Melissa-Rose Abrahams ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Viral Evolution ◽  
Neutralizing Antibody ◽  
Protective Role ◽  
Viral Escape ◽  
Immune Pressure ◽  
Control Virus ◽  
Kinetics Of ◽  
Hiv 1

Despite antibody-dependent cellular cytotoxicity (ADCC) responses being implicated in protection from HIV-1 infection, there is limited evidence that they control virus replication. The high mutability of HIV-1 enables the virus to rapidly adapt, and thus evidence of viral escape is a very sensitive approach to demonstrate the importance of this response. To enable us to deconvolute ADCC escape from neutralizing antibody (nAb) escape, we identified individuals soon after infection with detectable ADCC responses, but no nAb responses. We evaluated the kinetics of ADCC and nAb responses, and viral escape, in five recently HIV-1-infected individuals. In one individual we detected viruses that escaped from ADCC responses but were sensitive to nAbs. In the remaining four participants, we did not find evidence of viral evolution exclusively associated with ADCC-mediating non-neutralizing Abs (nnAbs). However, in all individuals escape from nAbs was rapid, occurred at very low titers, and in three of five cases we found evidence of viral escape before detectable nAb responses. These data show that ADCC-mediating nnAbs can drive immune escape in early infection, but that nAbs were far more effective. This suggests that if ADCC responses have a protective role, their impact is limited after systemic virus dissemination.

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.

scholarly journals What Do Chaotrope-Based Avidity Assays for Antibodies to HIV-1 Envelope Glycoproteins Measure?

2015 ◽  
Vol 89 (11) ◽  
pp. 5981-5995 ◽  
Author(s):  
Marina R. Alexander ◽  
Rajesh Ringe ◽  
Rogier W. Sanders ◽  
James E. Voss ◽  
John P. Moore ◽  
...  
Keyword(s):  
Antibody Binding ◽  
Antibody Responses ◽  
Envelope Glycoproteins ◽  
Target Cells ◽  
High Avidity ◽  
Simple Relationship ◽  
Avidity Index ◽  
Vaccine Candidates ◽  
Avidity Assay ◽  
Hiv 1

ABSTRACTWhen HIV-1 vaccine candidates that include soluble envelope glycoproteins (Env) are tested in humans and other species, the resulting antibody responses to Env are sifted for correlates of protection or risk. One frequently used assay measures the reduction in antibody binding to Env antigens by an added chaotrope (such as thiocyanate). Based on that assay, an avidity index was devised for assessing the affinity maturation of antibodies of unknown concentration in polyclonal sera. Since a high avidity index was linked to protection in animal models of HIV-1 infection, it has become a criterion for evaluating antibody responses to vaccine candidates. But what does the assay measure and what does an avidity index mean? Here, we have used a panel of monoclonal antibodies to well-defined epitopes on Env (gp120, gp41, and SOSIP.664 trimers) to explore how the chaotrope acts. We conclude that the chaotrope sensitivity of antibody binding to Env depends on several properties of the epitopes (continuity versus tertiary- and quaternary-structural dependence) and that the avidity index has no simple relationship to antibody affinity for functional Env spikes on virions. We show that the binding of broadly neutralizing antibodies against quaternary-structural epitopes is particularly sensitive to chaotrope treatment, whereas antibody binding to epitopes in variable loops and to nonneutralization epitopes in gp41 is generally resistant. As a result of such biases, the avidity index may at best be a mere surrogate for undefined antibody or other immune responses that correlate weakly with protection.IMPORTANCEAn effective HIV-1 vaccine is an important goal. Such a vaccine will probably need to induce antibodies that neutralize typically transmitted variants of HIV-1, preventing them from infecting target cells. Vaccine candidates have so far failed to induce such antibody responses, although some do protect weakly against infection in animals and, possibly, humans. In the search for responses associated with protection, an avidity assay based on chemical disruption is often used to measure the strength of antibody binding. We have analyzed this assay mechanistically and found that the epitope specificity of an antibody has a greater influence on the outcome than does its affinity. As a result, the avidity assay is biased toward the detection of some antibody specificities while disfavoring others. We conclude that the assay may yield merely indirect correlations with weak protection, specifically when Env vaccination has failed to induce broad neutralizing responses.

scholarly journals Pace of Coreceptor Tropism Switch in HIV-1-Infected Individuals after Recent Infection

2017 ◽  
Vol 91 (19) ◽  
Author(s):  
Muhammad Shoaib Arif ◽  
James Hunter ◽  
Ana Rachel Léda ◽  
Jean Paulo Lopes Zukurov ◽  
Sadia Samer ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Regression Analysis ◽  
Disease Progression ◽  
Logistic Regression Analysis ◽  
Target Cells ◽  
Human Host ◽  
Cell Counts ◽  
Ccr5 Antagonists ◽  
Hiv 1 ◽  
Over Time

ABSTRACT HIV-1 entry into target cells influences several aspects of HIV-1 pathogenesis, including viral tropism, HIV-1 transmission and disease progression, and response to entry inhibitors. The evolution from CCR5- to CXCR4-using strains in a given human host is still unpredictable. Here we analyzed timing and predictors for coreceptor evolution among recently HIV-1-infected individuals. Proviral DNA was longitudinally evaluated in 66 individuals using Geno2pheno[coreceptor]. Demographics, viral load, CD4+ and CD8+ T cell counts, CCR5Δ32 polymorphisms, GB virus C (GBV-C) coinfection, and HLA profiles were also evaluated. Ultradeep sequencing was performed on initial samples from 11 selected individuals. A tropism switch from CCR5- to CXCR4-using strains was identified in 9/49 (18.4%) individuals. Only a low baseline false-positive rate (FPR) was found to be a significant tropism switch predictor. No minor CXCR4-using variants were identified in initial samples of 4 of 5 R5/non-R5 switchers. Logistic regression analysis showed that patients with an FPR of >40.6% at baseline presented a stable FPR over time whereas lower FPRs tend to progressively decay, leading to emergence of CXCR4-using strains, with a mean evolution time of 27.29 months (range, 8.90 to 64.62). An FPR threshold above 40.6% determined by logistic regression analysis may make it unnecessary to further determine tropism for prediction of disease progression related to emergence of X4 strains or use of CCR5 antagonists. The detection of variants with intermediate FPRs and progressive FPR decay over time not only strengthens the power of Geno2pheno in predicting HIV tropism but also indirectly confirms a continuous evolution from earlier R5 variants toward CXCR4-using strains. IMPORTANCE The introduction of CCR5 antagonists in the antiretroviral arsenal has sparked interest in coreceptors utilized by HIV-1. Despite concentrated efforts, viral and human host features predicting tropism switch are still poorly understood. Limited longitudinal data are available to assess the influence that these factors have on predicting tropism switch and disease progression. The present study describes longitudinal tropism evolution in a group of recently HIV-infected individuals to determine the prevalence and potential correlates of tropism switch. We demonstrated here that a low baseline FPR determined by the Geno2pheno[coreceptor] algorithm can predict tropism evolution from CCR5 to CXCR4 coreceptor use.

scholarly journals Clinical and Virologic Outcomes Following Initiation of Antiretroviral Therapy Among Seroconverters in the Microbicide Trials Network-020 Phase III Trial of the Dapivirine Vaginal Ring

2018 ◽  
Vol 69 (3) ◽  
pp. 523-529 ◽  
Author(s):  
Sharon A Riddler ◽  
Jennifer E Balkus ◽  
Urvi M Parikh ◽  
John W Mellors ◽  
Carolyne Akello ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Disease Progression ◽  
Virologic Failure ◽  
Vaginal Ring ◽  
Phase Iii ◽  
Virologic Suppression ◽  
Cell Counts ◽  
The Impact ◽  
Hiv 1

Abstract Background A vaginal ring containing dapivirine, a non-nucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor (NNRTI), was safe and effective in preventing HIV-1 infection in African women. We examined the impact of dapivirine ring use at the time of HIV-1 acquisition on subsequent HIV-1 disease progression and responses to NNRTI-containing antiretroviral therapy (ART). Methods HIV-1 disease progression and virologic failure following initiation of ART were assessed among women who acquired HIV-1 while participating in Microbicide Trials Network–020, a randomized, placebo-controlled trial of a monthly, dapivirine vaginal ring. Results Among the 158 participants who acquired HIV-1 (65 dapivirine, 93 placebo), no differences between dapivirine and placebo participants were observed in CD4+ cell counts or plasma HIV-1 RNA over the first year after infection (prior to ART). During follow-up, 100/158 (63%) participants initiated NNRTI-containing ART (dapivirine: 39/65; placebo: 61/93); the median time to HIV-1 RNA <200 copies/ml was approximately 90 days for both dapivirine and placebo ring recipients (log-rank P = .40). Among the 81 participants with at least 6 months of post-ART follow-up, 19 (24%) experienced virologic failure (dapivirine: 6/32, 19%; placebo: 13/39, 27%; P = .42). Conclusions The acquisition of HIV-1 infection during dapivirine or placebo treatment in ASPIRE did not lead to differences in HIV-1 disease progression. After the initiation of NNRTI-containing ART, dapivirine and placebo participants had similar times to virologic suppression and risks of virologic failure. These results provide reassurance that NNRTI-based ART regimens are effective among women who acquired HIV-1 while receiving the dapivirine vaginal ring. Clinical Trials Registration NCT016170096 and NCT00514098.

Mycoplasma Species in Rapid and Slow HIV Progressors

2000 ◽  
Vol 11 (2) ◽  
pp. 76-79 ◽  
Author(s):  
J G Ainsworth ◽  
S Hourshid ◽  
P J Easterbrook ◽  
C B Gilroy ◽  
J N Weber ◽  
...  
Keyword(s):  
Cell Count ◽  
Disease Progression ◽  
Mononuclear Cells ◽  
Mycoplasma Species ◽  
Cd4 Cell Count ◽  
Symptomatic Disease ◽  
Rapid Progressors ◽  
Slow Progressors ◽  
Cd4 Cell ◽  
Hiv 1

We determined the relationship between the presence of Mycoplasma fermentans and Mycoplasma penetrans and the rate of progression of HIV-associated disease in a nested case-control study based on a cohort of 159 HIV-infected patients with different rates of disease progression. Study participants were divided into 3 progression groups: non-progressors who had been HIV-1 seropositive for at least 9 years and had remained asymptomatic with a CD4 cell count of >500/mm3; slow progressors who had been HIV-1 seropositive for at least 9 years and whose CD4 cell count had fallen below 500 cells, and who had developed symptomatic disease or AIDS; and rapid progressors who had developed AIDS within 5 years of HIV infection. Peripheral blood mononuclear cells (PBMCs) were collected at enrolment and examined by mycoplasma polymerase chain reaction (PCR) assays. Three (7%) of 46 non-progressors, 3 (3%) of 86 slow progressors, and 2 (7%) of 27 rapid progressors were M. fermentans positive. The PBMCs from 91 subjects were tested for M. penetrans DNA and none was positive. The small proportion of M. fermentans-positive patients indicates that the mycoplasma cannot be important in the development of AIDS in the large majority of patients. Furthermore, no association was found between its presence and more rapid HIV disease progression.

scholarly journals Phenotype Variation in Human Immunodeficiency virus Type 1 Transmission and Disease Progression

2009 ◽  
Vol 27 (3-4) ◽  
pp. 121-136 ◽  
Author(s):  
Mariangela Cavarelli ◽  
Gabriella Scarlatti
Keyword(s):  
Human Immunodeficiency Virus ◽  
Disease Progression ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Receptor Expression ◽  
Target Cells ◽  
Type I ◽  
Intrinsic Variability ◽  
Immunodeficiency Virus ◽  
Hiv 1

Human immunodeficiency virus type I (HIV-1) infects target cells through interaction with the CD4 molecule and chemokine receptors, mainly CCR5 and CXCR4. Viral isolates can be phenotypically classified based on the co-receptor they utilize to infect target cells. Thus, R5 and X4 virus use respectively CCR5 and CXCR4, whereas R5X4 virus can use either CCR5 or CXCR4. This review describes the central role played by co-receptor expression and usage for HIV-1 cell tropism, transmission and pathogenesis. We discuss various hypotheses proposed to explain the preferential transmission of R5 viruses and the mechanisms driving the change of HIV-1 co-receptor usage in the course of infection. Recent insights in the intrinsic variability of R5 viruses and their role in influencing disease progression in both adults and children are also discussed.

Sign in / Sign up

Export Citation Format

Share Document