Kinetics of Appearance of Neutralizing Antibodies in 12 Patients with Primary or Recent HIV-1 Infection and Relationship with Plasma and Cellular Viral Loads

The influence of human T-cell leukemia/lymphoma virus type II (HTLV-II) in individuals also infected with HIV-1 is poorly understood. To evaluate the reciprocal influence of HTLV-II and HIV-1 infection, primary peripheral blood mononuclear cell (PBMC) cultures from coinfected individuals were established in the presence of interleukin 2 (IL-2). In these cultures, the kinetics of HTLV-II replication always preceded those of HIV-1. Noteworthy, the kinetics of HIV-1 production were inversely correlated to the HTLV-II proviral load in vivo and its replication ex vivo. These observations suggested a potential interaction between the 2 retroviruses. In this regard, the levels of IL-2, IL-6, and tumor necrosis factor- (TNF-) were measured in the same coinfected PBMC cultures. Endogenous IL-2 was not produced, whereas IL-6 and TNF- were secreted at levels compatible with their known ability to up-regulate HIV-1 expression. The HIV-suppressive CC-chemokines RANTES, macrophage inflammatory protein-1 (MIP-1), and MIP-1β were also determined in IL-2–stimulated PBMC cultures. Of interest, their kinetics and concentrations were inversely related to those of HIV-1 replication. Experiments were performed in which CD8+ T cells or PBMCs from HTLV-II monoinfected individuals were cocultivated with CD4+ T cells from HIV-1 monoinfected individuals separated by a semipermeable membrane in the presence or absence of antichemokine neutralizing antibodies. The results indicate that HTLV-II can interfere with the replicative potential of HIV-1 by up-regulating viral suppressive CC-chemokines and, in particular, MIP-1. This study is the first report indicating that HTLV-II can influence HIV replication, at least in vitro, via up-regulation of HIV-suppressive chemokines.

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Kinetics of Nucleocapsid, Spike and Neutralizing Antibodies, and Viral Load in Patients with Severe COVID-19 Treated with Convalescent Plasma

Viruses ◽

10.3390/v13091844 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1844

Author(s):

Thomas P. Thomopoulos ◽

Margherita Rosati ◽

Evangelos Terpos ◽

Dimitris Stellas ◽

Xintao Hu ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Rna Binding ◽

Neutralizing Antibody ◽

Binding Domain ◽

High Morbidity ◽

Viral Loads ◽

Effective Treatment Modality ◽

Meta Analyses ◽

Humoral Responses ◽

Kinetics Of

COVID-19 is an ongoing pandemic with high morbidity and mortality. Despite meticulous research, only dexamethasone has shown consistent mortality reduction. Convalescent plasma (CP) infusion might also develop into a safe and effective treatment modality on the basis of recent studies and meta-analyses; however, little is known regarding the kinetics of antibodies in CP recipients. To evaluate the kinetics, we followed 31 CP recipients longitudinally enrolled at a median of 3 days post symptom onset for changes in binding and neutralizing antibody titers and viral loads. Antibodies against the complete trimeric Spike protein and the receptor-binding domain (Spike-RBD), as well as against the complete Nucleocapsid protein and the RNA binding domain (N-RBD) were determined at baseline and weekly following CP infusion. Neutralizing antibody (pseudotype NAb) titers were determined at the same time points. Viral loads were determined semi-quantitatively by SARS-CoV-2 PCR. Patients with low humoral responses at entry showed a robust increase of antibodies to all SARS-CoV-2 proteins and Nab, reaching peak levels within 2 weeks. The rapid increase in binding and neutralizing antibodies was paralleled by a concomitant clearance of the virus within the same timeframe. Patients with high humoral responses at entry demonstrated low or no further increases; however, virus clearance followed the same trajectory as in patients with low antibody response at baseline. Together, the sequential immunological and virological analysis of this well-defined cohort of patients early in infection shows the presence of high levels of binding and neutralizing antibodies and potent clearance of the virus.

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

PLoS Pathogens ◽

10.1371/journal.ppat.1010046 ◽

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.

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Effect of HIV-1 Env on SERINC5 Antagonism

Journal of Virology ◽

10.1128/jvi.02214-16 ◽

2016 ◽

Vol 91 (4) ◽

Cited By ~ 45

Author(s):

Saina Beitari ◽

Shilei Ding ◽

Qinghua Pan ◽

Andrés Finzi ◽

Chen Liang

Keyword(s):

Antiviral Activity ◽

High Frequency ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Viral Loads ◽

Virion Incorporation ◽

Viral Particles ◽

Ccr5 Inhibitor ◽

Hiv 1

ABSTRACT SERINC5 is able to restrict HIV-1 infection by drastically impairing the infectivity of viral particles. Studies have shown that the HIV-1 Nef protein counters SERINC5 through downregulating SERINC5 from the cell surface and preventing the virion incorporation of SERINC5. In addition, the Env proteins of some HIV-1 strains can also overcome SERINC5 inhibition. However, it is unclear how HIV-1 Env does so and why HIV-1 has two mechanisms to resist SERINC5 inhibition. The results of this study show that neither Env nor Nef prevents high levels of ectopic SERINC5 from being incorporated into HIV-1 particles, except that Env, but not Nef, is able to resist inhibition by virion-associated SERINC5. Testing of a panel of HIV-1 Env proteins from different subtypes revealed a high frequency of SERINC5-resistant Envs. Interestingly, although the SERINC5-bearing viruses were not inhibited by SERINC5 itself, they became more sensitive to the CCR5 inhibitor maraviroc and some neutralizing antibodies than the SERINC5-free viruses, which suggests a possible influence of SERINC5 on Env function. We conclude that HIV-1 Env is able to overcome SERINC5 without preventing SERINC5 virion incorporation. IMPORTANCE HIV-1 Nef is known to enhance the infectivity of HIV-1 particles and to contribute to the maintenance of high viral loads in patients. However, the underlying molecular mechanism remained elusive until the recent discovery of the antiviral activity of SERINC5. SERINC5 profoundly inhibits HIV-1 but is antagonized by Nef, which prevents the incorporation of SERINC5 into viral particles. Here, we show that HIV-1 Env, but not Nef, is able to resist high levels of SERINC5 without excluding SERINC5 from incorporation into viral particles. However, the virion-associated SERINC5 renders HIV-1 more sensitive to some broadly neutralizing antibodies. It is possible that, under the pressure of some neutralizing antibodies in vivo, HIV-1 needs Nef to remove SERINC5 from viral particles, even though viral Env is able to resist virion-associated SERINC5.

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Positive Selection at Key Residues in the HIV Envelope Distinguishes Broad and Strain-Specific Plasma Neutralizing Antibodies

Journal of Virology ◽

10.1128/jvi.01685-18 ◽

2018 ◽

Vol 93 (6) ◽

Cited By ~ 6

Author(s):

Batsirai M. Mabvakure ◽

Cathrine Scheepers ◽

Nigel Garrett ◽

Salim Abdool Karim ◽

Carolyn Williamson ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Sequence Data ◽

Viral Evolution ◽

Viral Diversity ◽

Viral Loads ◽

Immunization Strategies ◽

Key Residues ◽

Hiv Envelope ◽

Kinetics Of ◽

Positively Selected Sites

ABSTRACTThe development of HIV broadly neutralizing antibodies (bNAbs) has previously been shown to be associated with viral evolution and high levels of genetic diversity in the HIV envelope (Env) glycoprotein. However, few studies have examined Env evolution in those who fail to develop neutralization breadth in order to assess whether bNAbs result from distinct evolutionary pathways. We compared Env evolution in eight HIV-1-infected participants who developed bNAbs to six donors with similar viral loads who did not develop bNAbs over three years of infection. We focused on Env V1V2 and C3V4, as these are major targets for both strain-specific neutralizing antibodies (nAbs) and bNAbs. Overall evolutionary rates (ranging from 9.92 × 10−3to 4.1 × 10−2substitutions/site/year) and viral diversity (from 1.1% to 6.5%) across Env, and within targeted epitopes, did not distinguish bNAb donors from non-bNAb donors. However, bNAb participants had more positively selected residues within epitopes than those without bNAbs, and several of these were common among bNAb donors. A comparison of the kinetics of strain-specific nAbs and bNAbs indicated that selection pressure at these residues increased with the onset of breadth. These data suggest that highly targeted viral evolution rather than overall envelope diversity is associated with neutralization breadth. The association of shared positively selected sites with the onset of breadth highlights the importance of diversity at specific positions in these epitopes for bNAb development, with implications for the development of sequential and cocktail immunization strategies.IMPORTANCEMillions of people are still being infected with HIV decades after the first recognition of the virus. Currently, no vaccine is able to elicit bNAbs that will prevent infection by global HIV strains. Several studies have implicated HIV Env diversity in the development of breadth. However, Env evolution in individuals who fail to develop breadth despite mounting potent strain-specific neutralizing responses has not been well defined. Using longitudinal neutralization, epitope mapping, and sequence data from 14 participants, we found that overall measures of viral diversity were similar in all donors. However, the number of positively selected sites within Env epitopes was higher in bNAb participants than in strain-specific donors. We further identified common sites that were positively selected as bNAbs developed. These data indicate that while viral diversity is required for breadth, this should be highly targeted to specific residues to shape the elicitation of bNAbs by vaccination.

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Evolutionary Dynamics of the Glycan Shield of theHuman Immunodeficiency Virus Envelope during Natural Infection andImplications for Exposure of the 2G12Epitope

Journal of Virology ◽

10.1128/jvi.78.22.12625-12637.2004 ◽

2004 ◽

Vol 78 (22) ◽

pp. 12625-12637 ◽

Cited By ~ 50

Author(s):

Laurent Dacheux ◽

Alain Moreau ◽

Yasemin Ataman-Önal ◽

François Biron ◽

Bernard Verrier ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Primary Infection ◽

Evolutionary Dynamics ◽

Natural Infection ◽

Virus Envelope ◽

Glycosylation Sites ◽

Immunodeficiency Virus ◽

Kinetics Of ◽

Hiv 1 ◽

2G12 Binding

ABSTRACT Elucidation of the kinetics of exposure of neutralizing epitopes on the envelope of human immunodeficiency virus type 1 (HIV-1) during the course of infection may provide key information about how HIV escapes the immune system or why its envelope is such a poor immunogen to induce broadly efficient neutralizing antibodies. We analyzed the kinetics of exposure of the epitopes corresponding to the broadly neutralizing human monoclonal antibodies immunoglobulin G1b12 (IgG1b12), 2G12, and 2F5 at the quasispecies level during infection. We studied the antigenicity and sequences of 94 full-length envelope clones present during primary infection and at least 4 years later in four HIV-1 clade B-infected patients. No or only minor exposure differences were observed for the 2F5 and IgG1b12 epitopes between the early and late clones. Conversely, the envelope glycoproteins of the HIV-1 quasispecies present during primary infection did not expose the 2G12 neutralizing epitope, unlike those present after several years in three of the four patients. Sequence analysis revealed major differences at potential N-linked glycosylation sites between early and late clones, particularly at positions known to be important for 2G12 binding. Our study, in natural mutants, confirms that the glycosylation sites N295, N332, and N392 are essential for 2G12 binding. This study demonstrates the relationship between the evolving “glycan shield ” of HIV and the kinetics of exposure of the 2G12 epitope during the course of natural infection.

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Neutralizing antibodies inhibit HIV-1 transfer from primary dendritic cells to autologous CD4 T lymphocytes

Blood ◽

10.1182/blood-2012-03-418913 ◽

2012 ◽

Vol 120 (18) ◽

pp. 3708-3717 ◽

Cited By ~ 31

Author(s):

Bin Su ◽

Ke Xu ◽

Alexandre Lederle ◽

Maryse Peressin ◽

Marina Elizabeth Biedma ◽

...

Keyword(s):

Dendritic Cells ◽

T Lymphocytes ◽

Neutralizing Antibodies ◽

Sexual Transmission ◽

Viral Particles ◽

In Trans ◽

In Cis ◽

Kinetics Of ◽

Hiv 1 ◽

Dc Maturation

AbstractDendritic cells (DCs) support only low levels of HIV-1 replication, but have been shown to transfer infectious viral particles highly efficiently to neighboring permissive CD4 T lymphocytes. This mode of cell-to-cell HIV-1 spread may be a predominant mode of infection and dissemination. In the present study, we analyzed the kinetics of fusion, replication, and the ability of HIV-1–specific Abs to inhibit HIV-1 transfer from immature DCs to autologous CD4 T lymphocytes. We found that neutralizing mAbs prevented HIV-1 transfer to CD4 T lymphocytes in trans and in cis, whereas nonneutralizing Abs did not. Neutralizing Abs also significantly decreased HIV-1 replication in DCs, even when added 2 hours after HIV-1 infection. Interestingly, a similar inhibition of HIV-1 replication in DCs was detected with some nonneutralizing Abs and was correlated with DC maturation. We suggest that the binding of HIV-1-specific Abs to FcγRs leads to HIV-1 inhibition in DCs by triggering DC maturation. This efficient inhibition of HIV-1 transfer by Abs highlights the importance of inducing HIV-specific Abs by vaccination directly at the mucosal portal of HIV-1 entry to prevent early dissemination after sexual transmission.

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Protection in Macaques Immunized with HIV-1 Candidate Vaccines Can Be Predicted Using the Kinetics of Their Neutralizing Antibodies

PLoS ONE ◽

10.1371/journal.pone.0028974 ◽

2011 ◽

Vol 6 (12) ◽

pp. e28974 ◽

Cited By ~ 3

Author(s):

David Davis ◽

Wim Koornstra ◽

Daniella Mortier ◽

Zahra Fagrouch ◽

Ernst J. Verschoor ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Kinetics Of ◽

Hiv 1

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Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection

Journal of Virology ◽

10.1128/jvi.01077-19 ◽

2019 ◽

Vol 93 (20) ◽

Cited By ~ 3

Author(s):

Yanling Wu ◽

Jing Xue ◽

Chunyu Wang ◽

Wei Li ◽

Lili Wang ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Treatment Failure ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Viral Reservoirs ◽

Acute Period ◽

Viral Loads ◽

Immunodeficiency Virus ◽

Shiv Infection ◽

Hiv 1

ABSTRACT Early human immunodeficiency virus type 1 (HIV-1) treatment during the acute period of infection can significantly limit the seeding of viral reservoirs and modify the course of disease. However, while a number of HIV-1 broadly neutralizing antibodies (bnAbs) have demonstrated remarkable efficacy as prophylaxis in macaques chronically infected with simian-human immunodeficiency virus (SHIV), intriguingly, their inhibitory effects were largely attenuated in the acute period of SHIV infection. To investigate the mechanism for the disparate performance of bnAbs in different periods of SHIV infection, we used LSEVh-LS-F, a bispecific bnAb targeting the CD4 binding site and CD4-induced epitopes, as a representative bnAb and assessed its potential therapeutic benefit in controlling virus replication in acutely or chronically SHIV-infected macaques. We found that a single infusion of LSEVh-LS-F resulted in rapid decline of plasma viral loads to undetectable levels without emergence of viral resistance in the chronically infected macaques. In contrast, the inhibitory effect was robust but transient in the acutely infected macaques, despite the fact that all macaques had comparable plasma viral loads initially. Infusing multiple doses of LSEVh-LS-F did not extend its inhibitory duration. Furthermore, the pharmacokinetics of the infused LSEVh-LS-F in the acutely SHIV-infected macaques significantly differed from that in the uninfected or chronically infected macaques. Host SHIV-specific immune responses may play a role in the viremia-dependent pharmacokinetics. Our results highlight the correlation between the fast clearance of infused bnAbs and the treatment failure in the acute period of SHIV infection and may have important implications for the therapeutic use of bnAbs to treat acute HIV infections. IMPORTANCE Currently, there is no bnAb-based monotherapy that has been reported to clear the virus in the acute SHIV infection period. Since early HIV treatment is considered critical to restricting the establishment of viral reservoirs, investigation into the mechanism for treatment failure in acutely infected macaques would be important for the therapeutic use of bnAbs and eventually towards the functional cure of HIV/AIDS. Here we report the comparative study of the therapeutic efficacy of a bnAb in acutely and chronically SHIV-infected macaques. This study revealed the correlation between the fast clearance of infused bnAbs and treatment failure during the acute period of infection.

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mRNA Vaccines Induce Rapid Antibody Responses in Mice

10.1101/2021.11.01.466863 ◽

2021 ◽

Author(s):

Makda Gebre ◽

Susanne Rauch ◽

Nicole Roth ◽

Janina Gergen ◽

Jingyou Yu ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Specific Binding ◽

Disease Outbreaks ◽

Antibody Responses ◽

Infectious Disease Outbreaks ◽

Rapid Induction ◽

Kinetics Of ◽

Hiv 1 ◽

Envelope Antigen ◽

Rapid Antibody

mRNA vaccines can be developed and produced quickly, making them attractive for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. We sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first examined immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA, but not DNA, immunization. The mRNA vaccine also induced increased levels of IL-5, IL-6 and MCP-1. We then evaluated immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines with the same HIV-1 envelope antigen in mice. Induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7-14 following DNA, protein, and RhAd52 vaccination. Eliciting rapid humoral immunity may be an advantageous property of mRNA vaccines for controlling infectious disease outbreaks.

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