scholarly journals Antibody responses induced by SHIV infection are more focused than those induced by soluble native HIV-1 envelope trimers in non-human primates

2021 ◽  
Vol 17 (8) ◽  
pp. e1009736
Author(s):  
Jelle van Schooten ◽  
Marlies M. van Haaren ◽  
Hui Li ◽  
Laura E. McCoy ◽  
Colin Havenar-Daughton ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Broadly Neutralizing Antibodies ◽  
Antibody Diversity ◽  
Infected Infant ◽  
Immunodeficiency Virus ◽  
Shiv Infection ◽  
Hiv 1

The development of an effective human immunodeficiency virus (HIV-1) vaccine is a high global health priority. Soluble native-like HIV-1 envelope glycoprotein trimers (Env), including those based on the SOSIP design, have shown promise as vaccine candidates by inducing neutralizing antibody responses against the autologous virus in animal models. However, to overcome HIV-1’s extreme diversity a vaccine needs to induce broadly neutralizing antibodies (bNAbs). Such bNAbs can protect non-human primates (NHPs) and humans from infection. The prototypic BG505 SOSIP.664 immunogen is based on the BG505 env sequence isolated from an HIV-1-infected infant from Kenya who developed a bNAb response. Studying bNAb development during natural HIV-1 infection can inform vaccine design, however, it is unclear to what extent vaccine-induced antibody responses to Env are comparable to those induced by natural infection. Here, we compared Env antibody responses in BG505 SOSIP-immunized NHPs with those in BG505 SHIV-infected NHPs, by analyzing monoclonal antibodies (mAbs). We observed three major differences between BG505 SOSIP immunization and BG505 SHIV infection. First, SHIV infection resulted in more clonal expansion and less antibody diversity compared to SOSIP immunization, likely because of higher and/or prolonged antigenic stimulation and increased antigen diversity during infection. Second, while we retrieved comparatively fewer neutralizing mAbs (NAbs) from SOSIP-immunized animals, these NAbs targeted more diverse epitopes compared to NAbs from SHIV-infected animals. However, none of the NAbs, either elicited by vaccination or infection, showed any breadth. Finally, SOSIP immunization elicited antibodies against the base of the trimer, while infection did not, consistent with the base being placed onto the virus membrane in the latter setting. Together these data provide new insights into the antibody response against BG505 Env during infection and immunization and limitations that need to be overcome to induce better responses after vaccination.

scholarly journals Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 76 ◽  
Author(s):  
Mitch Brinkkemper ◽  
Kwinten Sliepen
Keyword(s):  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Broadly Neutralizing Antibodies ◽  
Viral Membrane ◽  
Immunodeficiency Virus ◽  
Hiv 1

The enormous sequence diversity between human immunodeficiency virus type 1 (HIV-1) strains poses a major roadblock for generating a broadly protective vaccine. Many experimental HIV-1 vaccine efforts are therefore aimed at eliciting broadly neutralizing antibodies (bNAbs) that are capable of neutralizing the majority of circulating HIV-1 strains. The envelope glycoprotein (Env) trimer on the viral membrane is the sole target of bNAbs and the key component of vaccination approaches aimed at eliciting bNAbs. Multimeric presentation of Env on nanoparticles often plays a critical role in these strategies. Here, we will discuss the different aspects of nanoparticles in Env vaccination, including recent insights in immunological processes underlying their perceived advantages, the different nanoparticle platforms and the various immunogenicity studies that employed nanoparticles to improve (neutralizing) antibody responses against Env.

Development of a Norovirus P Particle Platform for Eliciting Neutralizing Antibody Responses to the Membrane Proximal External Region of Human Immunodeficiency Virus Type 1 Envelope

2014 ◽  
Vol 21 (12) ◽  
pp. 1230-1239
Author(s):  
Yang Zang ◽  
Jinpeng Bi ◽  
Dongchuan Du ◽  
Xintao Liu ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Broadly Neutralizing Antibodies ◽  
External Region ◽  
Membrane Proximal External Region ◽  
Immunodeficiency Virus ◽  
Hiv 1

Eliciting efficient broadly neutralizing antibodies (BnAbs) is an important goal that has yet to be achieved for human immunodeficiency type 1 (HIV-1) vaccine development, although they are rarely produced in virus-infected individuals. In particular, inducing specific neutralizing antibodies to the gp41 membrane proximal external region (MPER) has proven a difficult task. In this study, we introduce Norovirus P particles as a new platform to display the MPER epitope of HIV-1 as a vaccine with the aim of enhancing immune responses. The results showed that HIV-1 chimeric P particles were capable of inducing MPER-specific antibody responses in immunized guinea pigs, although only weakly neutralizing activity could be detected. These findings are consistent with other previous studies which have also focused on the well-studied 2F5 and 4E10 BnAbs. Our findings provide an alternate strategy for design of vaccines against HIV-1. However, great challenges remain in the effort to develop vaccines that can induce efficient HIV-1 neutralizing antibodies.

scholarly journals Plasma neutralizing antibodies in an infant with interclade HIV-1 superinfection preferentially neutralize superinfecting HIV-1 strains

2020 ◽  
Author(s):  
Nitesh Mishra ◽  
Shaifali Sharma ◽  
Ayushman Dobhal ◽  
Sanjeev Kumar ◽  
Himanshi Chawla ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Broadly Neutralizing Antibodies ◽  
Infected Infant ◽  
Polyvalent Vaccine ◽  
Clade C ◽  
Sequential Infection ◽  
Hiv 1

AbstractHIV-1 superinfection is defined as infection by an unrelated second strain of HIV-1 after seroconversion due to primary infecting strain and has been associated with development of breadth in the neutralizing antibody (nAb) response, altered disease progression and efficacy of antiretrovirals; though conflicting observations have also been reported. Superinfection has been reported in HIV-1 infected adults. Recently we observed that multivariant infection in infants was associated with early induction of plasma broadly neutralizing antibodies (bnAbs) targeting diverse autologous viruses, however, there is paucity of information on infants with HIV-1 superinfection. Furthermore, the mechanisms by which superinfection in an infant, after priming by an initial infection, potentiate the evolution of a bnAb response have not been evaluated. Herein, we performed a longitudinal analysis and observed evolution of nAb responses in an antiretroviral naïve perinatally HIV-1 infected infant, with interclade superinfection (clade C followed by a unique A1C recombinant). The nAb responses broadened rapidly after superinfection targeted an undefined glycan-dependent epitope on the superinfecting variant, while no enrichment of nAb response against the primary infecting strain occurred. Defining virological features in infants with sequential infection with highly divergent circulating viruses that improve nAb responses will contribute information that could be leveraged for optimization of multicomponent candidate vaccines.ImportanceHIV-1 infected infants develop bnAbs rapidly suggesting factors governing bnAb induction in infants are distinct from adults. HIV-1 superinfection is more common in adults whereas the stringent genetic bottleneck for transmission in infants often leads to infection by a single transmitted/founder HIV-1 strain. Longitudinal studies in infants with HIV-1 superinfection can provide key information on the viral factors that induce a bnAb response towards development of a polyvalent vaccine. Herein, we show that in infant who was sequentially infected with two HIV-1 strains from different clades, antibody responses were primarily generated against the superinfecting, second strain of HIV-1.These antibody responses were dependent on glycans, and targeted an undefined epitope in the C3V4 region of HIV-1 Env. A better understanding of how neutralizing antibody responses develop during natural HIV-1 superinfection in infants will provide information relevant to HIV Env vaccine development and evaluation.

scholarly journals Neutralizing Antibody Responses in Acute Human Immunodeficiency Virus Type 1 Subtype C Infection

2007 ◽  
Vol 81 (12) ◽  
pp. 6187-6196 ◽  
Author(s):  
E. S. Gray ◽  
P. L. Moore ◽  
I. A. Choge ◽  
J. M. Decker ◽  
F. Bibollet-Ruche ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Subtype C ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The study of the evolution and specificities of neutralizing antibodies during the course of human immunodeficiency virus type 1 (HIV-1) infection may be important in the discovery of possible targets for vaccine design. In this study, we assessed the autologous and heterologous neutralization responses of 14 HIV-1 subtype C-infected individuals, using envelope clones obtained within the first 2 months postinfection. Our data show that potent but relatively strain-specific neutralizing antibodies develop within 3 to 12 months of HIV-1 infection. The magnitude of this response was associated with shorter V1-to-V5 envelope lengths and fewer glycosylation sites, particularly in the V1-V2 region. Anti-MPER antibodies were detected in 4 of 14 individuals within a year of infection, while antibodies to CD4-induced (CD4i) epitopes developed to high titers in 12 participants, in most cases before the development of autologous neutralizing antibodies. However, neither anti-MPER nor anti-CD4i antibody specificity conferred neutralization breadth. These data provide insights into the kinetics, potency, breadth, and epitope specificity of neutralizing antibody responses in acute HIV-1 subtype C infection.

scholarly journals Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants

2014 ◽  
Vol 211 (12) ◽  
pp. 2361-2372 ◽  
Author(s):  
Florian Klein ◽  
Lilian Nogueira ◽  
Yoshiaki Nishimura ◽  
Ganesh Phad ◽  
Anthony P. West ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Viral Escape ◽  
Humanized Mice ◽  
Broadly Neutralizing Antibodies ◽  
Virus Escape ◽  
Immunodeficiency Virus ◽  
Shiv Infection ◽  
Hiv 1

Antibody-mediated immunotherapy is effective in humanized mice when combinations of broadly neutralizing antibodies (bNAbs) are used that target nonoverlapping sites on the human immunodeficiency virus type 1 (HIV-1) envelope. In contrast, single bNAbs can control simian–human immunodeficiency virus (SHIV) infection in immune-competent macaques, suggesting that the host immune response might also contribute to the control of viremia. Here, we investigate how the autologous antibody response in intact hosts can contribute to the success of immunotherapy. We find that frequently arising antibodies that normally fail to control HIV-1 infection can synergize with passively administered bNAbs by preventing the emergence of bNAb viral escape variants.

scholarly journals Viral Phenotypes and Antibody Responses in Long-Term Survivors Infected with Attenuated Human Immunodeficiency Virus Type 1 Containing Deletions in the nef and Long Terminal Repeat Regions

2007 ◽  
Vol 81 (17) ◽  
pp. 9268-9278 ◽  
Author(s):  
Erin E. Verity ◽  
Dimitra Zotos ◽  
Kim Wilson ◽  
Catherine Chatfield ◽  
Victoria A. Lawson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Wild Type Virus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The Sydney Blood Bank Cohort (SBBC) consists of eight blood transfusion recipients infected with nef-attenuated human immunodeficiency virus type 1 (HIV-1) acquired from a single donor. Here, we show that viral phenotypes and antibody responses differ considerably between individual cohort members, despite the single source of infection. Replication of isolated virus varied from barely detectable to similar to that of the wild-type virus, and virus isolated from five SBBC members showed coreceptor usage signatures unique to each individual. Higher viral loads and stronger neutralizing antibody responses were associated with better-replicating viral strains, and detectable viral replication was essential for the development of strong and sustained humoral immune responses. Despite the presence of strong neutralizing antibodies in a number of SBBC members, disease progression was not prevented, and each cohort member studied displayed a unique outcome of infection with nef-attenuated HIV-1.

scholarly journals Human Immunodeficiency Virus Type 1 Superinfection Occurs despite Relatively Robust Neutralizing Antibody Responses

2008 ◽  
Vol 82 (24) ◽  
pp. 12094-12103 ◽  
Author(s):  
Catherine A. Blish ◽  
Ozge C. Dogan ◽  
Nina R. Derby ◽  
Minh-An Nguyen ◽  
Bhavna Chohan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Superinfection by a second human immunodeficiency virus type 1 (HIV-1) strain indicates that gaps in protective immunity occur during natural infection. To define the role of HIV-1-specific neutralizing antibodies (NAbs) in this setting, we examined NAb responses in 6 women who became superinfected between ∼1 to 5 years following initial infection compared to 18 women with similar risk factors who did not. Although superinfected individuals had less NAb breadth than matched controls at ∼1 year postinfection, no significant differences in the breadth or potency of NAb responses were observed just prior to the second infection. In fact, four of the six subjects had relatively broad and potent NAb responses prior to infection by the second strain. To more specifically examine the specificity of the NAbs against the superinfecting virus, these variants were cloned from five of the six individuals. The superinfecting variants did not appear to be inherently neutralization resistant, as measured against a pool of plasma from unrelated HIV-infected individuals. Moreover, the superinfected individuals were able to mount autologous NAb responses to these variants following reinfection. In addition, most superinfected individuals had NAbs that could neutralize their second viral strains prior to their reinfection, suggesting that the level of NAbs elicited during natural infection was not sufficient to block infection. These data indicate that preventing infection by vaccination will likely require broader and more potent NAb responses than those found in HIV-1-infected individuals.

scholarly journals Improved Elicitation of Neutralizing Antibodies against Primary Human Immunodeficiency Viruses by Soluble Stabilized Envelope Glycoprotein Trimers

2001 ◽  
Vol 75 (3) ◽  
pp. 1165-1171 ◽  
Author(s):  
Xinzhen Yang ◽  
Richard Wyatt ◽  
Joseph Sodroski
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Viruses ◽  
Functional Envelope ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus (HIV-1) envelope glycoprotein subunits, such as the gp120 exterior glycoprotein, typically elicit antibodies that neutralize T-cell-line-adapted (TCLA), but not primary, clinical isolates of HIV-1. Here we compare the immunogenicity of gp120 and soluble stabilized trimers, which were designed to resemble the functional envelope glycoprotein oligomers of primary and TCLA HIV-1 strains. For both primary and TCLA virus proteins, soluble stabilized trimers generated neutralizing antibody responses more efficiently than gp120 did. Trimers derived from a primary isolate elicited antibodies that neutralized primary and TCLA HIV-1 strains. By contrast, trimers derived from a TCLA isolate generated antibodies that neutralized only the homologous TCLA virus. Thus, soluble stabilized envelope glycoprotein trimers derived from primary HIV-1 isolates represent defined immunogens capable of eliciting neutralizing antibodies that are active against clinically relevant HIV-1 strains.

scholarly journals Elicitation of potent serum neutralizing antibody responses in rabbits by immunization with an HIV-1 clade C trimeric Env derived from an Indian elite neutralizer

2020 ◽  
Author(s):  
Rajesh Kumar ◽  
Suprit Deshpande ◽  
Leigh M. Sewall ◽  
Gabriel Ozorowski ◽  
Christopher A. Cottrell ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Clade C ◽  
Immunogen Design ◽  
Env Protein ◽  
Immunogenic Properties ◽  
Hiv 1

AbstractEvaluating the structure-function relationship of viral envelope (Env) evolution and the development of broadly cross-neutralizing antibodies (bnAbs) in natural infection can inform rational immunogen design. In the present study, we examined the magnitude and specificity of autologous neutralizing antibodies induced in rabbits by a novel HIV-1 clade C Env protein (1PGE-THIVC) vis-à-vis those developed in an elite neutralizer from whom the env sequence was obtained that was used to prepare the soluble Env protein. The thermostable 1PGE-THIVC Env displayed a native like pre-fusion closed conformation in solution as determined by small angle X-ray scattering (SAXS) and negative stain electron microscopy (EM). This closed spike conformation of 1PGE-THIVC Env trimers was correlated with weak or undetectable binding of non-neutralizing monoclonal antibodies (mAbs) compared to neutralizing mAbs. Furthermore, 1PGE-THIVC SOSIP induced potent neutralizing antibodies in rabbits to autologous virus variants. The autologous neutralizing antibody specificity induced in rabbits by 1PGE-THIVC was mapped to the C3/V4 region (T362/P401) of viral Env. This observation agreed with electron microscopy polyclonal epitope mapping (EMPEM) of the Env trimer complexed with IgG Fab prepared from the immunized rabbit sera. While the specificity of antibodies elicited in rabbits associated with neutralizing autologous viruses were distinct to those developed in the elite neutralizer, EMPEM analysis demonstrated significant changes to Env conformations when incubated with polyclonal antibody sera from the elite neutralizer, suggesting these antibodies lead to the destabilization of Env trimers. Our study not only shows distinct mechanisms associated with potent neutralization of sequence matched and unmatched autologous viruses by antibodies induced in rabbits and in the elite neutralizer, but also highlights how neutralizing antibodies developed during the course of natural infection can impact viral Env conformations.Author SummaryThe interplay between circulating virus variants and broadly cross neutralizing polyclonal antibodies developed in a subset of elite neutralizers is widely believed to provide strategies for rational immunogen design. In the present study, we studied the structural, antigenic and immunogenic properties of a thermostable soluble trimeric protein with near native pre-fusion conformation prepared using the primary sequence of an HIV-1 clade C env isolated from the broadly cross neutralizing plasma of an elite neutralizer. This novel SOSIP Env trimer demonstrated comparable antigenic, structural and immunogenic properties that favoured several ongoing subunit vaccine design efforts. The novel clade C SOSIP induced polyclonal neutralizing antibody response developed in rabbits not only differed in its epitope specificity compared to that elicited in natural infection in presence of pool of viral quasispecies but also showed how they differ in their ability to influence Env structure and conformation. A better understanding of how vaccine-induced polyclonal neutralizing antibody responses compares to responses that developed in natural infection will improve our knowledge in designing better vaccine design strategies.

scholarly journals Biochemical and Immunogenic Characterization of Soluble Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Trimers Expressed by Semliki Forest Virus

2005 ◽  
Vol 79 (17) ◽  
pp. 10902-10914 ◽  
Author(s):  
Mattias N. E. Forsell ◽  
Yuxing Li ◽  
Maria Sundbäck ◽  
Krisha Svehla ◽  
Peter Liljeström ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Semliki Forest Virus ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The current lack of envelope glycoprotein immunogens that elicit broadly neutralizing antibody responses remains a major challenge for human immunodeficiency virus type 1 (HIV-1) vaccine development. However, the recent design and construction of stable soluble gp140 trimers have shown that some neutralization breadth can be achieved by using immunogens that better mimic the functional viral spike complex. The use of genetic delivery systems to drive the in vivo expression of such immunogens for the stimulation of neutralizing antibodies against HIV-1 may offer advantages by maintaining the quaternary structure of the trimeric envelope glycoproteins. Here, we describe the biochemical and immunogenic properties of soluble HIV-1 envelope glycoprotein trimers expressed by recombinant Semliki Forest virus (rSFV). The results presented here demonstrate that rSFV supports the expression of stable soluble gp140 trimers that retain recognition by conformationally sensitive antibodies. Further, we show that rSFV particle immunizations efficiently primed immune responses as measured after a single boost with purified trimeric gp140 protein, resulting in a Th1-biased antibody response. This differed from the Th2-biased antibody response obtained after repeated immunizations with purified gp140 protein trimers. Despite this difference, both regimens stimulated neutralizing antibody responses of similar potency. This suggests that rSFV may be a useful component of a viral vector prime-protein boost regimen aimed at stimulating both cell-mediated immune responses and neutralizing antibodies against HIV-1.

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