scholarly journals Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection

mSphere ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e00880-20
Author(s):  
M. Muenchhoff ◽  
A. W. Chung ◽  
J. Roider ◽  
Anne-Sophie Dugast ◽  
Simone Richardson ◽  
...  
Keyword(s):  
Potential Role ◽  
Sexual Debut ◽  
Neutralizing Antibody ◽  
Affinity Maturation ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Effector Functions ◽  
Systems Immunology ◽  
Broadly Neutralizing Antibody

ABSTRACTA prophylactic HIV vaccine would ideally induce protective immunity prior to sexual debut. Children develop broadly neutralizing antibody (bnAb) responses faster and at higher frequencies than adults, but little is known about the underlying mechanisms or the potential role of Fc-mediated effector functions in disease progression. We therefore performed systems immunology, with immunoglobulin profiling, on HIV-infected children with progressive and nonprogressive disease. Pediatric nonprogressors (PNPs) showed distinct immunoglobulin profiles with an increased ability to elicit potent Fc-mediated natural killer (NK)-cell effector functions. In contrast to previous reports in adults, both groups of children showed high levels of gp120-specific IgG Fc glycan sialylation compared to bulk IgG. Importantly, higher levels of Fc glycan sialylation were associated with increased bnAb breadth, providing the first evidence that Fc sialylation may drive affinity maturation of HIV-specific antibodies in children, a mechanism that could be exploited for vaccination strategies.IMPORTANCE To protect future generations against HIV, a vaccine will need to induce immunity by the time of sexual debut and hence requires immunization during childhood. Current strategies for a prophylactic HIV vaccine include the induction of a broadly neutralizing antibody response and the recruitment of potent effector functions of immune cells via the constant antibody Fc region. In this study, we show that nonprogressing HIV-infected children mounted antibody responses against HIV that were able to mediate potent Fc effector functions, which may contribute to the control of HIV replication. Children who had specific glycan structures on the Fc portion of antibodies against HIV were able to neutralize a broader range of HIV variants, providing evidence of a potential role of Fc glycovariation in the development of bnAbs against HIV. These findings complement our knowledge of the distinct immune landscape in early life that could be exploited in the development of vaccine strategies.

scholarly journals Chimpanzee SIV Envelope trimer: structure and deployment as an HIV vaccine template

2018 ◽  
Author(s):  
Raiees Andrabi ◽  
Jesper Pallesen ◽  
Joel Allen ◽  
Ge Song ◽  
Jinsong Zhang ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Attractive Potential ◽  
Induced Responses ◽  
Potential Component ◽  
Broadly Neutralizing Antibody ◽  
Cross Neutralization

SummaryEpitope-targeted HIV vaccine design seeks to focus antibody responses to broadly neutralizing antibody (bnAb) sites by sequential immunization. Chimpanzee SIV Envelope (Env) shares a single bnAb site, the V2-apex, with HIV, suggesting its possible utility in an HIV immunization strategy. Accordingly, we generated a chimpanzee SIV Env trimer, MT145K, which displays selective binding to HIV V2-apex bnAbs and precursor versions, but no binding to other HIV specificities. We determined the structure of the MT145K trimer by cryo-EM and showed its architecture was remarkably similar to HIV Env. Immunization of an HIV V2-apex bnAb precursor Ab-expressing knock-in mouse with chimpanzee MT145K trimer induced HIV V2-specific neutralizing responses. Subsequent boosting with an HIV trimer cocktail induced responses exhibiting some virus cross-neutralization. Overall, the chimpanzee MT145K trimer behaves as expected from design both in vitro and in vivo and is an attractive potential component of a sequential immunization regimen to induce V2-apex bnAbs.

scholarly journals Contrasting Adult and Infant Immune Responses to HIV Infection and Vaccination

2015 ◽  
Vol 23 (2) ◽  
pp. 84-94 ◽  
Author(s):  
David R. Martinez ◽  
Sallie R. Permar ◽  
Genevieve G. Fouda
Keyword(s):  
Immune Responses ◽  
Hiv Infection ◽  
Vaccine Efficacy ◽  
Neutralizing Antibody ◽  
Hiv Vaccine ◽  
Antibody Responses ◽  
Hiv Vaccines ◽  
Vaccine Candidates ◽  
Protective Antibodies ◽  
Pediatric Populations

ABSTRACTExtensive studies have demonstrated that infant immune responses are distinct from those of adults. Despite these differences, infant immunization can elicit protective immune responses at levels comparable to or, in some cases, higher than adult immune responses to many vaccines. To date, only a few HIV vaccine candidates have been tested in infant populations, and none of them evaluated vaccine efficacy. Recent exciting studies showing that HIV-infected infants can develop broad neutralizing antibody responses and that some HIV vaccine regimens can elicit high levels of potentially protective antibodies in infants provide support for the development and testing of HIV vaccines in pediatric populations. In this review, we discuss the differences in adult and infant immune responses in the setting of HIV infection and vaccination.

scholarly journals Induction of Neutralizing Antibodies against Human Immunodeficiency Virus Type 1 Primary Isolates by Gag-Env Pseudovirion Immunization

2005 ◽  
Vol 79 (23) ◽  
pp. 14804-14814 ◽  
Author(s):  
Jason Hammonds ◽  
Xuemin Chen ◽  
Timothy Fouts ◽  
Anthony DeVico ◽  
David Montefiori ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Oil Emulsion ◽  
Cpg Oligodeoxynucleotides ◽  
Immunodeficiency Virus ◽  
Monomeric Gp120

ABSTRACT A major challenge for the development of an effective HIV vaccine is to elicit neutralizing antibodies against a broad array of primary isolates. Monomeric gp120-based vaccine approaches have not been successful in inducing this type of response, prompting a number of approaches designed to recreate the native glycoprotein complex that exists on the viral membrane. Gag-Env pseudovirions are noninfectious viruslike particles that recreate the native envelope glycoprotein structure and have the potential to generate neutralizing antibody responses against primary isolates. In this study, an inducible cell line was created in order to generate Gag-Env pseudovirions for examination of neutralizing antibody responses in guinea pigs. Unadjuvanted pseudovirions generated relatively weak anti-gp120 responses, while the use of a block copolymer water-in-oil emulsion or aluminum hydroxide combined with CpG oligodeoxynucleotides resulted in high levels of antibodies that bind to gp120. Sera from immunized animals neutralized a panel of human immunodeficiency virus (HIV) type 1 primary isolate viruses at titers that were significantly higher than that of the corresponding monomeric gp120 protein. Interpretation of these results was complicated by the occurrence of neutralizing antibodies directed against cellular (non-envelope protein) components of the pseudovirion. However, a major component of the pseudovirion-elicited antibody response was directed specifically against the HIV envelope. These results provide support for the role of pseudovirion-based vaccines in generating neutralizing antibodies against primary isolates of HIV and highlight the potential confounding role of antibodies directed at non-envelope cell surface components.

scholarly journals Maternal Broadly Neutralizing Antibodies Can Select for Neutralization-Resistant, Infant-Transmitted/Founder HIV Variants

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
David R. Martinez ◽  
Joshua J. Tu ◽  
Amit Kumar ◽  
Jesse F. Mangold ◽  
Riley J. Mangan ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Maternal Plasma ◽  
Small Subset ◽  
Maternal Hiv ◽  
Broadly Neutralizing Antibody ◽  
Specific Igg ◽  
Hiv Envelope ◽  
Mother To Child

ABSTRACT Each year, >180,000 infants become infected via mother-to-child transmission (MTCT) of HIV despite the availability of effective maternal antiretroviral treatments, underlining the need for a maternal HIV vaccine. We characterized 224 maternal HIV envelope (Env)-specific IgG monoclonal antibodies (MAbs) from seven nontransmitting and transmitting HIV-infected U.S. and Malawian mothers and examined their neutralization activities against nontransmitted autologous circulating viruses and infant-transmitted founder (infant-T/F) viruses. Only a small subset of maternal viruses, 3 of 72 (4%), were weakly neutralized by maternal linear V3 epitope-specific IgG MAbs, whereas 6 out of 6 (100%) infant-T/F viruses were neutralization resistant to these V3-specific IgG MAbs. We also show that maternal-plasma broadly neutralizing antibody (bNAb) responses targeting the V3 glycan supersite in a transmitting woman may have selected for an N332 V3 glycan neutralization-resistant infant-T/F virus. These data have important implications for bNAb-eliciting vaccines and passively administered bNAbs in the setting of MTCT. IMPORTANCE Efforts to eliminate MTCT of HIV with antiretroviral therapy (ART) have met little success, with >180,000 infant infections each year worldwide. It is therefore likely that additional immunologic strategies that can synergize with ART will be required to eliminate MTCT of HIV. To this end, understanding the role of maternal HIV Env-specific IgG antibodies in the setting of MTCT is crucial. In this study, we found that maternal-plasma broadly neutralizing antibody (bNAb) responses can select for T/F viruses that initiate infection in infants. We propose that clinical trials testing the efficacy of single bNAb specificities should not include HIV-infected pregnant women, as a single bNAb might select for neutralization-resistant infant-T/F viruses.

scholarly journals Serological Diagnostic Assays for HIV-Associated Tuberculosis in Sub-Saharan Africa?

2014 ◽  
Vol 21 (6) ◽  
pp. 787-790 ◽  
Author(s):  
Stephen D. Lawn
Keyword(s):  
Potential Role ◽  
Point Of Care ◽  
Antibody Responses ◽  
Sub Saharan Africa ◽  
Simple Point ◽  
Content Type ◽  
Diagnostic Assays ◽  
Hiv Coinfection ◽  
Sub Saharan

ABSTRACTIn this issue ofClinical and Vaccine Immunology, Siev and colleagues present an evaluation of antibody responses to four immunodominant proteins ofMycobacterium tuberculosisin patients with HIV-associated pulmonary tuberculosis (TB) in South Africa (M. Siev, D. Wilson, S. Kainth, V. O. Kasprowicz, C. M. Feintuch, E. Jenny-Avital, and J. J. Achkar, 21:791–798, 2014, doi:http://dx.doi.org/10.1128/CVI.00805-13). This commentary discusses the enormous need for simple point-of-care assays for tuberculosis (TB) diagnosis in patients with and without HIV coinfection in high-burden settings and considers the potential role of serological assays and the huge challenges inherent in developing and validating such assays.

scholarly journals Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort

2016 ◽  
Vol 12 (1) ◽  
pp. e1005369 ◽  
Author(s):  
Elise Landais ◽  
Xiayu Huang ◽  
Colin Havenar-Daughton ◽  
Ben Murrell ◽  
Matt A. Price ◽  
...  
Keyword(s):  
Primary Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Broadly Neutralizing Antibody ◽  
Sub Saharan
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