HIV-1 clade C escapes broadly neutralizing autologous antibodies with N332 glycan specificity by distinct mechanisms

ABSTRACT As part of the continuing effort to develop an effective HIV vaccine, we generated a poxviral vaccine vector (previously described) designed to improve on the results of the RV144 phase III clinical trial. The construct, NYVAC-KC, is a replication-competent, attenuated recombinant of the vaccinia virus strain NYVAC. NYVAC is a vector that has been used in many previous clinical studies but is replication deficient. Here, we report a side-by-side comparison of replication-restricted NYVAC and replication-competent NYVAC-KC in a nonhuman primate study, which utilized a prime-boost regimen similar to that of RV144. NYVAC-C and NYVAC-C-KC express the HIV-1 antigens gp140, and Gag/Gag-Pol-Nef-derived virus-like particles (VLPs) from clade C and were used as the prime, with recombinant virus plus envelope protein used as the boost. In nearly every T and B cell immune assay against HIV-1, including neutralization and antibody binding, NYVAC-C-KC induced a greater immune response than NYVAC-C, indicating that replication competence in a poxvirus may improve upon the modestly successful regimen used in the RV144 clinical trial. IMPORTANCE Though the RV144 phase III clinical trial showed promise that an effective vaccine against HIV-1 is possible, a successful vaccine will require improvement over the vaccine candidate (ALVAC) used in the RV144 study. With that goal in mind, we have tested in nonhuman primates an attenuated but replication-competent vector, NYVAC-KC, in direct comparison to its parental vector, NYVAC, which is replication restricted in human cells, similar to the ALVAC vector used in RV144. We have utilized a prime-boost regimen for administration of the vaccine candidate that is similar to the one used in the RV144 study. The results of this study indicate that a replication-competent poxvirus vector may improve upon the effectiveness of the RV144 clinical trial vaccine candidate.

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Frequencies of circulating Th1-biased T follicular helper cells in acute HIV-1 infection correlate with the development of HIV-specific antibody responses and lower set point viral load

10.1101/304329 ◽

2018 ◽

Cited By ~ 1

Author(s):

Omolara Baiyegunhi ◽

Bongiwe Ndlovu ◽

Funsho Ogunshola ◽

Nasreen Ismail ◽

Bruce D. Walker ◽

...

Keyword(s):

Viral Load ◽

Neutralizing Antibodies ◽

Acute Infection ◽

Antibody Responses ◽

Set Point ◽

Follicular Helper ◽

Clade C ◽

Acute Hiv ◽

Anti Hiv ◽

Hiv 1

AbstractDespite decades of focused research, the field has yet to develop a prophylactic vaccine. In the RV144 vaccine trial, non-neutralizing antibody responses were identified as a correlate for prevention of HIV acquisition. However, factors that predict the development of such antibodies are not fully elucidated. We sought to define the contribution of circulating T follicular helper (cTfh) cell subsets to the development of non-neutralizing antibodies in HIV-1 clade C infection. Study participants were recruited from an acute HIV-1 clade C infection cohort. Plasma anti-gp41, -gp120, -p24 and -p17 antibodies were screened using a customized multivariate Luminex assay. Phenotypic and functional characterization of cTfh were performed using HLA class II tetramers and intracellular cytokine staining. In this study, we found that acute HIV-1 clade C infection skewed differentiation of functional cTfh subsets towards increased Tfh1 (p=0.02) and Tfh2 (p<0.0001) subsets, with a concomitant decrease in overall Tfh1-17 (that shares both Tfh1 and Tfh17 properties) (p=0.01) and Tfh17 subsets (p<0.0001) compared to HIV negative subjects. Interestingly, the frequencies of Tfh1 during acute infection (5.0-8.0 weeks post-infection) correlated negatively with set point viral load (p=0.03, r=-60) and were predictive of p24-specific plasma IgG titers at one year of infection (p=0.003, r=0.85). Taken together, our results suggest that circulating the Tfh1 subset plays an important role in the development of anti-HIV antibody responses and contributes to HIV suppression during acute HIV-1 infection. These results have implications for vaccine studies aimed at inducing long lasting anti-HIV antibody responses.ImportanceThe HIV epidemic in southern Africa accounts for almost half of the global HIV burden with HIV-1 clade C being the predominant strain. It is therefore important to define immune correlates of clade C HIV control that might have implications for vaccine design in this region. T follicular helper (Tfh) cells are critical for the development of HIV-specific antibody responses and could play a role in viral control. Here we showed that the early induction of circulating Tfh1 cells during acute infection correlated positively with the magnitude of p24-specific IgG and was associated with lower set point viral load. This study highlights a key Tfh cell subset that could limit HIV replication by enhancing antibody generation. This study underscores the importance of circulating Tfh cells in promoting non-neutralizing antibodies during HIV-1 infection.

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Neutralizing antibodies induced by first-generation gp41-stabilized HIV-1 envelope trimers and nanoparticles

10.1101/2020.12.02.408328 ◽

2020 ◽

Author(s):

Sonu Kumar ◽

Xiaohe Lin ◽

Timothy Ngo ◽

Benjamin Shapero ◽

Cindy Sou ◽

...

Keyword(s):

Cell Sorting ◽

Neutralizing Antibodies ◽

First Generation ◽

Heptad Repeat ◽

X Ray ◽

X Ray Crystallography ◽

Clade C ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing ◽

Hiv 1

ABSTRACTAntigen-specific B-cell sorting and next-generation sequencing (NGS) were combined to isolate HIV-1 neutralizing antibodies (NAbs) from mice and rabbits immunized with BG505 trimers and nanoparticles. Three mouse NAbs potently neutralize BG505.T332N and recognize a glycan epitope centered at the C3/V4 region, as revealed by electron microscopy (EM), x-ray crystallography, and epitope mapping. Three potent NAbs were sorted from rabbit B cells that target glycan holes on the BG505 envelope glycoprotein (Env) and account for a significant portion of autologous NAb response. We then determined a 3.4Å-resolution crystal structure for the clade C transmitted/founder Du172.17 Env with a redesigned heptad repeat 1 (HR1) bend. This clade C Env, as a soluble trimer and attached to a ferritin nanoparticle, along with a clade A Q482-d12 Env trimer, elicited distinct NAb responses in rabbits. Our study demonstrates that nanoparticles presenting gp41-stabilized trimers can induce potent NAb responses in mice and rabbits with Env-dependent breadth.TEASERMouse and rabbit NAbs elicited by gp41-stabilized trimers and nanoparticles neutralize autologous HIV-1 by targeting different epitopes

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Differential Immunogenicity of HIV‐1 Clade C Proteins in Eliciting CD8+and CD4+Cell Responses

The Journal of Infectious Diseases ◽

10.1086/496894 ◽

2005 ◽

Vol 192 (9) ◽

pp. 1588-1596 ◽

Cited By ~ 45

Author(s):

Danni Ramduth ◽

Polan Chetty ◽

Nolwandle Cyloria Mngquandaniso ◽

Nonhlanhla Nene ◽

Jason Davis Harlow ◽

...

Keyword(s):

Cell Responses ◽

Clade C ◽

C Proteins ◽

Cd4 Cell ◽

Hiv 1

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Low prevalence of primary antiretroviral resistance mutations and predominance of HIV-1 clade C at polymerase gene in newly diagnosed individuals from south Brazil

Virus Research ◽

10.1016/j.virusres.2005.10.004 ◽

2006 ◽

Vol 116 (1-2) ◽

pp. 201-207 ◽

Cited By ~ 50

Author(s):

Rosangela Rodrigues ◽

Luciene C. Scherer ◽

Cristina M. Oliveira ◽

Heitor Moreira Franco ◽

Rosa Dea Sperhacke ◽

...

Keyword(s):

Newly Diagnosed ◽

Polymerase Gene ◽

Resistance Mutations ◽

Antiretroviral Resistance ◽

Clade C ◽

Low Prevalence ◽

Hiv 1 ◽

South Brazil

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Favorable and Unfavorable HLA Class I Alleles and Haplotypes in Zambians Predominantly Infected with Clade C Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.76.16.8276-8284.2002 ◽

2002 ◽

Vol 76 (16) ◽

pp. 8276-8284 ◽

Cited By ~ 106

Author(s):

Jianming Tang ◽

Shenghui Tang ◽

Elena Lobashevsky ◽

Angela D. Myracle ◽

Ulgen Fideli ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Hla Class I ◽

Class I ◽

Hla Class I Molecules ◽

Immunodeficiency Virus ◽

Clade C ◽

Hiv 1

ABSTRACT The setpoint of viral RNA concentration (viral load [VL]) during chronic human immunodeficiency virus type 1 (HIV-1) infection reflects a virus-host equilibration closely related to CD8+ cytotoxic T-lymphocyte (CTL) responses, which rely heavily on antigen presentation by the human major histocompatibility complex (MHC) (i.e., HLA) class I molecules. Differences in HIV-1 VL among 259 mostly clade C virus-infected individuals (137 females and 122 males) in the Zambia-UAB HIV Research Project (ZUHRP) were associated with several HLA class I alleles and haplotypes. In particular, general linear model analyses revealed lower log10 VL among those with HLA allele B*57 (P = 0.002 [without correction]) previously implicated in favorable response and in those with HLA B*39 and A*30-Cw*03 (P = 0.002 to 0.016); the same analyses also demonstrated higher log10 VL among individuals with A*02-Cw*16, A*23-B*14, and A*23-Cw*07 (P = 0.010 to 0.033). These HLA effects remained strong (P = 0.0002 to 0.075) after adjustment for age, gender, and duration of infection and persisted across three orders of VL categories (P = 0.001 to 0.084). In contrast, neither B*35 (n = 15) nor B*53 (n = 53) showed a clear disadvantage such as that reported elsewhere for these closely related alleles. Other HLA associations with unusually high (A*68, B*41, B*45, and Cw*16) or low (B*13, Cw*12, and Cw*18) VL were either unstable or reflected their tight linkage respecting disequilibria with other class I variants. The three consistently favorable HLA class I variants retained in multivariable models and in alternative analyses were present in 30.9% of subjects with the lowest (<10,000 copies per ml) and 3.1% of those with the highest (>100,000) VL. Clear differential distribution of HLA profiles according to level of viremia suggests important host genetic contribution to the pattern of immune control and escape during HIV-1 infection.

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