Viral Characteristics Associated with Maintenance of Elite Neutralizing Activity in Chronically HIV-1 Clade C-Infected Monozygotic Pediatric Twins

ABSTRACT Broad and potent neutralizing antibodies (bnAbs) with multiple epitope specificities evolve in HIV-1-infected children. Herein, we studied two antiretroviral-naive chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, with potent plasma bnAbs. Elite plasma neutralizing activity was observed since the initial sampling at 78 months of age in AIIMS_330 and persisted throughout, while in AIIMS_329 it was seen at 90 months of age, after which the potency decreased over time. We evaluated potential viral characteristics associated with the varied immune profiles by generating single genome-amplified pseudoviruses. The AIIMS_329 viruses generated from the 90-month time point were neutralization sensitive to bnAbs and contemporaneous plasma antibodies, while viruses from the 112-month and 117-month time points were resistant to most bnAbs and contemporaneous plasma. AIIMS_329 viruses developed resistance to plasma neutralizing antibodies (nAbs) plausibly by N160 glycan loss and V1 and V4 loop lengthening. The viruses generated from AIIMS_330 (at 90 and 117 months) showed varied susceptibility to bnAbs and autologous contemporaneous plasma antibodies, while the viruses of the 112-month time point, at which the plasma nAb specificities mapped to the V2 glycan, V3 glycan, and CD4 binding site (CD4bs), were resistant to contemporaneous plasma antibodies as well as to most bnAbs. Chimeric viruses were constructed from 90-month-time-point PG9-sensitive AIIMS_329 and AIIMS_330 viruses with swapped V1V2 regions of their respective evolved viruses (at 112 and 117 months), which led to higher resistance to neutralization by PG9 and autologous plasma antibodies. We observed the evolution of a viral pool in the AIIMS_330 donor comprising plasma antibody neutralization-sensitive or -resistant diverse autologous viruses that may have contributed to the development and maintenance of elite neutralizing activity. IMPORTANCE Herein, we report the longitudinal development of bnAbs in a pair of chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, who acquired the infection by vertical transmission. The plasma from both donors, sharing a similar genetic makeup and infecting virus, showed the evolvement of bnAbs targeting common epitopes in the V2 and V3 regions of the envelope, suggesting that bnAb development in these twins may perhaps be determined by specific sequences in the shared virus that can guide the development of immunogens aimed at eliciting V2 and V3 bNAbs. Characterization of the neutralization-sensitive and -resistant viruses coevolving with bNAbs in the contemporaneous AIIMS_330 plasma provides information toward understanding the viral alterations that may have contributed to the development of resistance to bnAbs. Further longitudinal studies in more monozygotic and dizygotic twin pairs will help in delineating the role of host and viral factors that may contribute to the development of bnAbs.

Download Full-text

Viral characteristics associated with sustenance of elite neutralizing activity in chronically HIV-1C infected monozygotic pediatric twins

10.1101/475822 ◽

2018 ◽

Cited By ~ 2

Author(s):

Nitesh Mishra ◽

Muzamil Ashraf Makhdoomi ◽

Shaifali Sharma ◽

Sanjeev Kumar ◽

Deep-shika Kumar ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Antibody Responses ◽

Autologous Plasma ◽

Neutralizing Activity ◽

Single Genome ◽

Plasma Antibody ◽

Twin Children ◽

Initial Sampling ◽

Hiv 1 ◽

Time Point

AbstractBroad and potent neutralizing antibodies (bnAbs) with multiple epitope specificities evolve in HIV-1 infected children. Herein we studied two antiretroviral naïve chronically HIV-1C in-fected monozygotic pediatric twins AIIMS_329 and AIIMS_330 with potent plasma bnAbs. Elite plasma neutralizing activity was observed since initial sampling at 78 months in AIIMS_330 and persisted throughout, while in AIIMS_329 it was seen at 90-months of age after which potency decreased overtime. We evaluated potential viral characteristics associated with the varied immune profile by generating single genome amplified pseudoviruses. The AIIMS_329 viruses generated from 90-month time point sampling were neutralization sensitive to second generation bnAbs and contemporaneous autologous plasma antibodies, while viruses from 112-months and 117-month timepoints were resistant to most bnAbs and autologous contemporaneous plasma. AIIMS_329 viruses developed resistance to plasma nAbs plausibly by N160-glycan loss, V1- and V4-loop lengthening. The viruses generated from AIIMS_330 at 90-month and 117-month timepoint showed varied susceptibility to bnAbs and autologous contemporaneous plasma antibodies while the viruses of 112-month timepoint, at which plasma nAb specificities mapped to the V2-glycan, V3-glycan and CD4bs, were resistant to autologous contemporaneous plasma antibodies as well as most bnAbs. We observed evolution of a viral pool in AIIMS_330 donor, comprising of plasma antibody neutralization sensitive or resistant diverse autologous viruses that in turn may have contributed to development and maintenance of elite neutralizing activity. The findings of this study provide information towards understanding factors involved in generation and maintenance of potent plasma nAbs.ImportanceChronically HIV-1 infected children that develop elite neutralizing activity are suitable candidates to understand the mechanisms that lead to the co-evolution of virus and antibody response. Here, we evaluated the alterations in virus and antibody responses over time in chronically HIV-1C infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, who had acquired the infection by vertical transmission. AIIMS_330 retained the elite plasma neutralizing activity throughout, while in AIIMS_329, the potency decreased post 90 months of age. The corresponding viral pool from post 90-month samples in AIIMS_330 showed varied susceptibility, while that in AIIMS_329, developed resistance to bnAbs and autologous plasma antibodies. The findings of this study, conducted in twin children of same genetic make-up and infected at birth with a single source of HIV-1C, suggest that a viral pool with varied susceptibility to antibodies could have been one of the factors responsible for sustained elite neutralizing activity in AIIMS_330.

Download Full-text

Griffithsin Retains Anti-HIV-1 Potency with Changes in gp120 Glycosylation and Complements Broadly Neutralizing Antibodies PGT121 and PGT126

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01084-19 ◽

2019 ◽

Vol 64 (1) ◽

Cited By ~ 1

Author(s):

Kathryn Fischer ◽

Kimberly Nguyen ◽

Patricia J. LiWang

Keyword(s):

Neutralizing Antibodies ◽

Glycosylation Site ◽

Significant Loss ◽

Broadly Neutralizing Antibodies ◽

Clade B ◽

Key Factor ◽

Clade C ◽

Cd4 Binding Site ◽

Gp120 Glycosylation ◽

Hiv 1

ABSTRACT Griffithsin (Grft) is an antiviral lectin that has been shown to potently inhibit HIV-1 by binding high-mannose N-linked glycosylation sites on HIV-1 gp120. A key factor for Grft potency is glycosylation at N295 of gp120, which is directly adjacent to N332, a target glycan for an entire class of broadly neutralizing antibodies (bNAbs). Here, we unify previous work on the importance of other glycans to Grft potency against HIV-1 and Grft’s role in mediating the conformational change of gp120 by mutating nearly every glycosylation site in gp120. In addition to a significant loss of Grft activity by the removal of glycosylation at N295, glycan absence at N332 or N448 was found to have moderate effects on Grft potency. Interestingly, in the absence of N295, Grft effectiveness could be improved by a mutation that results in the glycan at N448 shifting to N446, indicating that the importance of individual glycans may be related to their effect on glycosylation density. Grft’s ability to alter the structure of gp120, exposing the CD4 binding site, correlated with the presence of glycosylation at N295 only in clade B strains, not clade C strains. We further demonstrate that Grft can rescue the activity of the bNAbs PGT121 and PGT126 in the event of a loss or a shift of glycosylation at N332, where the bNAbs suffer a drastic loss of potency. Despite targeting the same region, Grft in combination with PGT121 and PGT126 produced additive effects. This indicates that Grft could be an important combinational therapeutic.

Download Full-text

Broadly Neutralizing Antibody Responses in a Subset of HIV-1-Infected Individuals in Chennai, India

Journal of the International Association of Providers of AIDS Care (JIAPAC) ◽

10.1177/1545109712467695 ◽

2016 ◽

Vol 16 (2) ◽

pp. 201-208

Author(s):

Syed Iqbal Hussain ◽

Nandagopal Panneerselvam ◽

Suniti Solomon ◽

Sunil S. Solomon ◽

Kaavya Adam ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Effective Vaccine ◽

Tier 2 ◽

Neutralizing Activity ◽

Tier 1 ◽

Clade C ◽

Treatment Naïve ◽

Broadly Neutralizing Antibody ◽

Hiv 1

Identification of broadly neutralizing antibodies (NAbs) generated during the course of HIV-1 infection is essential for effective HIV-1 vaccine design. The magnitude and breadth of neutralizing activity in the sera from 46 antiretroviral treatment–naive HIV-1 clade C-infected individuals was measured in a single round infection assay using TZM-bl cells and multisubtype panel of env-pseudotyped viruses. Higher levels of NAb response (NAb titer 500 to >40 000) were measured in these patients against tier 1 and tier 2 viruses. The average magnitude of the NAb responses of chronically infected individuals against heterologous viruses was consistently higher than the response observed from individuals with long-term nonprogressor ( P = .086). To conclude, high titers of HIV-1 cross-neutralizing activity were observed in the sera from a subset of HIV-1-infected individuals in Chennai, India. Additional studies of the epitopes recognized by these antibodies may facilitate the discovery of an effective vaccine immunogen.

Download Full-text

Germline VRC01 antibody recognition of a modified clade C HIV-1 envelope trimer and a glycosylated HIV-1 gp120 core

eLife ◽

10.7554/elife.37688 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 14

Author(s):

Andrew J Borst ◽

Connor E Weidle ◽

Matthew D Gray ◽

Brandon Frenz ◽

Joost Snijder ◽

...

Keyword(s):

Neutralizing Antibodies ◽

X Ray Crystallography ◽

Antibody Recognition ◽

Immunodeficiency Virus ◽

Gp120 Core ◽

Clade C ◽

Immunogen Design ◽

Cd4 Binding Site ◽

Variable Loops ◽

Hiv 1

VRC01 broadly neutralizing antibodies (bnAbs) target the CD4-binding site (CD4BS) of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (Env). Unlike mature antibodies, corresponding VRC01 germline precursors poorly bind to Env. Immunogen design has mostly relied on glycan removal from trimeric Env constructs and has had limited success in eliciting mature VRC01 bnAbs. To better understand elicitation of such bnAbs, we characterized the inferred germline precursor of VRC01 in complex with a modified trimeric 426c Env by cryo-electron microscopy and a 426c gp120 core by X-ray crystallography, biolayer interferometry, immunoprecipitation, and glycoproteomics. Our results show VRC01 germline antibodies interacted with a wild-type 426c core lacking variable loops 1–3 in the presence and absence of a glycan at position Asn276, with the latter form binding with higher affinity than the former. Interactions in the presence of an Asn276 oligosaccharide could be enhanced upon carbohydrate shortening, which should be considered for immunogen design.

Download Full-text

Virus Evolution and Neutralization Sensitivity in an HIV-1 Subtype B′ Infected Plasma Donor with Broadly Neutralizing Activity

Vaccines ◽

10.3390/vaccines9040311 ◽

2021 ◽

Vol 9 (4) ◽

pp. 311

Author(s):

Yuanyuan Hu ◽

Sen Zou ◽

Zheng Wang ◽

Ying Liu ◽

Li Ren ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Neutralization Sensitivity ◽

Autologous Plasma ◽

Neutralizing Activity ◽

Humoral Immune ◽

Immune Pressure ◽

Subtype B ◽

Immunogen Design ◽

Plasma Donor ◽

Hiv 1

We sought to analyze the evolutionary characteristics and neutralization sensitivity of viruses in a human immunodeficiency virus type 1 (HIV-1) subtype B′ infected plasma donor with broadly neutralizing activity, which may provide information for new broadly neutralizing antibodies (bNAbs) isolation and immunogen design. A total of 83 full-length envelope genes were obtained by single-genome amplification (SGA) from the patient’s plasma at three consecutive time points (2005, 2006, and 2008) spanning four years. In addition, 28 Env-pseudotyped viruses were constructed and their neutralization sensitivity to autologous plasma and several representative bNAbs were measured. Phylogenetic analysis showed that these env sequences formed two evolutionary clusters (Cluster I and II). Cluster I viruses vanished in 2006 and then appeared as recombinants two years later. In Cluster II viruses, the V1 length and N-glycosylation sites increased over the four years of the study period. Most viruses were sensitive to concurrent and subsequent autologous plasma, and to bNAbs, including 10E8, PGT121, VRC01, and 12A21, but all viruses were resistant to PGT135. Overall, 90% of Cluster I viruses were resistant to 2G12, while 94% of Cluster II viruses were sensitive to 2G12. We confirmed that HIV-1 continued to evolve even in the presence of bNAbs, and two virus clusters in this donor adopted different escape mechanisms under the same humoral immune pressure.

Download Full-text

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.

Download Full-text

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

Download Full-text

A Novel MVA-Based HIV Vaccine Candidate (MVA-gp145-GPN) Co-Expressing Clade C Membrane-Bound Trimeric gp145 Env and Gag-Induced Virus-Like Particles (VLPs) Triggered Broad and Multifunctional HIV-1-Specific T Cell and Antibody Responses

Viruses ◽

10.3390/v11020160 ◽

2019 ◽

Vol 11 (2) ◽

pp. 160 ◽

Cited By ~ 4

Author(s):

Beatriz Perdiguero ◽

Cristina Sánchez-Corzo ◽

Carlos Sorzano ◽

Lidia Saiz ◽

Pilar Mediavilla ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Candidate ◽

Hiv Vaccine ◽

Replication Capacity ◽

Virus Like Particles ◽

Modified Vaccinia Virus Ankara ◽

Clade C ◽

Membrane Bound ◽

Hiv 1

The development of an effective Human Immunodeficiency Virus (HIV) vaccine that is able to stimulate both the humoral and cellular HIV-1-specific immune responses remains a major priority challenge. In this study, we described the generation and preclinical evaluation of single and double modified vaccinia virus Ankara (MVA)-based candidates expressing the HIV-1 clade C membrane-bound gp145(ZM96) trimeric protein and/or the Gag(ZM96)-Pol-Nef(CN54) (GPN) polyprotein that was processed to form Gag-induced virus-like particles (VLPs). In vitro characterization of MVA recombinants revealed the stable integration of HIV-1 genes without affecting its replication capacity. In cells that were infected with Env-expressing viruses, the gp145 protein was inserted into the plasma membrane exposing critical epitopes that were recognized by broadly neutralizing antibodies (bNAbs), whereas Gag-induced VLPs were released from cells that were infected with GPN-expressing viruses. VLP particles as well as purified MVA virions contain Env and Gag visualized by immunoelectron microscopy and western-blot of fractions that were obtained after detergent treatments of purified virus particles. In BALB/c mice, homologous MVA-gp145-GPN prime/boost regimen induced broad and polyfunctional Env- and Gag-specific CD4 T cells and antigen-specific T follicular helper (Tfh) and Germinal Center (GC) B cells, which correlated with robust HIV-1-specific humoral responses. Overall, these results support the consideration of MVA-gp145-GPN vector as a potential vaccine candidate against HIV-1.

Download Full-text

Induction of Primary Virus-Cross-Reactive Human Immunodeficiency Virus Type 1-Neutralizing Antibodies in Small Animals by Using an Alphavirus-Derived In Vivo Expression System

Journal of Virology ◽

10.1128/jvi.77.5.3119-3130.2003 ◽

2003 ◽

Vol 77 (5) ◽

pp. 3119-3130 ◽

Cited By ~ 40

Author(s):

Ming Dong ◽

Peng Fei Zhang ◽

Franziska Grieder ◽

James Lee ◽

Govindaraj Krishnamurthy ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Neutralizing Activity ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Primary Virus

ABSTRACT We have studied the induction of neutralizing antibodies by in vivo expression of the human immunodeficiency virus type 1 (HIV-1) envelope by using a Venezuelan equine encephalitis virus (VEE) replicon system with mice and rabbits. The HIV-1 envelope, clone R2, has broad sensitivity to cross-reactive neutralization and was obtained from a donor with broadly cross-reactive, primary virus-neutralizing antibodies (donor of reference serum, HIV-1-neutralizing serum 2 [HNS2]). It was expressed as gp160, as secreted gp140, and as gp160ΔCT with the cytoplasmic tail deleted. gp140 was expressed in vitro at a high level and was predominantly uncleaved oligomer. gp160ΔCT was released by cells in the form of membrane-bound vesicles. gp160ΔCT induced stronger neutralizing responses than the other forms. Use of a helper plasmid for replicon particle packaging, in which the VEE envelope gene comprised a wild-type rather than a host range-adapted sequence, also enhanced immunogenicity. Neutralizing activity fractionated with immunoglobulin G. This activity was cross-reactive among a panel of five nonhomologous primary clade B strains and a Chinese clade C strain and minimally reactive against a Chinese clade E (circulating recombinant form 1) strain. The comparative neutralization of these strains by immune mouse sera was similar to the relative neutralizing effects of HNS2, and responses induced in rabbits were similar to those induced in mice. Together, these results demonstrate that neutralizing antibody responses can be induced in mice within 2 to 3 months that are similar in potency and cross-reactivity to those found in the chronically infected, long-term nonprogressive donor of HNS2. These findings support the expectation that induction of highly cross-reactive HIV-1 primary virus-neutralizing activity by vaccination may be realized.

Download Full-text

Neutralization Properties of Simian Immunodeficiency Viruses Infecting Chimpanzees and Gorillas

mBio ◽

10.1128/mbio.00296-15 ◽

2015 ◽

Vol 6 (2) ◽

Cited By ~ 17

Author(s):

Hannah J. Barbian ◽

Julie M. Decker ◽

Frederic Bibollet-Ruche ◽

Rachel P. Galimidi ◽

Anthony P. West ◽

...

Keyword(s):

T Cells ◽

Binding Site ◽

Pan Troglodytes ◽

Neutralizing Antibodies ◽

Gorilla Gorilla ◽

Protective Capacity ◽

Content Type ◽

Ccr5 Receptor ◽

Cd4 Binding Site ◽

Hiv 1

ABSTRACTBroadly cross-reactive neutralizing antibodies (bNabs) represent powerful tools to combat human immunodeficiency virus type 1 (HIV-1) infection. Here, we examined whether HIV-1-specific bNabs are capable of cross-neutralizing distantly related simian immunodeficiency viruses (SIVs) infecting central (Pan troglodytestroglodytes) (SIVcpzPtt) and eastern (Pan troglodytesschweinfurthii) (SIVcpzPts) chimpanzees (n= 11) as well as western gorillas (Gorilla gorilla gorilla) (SIVgor) (n= 1). We found that bNabs directed against the CD4 binding site (n= 10), peptidoglycans at the base of variable loop 3 (V3) (n= 5), and epitopes at the interface of surface (gp120) and membrane-bound (gp41) envelope glycoproteins (n= 5) failed to neutralize SIVcpz and SIVgor strains. In addition, apex V2-directed bNabs (n= 3) as well as llama-derived (heavy chain only) antibodies (n= 6) recognizing both the CD4 binding site and gp41 epitopes were either completely inactive or neutralized only a fraction of SIVcpzPttstrains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Igmim2, CD4-218.3-E51, and CD4-218.3-E51-mim2), as well as mono- and bispecific anti-human CD4 (iMab and LM52) and CCR5 (PRO140, PRO140-10E8) receptor antibodies neutralized >90% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4+T cells, with 50% inhibitory concentrations (IC50s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection.IMPORTANCESIVcpz is widespread in wild-living chimpanzees and can cause AIDS-like immunopathology and clinical disease. HIV-1 infection of humans can be controlled by antiretroviral therapy; however, treatment of wild-living African apes with current drug regimens is not feasible. Nonetheless, it may be possible to curb the spread of SIVcpz in select ape communities using vectored immunoprophylaxis and/or therapy. Here, we show that antibodies and antibody-like inhibitors developed to combat HIV-1 infection in humans are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4+T cells. These reagents provide an important first step toward translating intervention strategies currently developed to treat and prevent AIDS in humans to SIV-infected apes.

Download Full-text