116 results on '"Bibollet-Ruche F"'
Search Results
2. Loss of CXCR6 coreceptor usage characterizes pathogenic lentiviruses
- Author
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Wetzel, K. S., Yi, Y. J., Yadav, A., Bauer, A. M., Bello, E. A., Romero, D. C., Bibollet-Ruche, F., Hahn, B. H., Paiardini, M., Silvestri, G., Peeters, Martine, and Collman, R. G.
- Subjects
viruses ,virus diseases - Abstract
Pandemic HIV-1 originated from the cross-species transmission of SIVcpz, which infects chimpanzees, while SIVcpz itself emerged following the cross-species transmission and recombination of monkey SIVs, with env contributed by the SIVgsn/mus/mon lineage that infects greater spot-nosed, mustached and mona monkeys. SIVcpz and HIV-1 are pathogenic in their respective hosts, while the phenotype of their SIVgsn/mus/mon ancestors is unknown. However, two well-studied SIV infected natural hosts, sooty mangabeys (SMs) and African green monkeys (AGMs), typically remain healthy despite high viral loads; these species express low levels of the canonical coreceptor CCR5, and recent work shows that CXCR6 is a major coreceptor for SIV in these hosts. It is not known what coreceptors were used by the precursors of SIVcpz, whether coreceptor use changed during emergence of the SIVcpz/HIV-1 lineage, and what T cell subsets express CXCR6 in natural hosts. Using species-matched coreceptors and CD4, we show here that SIVcpz uses only CCR5 for entry and, like HIV-1, cannot use CXCR6. In contrast, SIVmus efficiently uses both CXCR6 and CCR5. Coreceptor selectivity was determined by Env, with CXCR6 use abrogated by Pro326 in the V3 crown, which is absent in monkey SIVs but highly conserved in SIVcpz/HIV-1. To characterize which cells express CXCR6, we generated a novel antibody that recognizes CXCR6 of multiple primate species. Testing lymphocytes from SM, the best-studied natural host, we found that CXCR6 is restricted to CD4+ effector memory cells, and is expressed by a sub-population distinct from those expressing CCR5. Thus, efficient CXCR6 use, previously identified in SM and AGM infection, also characterizes a member of the SIV lineage that gave rise to SIVcpz/HIV-1. Loss of CXCR6 usage by SIVcpz may have altered its cell tropism, shifting virus from CXCR6-expressing cells that may support replication without disrupting immune function or homeostasis, towards CCR5-expressing cells with pathogenic consequences.
- Published
- 2018
3. Chimpanzee reservoirs of pandemic and nonpandemic HIV-1
- Author
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Keele, B. F., Van Heuverswyn, F., Li, Y.Y., Bailes, E., Takehisa, J., Santiago, M. L., Bibollet Ruche, F., Chen, Y. L., Wain, L. V., Liégeois, Florian, Loul, S., Mpoudi Ngolé, E., Bienvenue, Y., Delaporte, Eric, Brookfield, J. F. Y., Sharp, P. M., Shaw, G. M., Peeters, Martine, and Hahn, B. H.
- Abstract
Human immunodeficiency virus type 1 (HIV-1), the cause of human acquired immunodeficiency syndrome ( AIDS), is a zoonotic infection of staggering proportions and social impact. Yet uncertainty persists regarding its natural reservoir. The virus most closely related to HIV-1 is a simian immunodeficiency virus ( SIV) thus far identified only in captive members of the chimpanzee subspecies Pan troglodytes troglodytes. Here we report the detection of SIVcpz antibodies and nucleic acids in fecal samples from wild-living P.t. troglodytes apes in southern Cameroon, where prevalence rates in some communities reached 29 to 35%. By sequence analysis of endemic SIVcpz strains, we could trace the origins of pandemic ( group M) and nonpandemic ( group N) HIV-1 to distinct, geographically isolated chimpanzee communities. These findings establish P. t. troglodytes as a natural reservoir of HIV-1.
- Published
- 2006
4. Widely varying SIV prevalence rates in naturally infected primate species from Cameroon
- Author
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Aghokeng Fobang, Avelin, Liu, W.M., Bibollet Ruche, F., Loul, S., Mpoudi Ngolé, E., Laurent, Christian, Mwenda, J.M., Langat, D.K., Chege, G.K., McClure, H.M., Delaporte, Eric, Shaw, G.M., Hahn, B.H., and Peeters, Martine
- Subjects
non human primates ,SIV ,prevalence ,HIV ,Cameroon - Abstract
Although it is now well established that a substantial proportion of wild-living primates in sub-Saharan Africa harbor SIV, no study to date has examined to what extent the various species are naturally infected. In this study, we first describe the development and validation of sensitive and specific SIV antibody detection assays representing all major known primate lentiviral lineages on a panel of 207 sera from 11 different primate species with known infection status. The newly developed assays were then used to determine SIV prevalence rates in nine primate species native to Cameroon. Analysis of 722 sera revealed widely varying prevalence rates, ranging from an apparent absence of SIV infection in crested mona (0/70), grey checked (0/36) and agile mangabeys (0/92), to prevalence rates of 3%, 4%, 11%, 27%, 39% and 52% for mustached (6/203), greater spot-nosed (8/193), northern talapoin (3/26), mantled guereza (14/52), De Brazza's (9/23) and mandrill (14/27) monkeys, respectively. The epidemiology of naturally occurring SIV infections is thus more complex than previously appreciated and the various non-human primate hosts seem to differ in their susceptibility to SIV infection. The newly developed assays should now permit to define with greater accuracy existing SIV reservoirs and associated human zoonotic risk. (C) 2005 Elsevier Inc. All rights reserved.
- Published
- 2006
5. Hybrid origin of SIV in chimpanzees
- Author
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Bailes, E., Gao, F., Bibollet-Ruche, F., Courgnaud, V., Peeters, M., Marx, Pa, Hahn, Bh, and Paul Sharp
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GENOME ,SIDA ,RECOMBINAISON GENETIQUE ,VIRUS ,PRIMATE ,PHYLOGENIE ,ANALYSE GENETIQUE - Published
- 2003
6. Multiple spliced env and nef transcripts of simian immunodeficiency virus from West African green monkey (SIVagm-sab)
- Author
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Bibollet-Ruche, F., Cuny, Gérard, Pourrut, Xavier, Brengues, Cécile, Galat-Luong, Anh, Galat, Gérard, and Delaporte, Eric
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PATHOGENIE ,viruses ,POLYMORPHISME GENETIQUE ,SIV.VIRUS IMMUNODEFICIENCE SIMIENNE ,VIRUS ,SINGE VERT ,MUTATION ,EXPRESSION GENETIQUE - Abstract
We have characterized the spliced transcripts of nef and envelope genes of SIVagm from African green monkey of the #sabaeus$ subspecies. Most of the transcripts we have studied, representing the most abundant mRNA species in our assay, have undergone a specific splicing event that removes a part of the trans-activation response (TAR) element. This region is predicted to form a stable secondary structure (four stem-loop elements in SIVagm-sab) that affects the trans-activation of viral gene expression by Tat and the translation of the viral transcripts. Contrary to what is observed in other viruses, in which this R-region splicing has also been described (e.g. , HIV-2), the LTR splicing in SIVagm-sab removes part of the first stem-loop and the following ones, nearly completely disrupting the TAR element secondary structure. Because LTR splicing seems to be a conserved feature among the strains we have characterized, these results suggest that this phenomenon could have important consequences for virus replication, pathogenicity, and latency. (Résumé d'auteur)
- Published
- 1998
7. An isolate of human immunodeficiency virus type 1 originally classified as subtype I represents a complex mosaic comprising three different group M subtypes (A, G, and I)
- Author
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Gao, F., Robertson, D. L., Carruthers, C. D., Li, Y., Bailes, E., Kostrikis, Leontios G., Salminen, M. O., Bibollet-Ruche, F., Peeters, M., Ho, David D., Shaw, G. M., Sharp, P. M., Hahn, B. H., and Kostrikis, Leontios G. [0000-0002-5340-7109]
- Subjects
Male ,virus virulence ,sequence analysis ,HIV Infections ,intravenous drug abuse ,gene sequence ,Genome, Viral ,human immunodeficiency virus infection ,phylogeny ,Genes, env ,human immunodeficiency virus prevalence ,geographic distribution ,Epidemiology, Molecular ,Humans ,human ,infection risk ,strain difference ,DNA Primers ,Recombination, Genetic ,nonhuman ,Base Sequence ,Mosaicism ,article ,nucleotide sequence ,homosexuality ,priority journal ,africa ,virus characterization ,HIV-1 ,Female ,cyprus - Abstract
Full-length reference clones and sequences are currently available for eight human immunodeficiency virus type 1 (HIV-1) group M subtypes (A through H), but none have been reported for subtypes I and J, which have only been identified in a few individuals. Phylogenetic information for subtype I, in particular, is limited since only about 400 bp of env gene sequences have been determined for just two epidemiologically linked viruses infecting a couple who were heterosexual intravenous drug users from Cyprus. To characterize subtype I in greater detail, we employed long-range PCR to clone a full-length provirus (94CY032.3) from an isolate obtained from one of the individuals originally reported to be infected with this subtype. Phylogenetic analysis of C2-V3 env gene sequences confirmed that 94CY032.3 was closely related to sequences previously classified as subtype I. However, analysis of the remainder of its genome revealed various regions in which 94CY032.3 was significantly clustered with either subtype A or subtype G. Only sequences located in vpr and nef, as well as the middle portions of pol and env, formed independent lineages roughly equidistant from all other known subtypes. Since these latter regions most likely have a common origin, we classify them all as subtype I. These results thus indicate that the originally reported prototypic subtype I isolate 94CY032 represents a triple recombinant (A/G/I) with at least 11 points of recombination crossover. We also screened HIV-1 recombinants with regions of uncertain subtype assignment for the presence of subtype I sequences. This analysis revealed that two of the earliest mosaics from Africa, Z321B (A/G/?) and MAL (A/D/?), contain short segments of sequence which clustered closely with the subtype I domains of 94CY032.3. Since Z321 was isolated in 1976, subtype I as well as subtypes A and G must have existed in Central Africa prior to that date. The discovery of subtype I in HIV-1 hybrids from widely distant geographic locations also suggests a more widespread distribution of this virus subtype, or at least segments of it, than previously recognized. 72 10234 10241 Cited By :81
- Published
- 1998
8. Neutralizing Antibody Responses in Acute Human Immunodeficiency Virus Type 1 Subtype C Infection
- Author
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Gray, E. S., primary, Moore, P. L., additional, Choge, I. A., additional, Decker, J. M., additional, Bibollet-Ruche, F., additional, Li, H., additional, Leseka, N., additional, Treurnicht, F., additional, Mlisana, K., additional, Shaw, G. M., additional, Karim, S. S. Abdool, additional, Williamson, C., additional, and Morris, L., additional
- Published
- 2007
- Full Text
- View/download PDF
9. CO20 - Chimpanzés, réservoirs des formes pandémiques et non pandémiques du VIH-1
- Author
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Keele, B.F., primary, Van Heuverswyn, F., additional, Li, Y., additional, Bailes, E., additional, Takehisa, J., additional, Santiago, M.L., additional, Bibollet-Ruche, F., additional, Chen, Y., additional, Wain, L.V., additional, Liegeois, F., additional, Loul, S., additional, Mpoudi Ngole, E., additional, Bienvenue, Y., additional, Delaporte, E., additional, Brookfield, J.F.Y., additional, Sharp, P.M., additional, Shaw, G.M., additional, Peeters, M., additional, and Hahn, B.H., additional
- Published
- 2007
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10. Genetic diversity of simian immunodeficiency viruses from West African green monkeys: evidence of multiple genotypes within populations from the same geographical locale
- Author
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Bibollet-Ruche, F, primary, Brengues, C, additional, Galat-Luong, A, additional, Galat, G, additional, Pourrut, X, additional, Vidal, N, additional, Veas, F, additional, Durand, J P, additional, and Cuny, G, additional
- Published
- 1997
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11. Simian immunodeficiency virus infection in a patas monkey (Erythrocebus patas): evidence for cross-species transmission from African green monkeys (Cercopithecus aethiops sabaeus) in the wild
- Author
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Bibollet-Ruche, F., primary, Galat-Luong, A., additional, Cuny, G., additional, Sarni-Manchado, P., additional, Galat, G., additional, Durand, J.-P., additional, Pourrut, X., additional, and Veas, F., additional
- Published
- 1996
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12. Regulatory genes of simian immunodeficiency viruses from west African green monkeys (Cercopithecus aethiops sabaeus)
- Author
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Jubier-Maurin, V, primary, Sarni-Manchado, P, additional, Veas, F, additional, Vidal, N, additional, Bibollet-Ruche, F, additional, Durand, J P, additional, Galat-Luong, A, additional, and Cuny, G, additional
- Published
- 1995
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13. Social Organisation and SIV Sero-Epidemiology of a Patas Monkey Population in Senegal
- Author
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Galat-Luong, A., primary, Bibollet-Ruche, F., additional, Pourrut, X., additional, Durand, J.P., additional, Sarni, P., additional, Pichon, G., additional, and Galat, G., additional
- Published
- 1994
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14. Ganciclovir resistance and UL97 gene mutations in cytomegalovirus blood isolates from patients with AIDS treated with ganciclovir
- Author
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Abraham, B., Lastere, S., Reynes, J., Bibollet-Ruche, F., Vidal, N., and Segondy, M.
- Published
- 1999
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15. Detection of HIV1 RNA in Two Consecutive Blood Donations Screened Negative for HIV Antibodies
- Author
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Roziers, N. Burin des, Coste, J., Courouce, A.-M., BibolletRuche, F., Guillard, A., and Nasr, O.
- Abstract
AbstractBackground and Objectives: An unusual serological pattern of HIV1 seroconversion in a blood donor is described. The seroconversion panel was used to investigate the sensitivity of existing screening assays. Materials and Methods: A volunteer blood donor who had given blood 79 times was diagnosed antiHIV1antibodypositive. The heteroduplex mobility assay identified a subtype B HIV1 strain. The frozen plasmas from the last four blood donations had been kept at 30°C. They were thawed and aliquoted for subsequent testing. Results: The last two blood donations contained HIV1 RNA, 2,800 copies/ml (October 26) and 170 copies/ml (November 23). Weak antip24 antibodies were detected by Western blot in the October 26 sample, and a clear p24 reactivity along with a faint gp160 reactivity was observed on November 23. HIV p24 antigen was undetectable in both samples. Out of 13 screening assays, only 6 gave positive results on the November sample and 7 negative results which were obtained by 1 competitive enzyme immunoassay (EIA) and 6 of the 9 sandwich EIAs. Conclusion: Most sandwich EIAs gave prolonged falsenegative results in the present case. p24 antigen testing was negative and would not have reduced the risk of HIV transmission. - Published
- 1998
16. Subtype-specific polymerase chain reaction for the identification of HIV-1 genetic subtypes circulating in Africa
- Author
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Peeters, M., Liegeois, F., Bibollet-Ruche, F., Patrel, D., Vidal, N., Esu-Wiliams, E., Mboup, S., Ngole, E. M., Koumare, B., Nzila, N., Perret, J. L., and Eric Delaporte
- Subjects
Africa ,HIV-1 ,Nucleic Acid Heteroduplexes ,Humans ,RNA, Viral ,HIV Infections ,Sequence Analysis, DNA ,Polymerase Chain Reaction
17. Nef-mediated TCR-CD3 and MHC-I down-modulation prevents CD4+ T cell depletion in natural SIV infection
- Author
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Sharp Paul, Sodora Donald L, Roques Pierre, Bailes Elizabeth, Courgnaud Valerie, Peeters Martine, Novembre Francis J, Müller-Trutwin Michaela C, Bibollet-Ruche Frederic, Santiago Mario L, Li Hui, Kutsch Olaf, Münch Jan, Schindler Michael, Silvestri Guido, Hahn Beatrice H, and Kirchhoff Frank
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Published
- 2006
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18. HIV-1 neutralizing antibodies in SHIV-infected macaques recapitulate structurally divergent modes of human V2 apex recognition with a single D gene.
- Author
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Roark RS, Habib R, Gorman J, Li H, Connell AJ, Bonsignori M, Guo Y, Hogarty MP, Olia AS, Sowers K, Zhang B, Bibollet-Ruche F, Callaghan S, Carey JW, Cerutti G, Harris DR, He W, Lewis E, Liu T, Mason RD, Park Y, Rando JM, Singh A, Wolff J, Lei QP, Louder MK, Doria-Rose NA, Andrabi R, Saunders KO, Seaman MS, Haynes BF, Kulp DW, Mascola JR, Roederer M, Sheng Z, Hahn BH, Shaw GM, Kwong PD, and Shapiro L
- Abstract
Broadly neutralizing antibodies targeting the V2 apex of the HIV-1 envelope trimer are among the most common specificities elicited in HIV-1-infected humans and simian-human immunodeficiency virus (SHIV)-infected macaques. To gain insight into the prevalent induction of these antibodies, we isolated and characterized 11 V2 apex-directed neutralizing antibody lineages from SHIV-infected rhesus macaques. Remarkably, all SHIV-induced V2 apex lineages were derived from reading frame two of the rhesus DH3-15*01 gene. Cryo-EM structures of envelope trimers in complex with antibodies from nine rhesus lineages revealed modes of recognition that mimicked three canonical human V2 apex-recognition modes. Notably, amino acids encoded by DH3-15*01 played divergent structural roles, inserting into a hole at the trimer apex, H-bonding to an exposed strand, or forming part of a loop scaffold. Overall, we identify a DH3-15*01-signature for rhesus V2 apex broadly neutralizing antibodies and show that highly selected genetic elements can play multiple roles in antigen recognition., Highlights: Isolated 11 V2 apex-targeted HIV-neutralizing lineages from 10 SHIV-infected Indian-origin rhesus macaquesCryo-EM structures of Fab-Env complexes for nine rhesus lineages reveal modes of recognition that mimic three modes of human V2 apex antibody recognitionAll SHIV-elicited V2 apex lineages, including two others previously published, derive from the same DH3-15*01 gene utilizing reading frame twoThe DH3-15*01 gene in reading frame two provides a necessary, but not sufficient, signature for V2 apex-directed broadly neutralizing antibodiesStructural roles played by DH3-15*01-encoded amino acids differed substantially in different lineages, even for those with the same recognition modePropose that the anionic, aromatic, and extended character of DH3-15*01 in reading frame two provides a selective advantage for V2 apex recognition compared to B cells derived from other D genes in the naïve rhesus repertoireDemonstrate that highly selected genetic elements can play multiple roles in antigen recognition, providing a structural means to enhance recognition diversity.
- Published
- 2024
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19. Single-cell transcriptomics identifies prothymosin α restriction of HIV-1 in vivo.
- Author
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Geretz A, Ehrenberg PK, Clifford RJ, Laliberté A, Prelli Bozzo C, Eiser D, Kundu G, Yum LK, Apps R, Creegan M, Gunady M, Shangguan S, Sanders-Buell E, Sacdalan C, Phanuphak N, Tovanabutra S, Russell RM, Bibollet-Ruche F, Robb ML, Michael NL, Ake JA, Vasan S, Hsu DC, Hahn BH, Kirchhoff F, and Thomas R
- Subjects
- Humans, Transcriptome genetics, RNA, Viral, HIV-1 genetics, HIV Infections genetics
- Abstract
Host restriction factors play key roles in innate antiviral defense, but it remains poorly understood which of them restricts HIV-1 in vivo. Here, we used single-cell transcriptomic analysis to identify host factors associated with HIV-1 control during acute infection by correlating host gene expression with viral RNA abundance within individual cells. Wide sequencing of cells from one participant with the highest plasma viral load revealed that intracellular viral RNA transcription correlates inversely with expression of the gene PTMA , which encodes prothymosin α. This association was genome-wide significant ( P
adjusted < 0.05) and was validated in 28 additional participants from Thailand and the Americas with HIV-1 CRF01_AE and subtype B infections, respectively. Overexpression of prothymosin α in vitro confirmed that this cellular factor inhibits HIV-1 transcription and infectious virus production. Our results identify prothymosin α as a host factor that restricts HIV-1 infection in vivo, which has implications for viral transmission and cure strategies.- Published
- 2023
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20. A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies.
- Author
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Bibollet-Ruche F, Russell RM, Ding W, Liu W, Li Y, Wagh K, Wrapp D, Habib R, Skelly AN, Roark RS, Sherrill-Mix S, Wang S, Rando J, Lindemuth E, Cruickshank K, Park Y, Baum R, Carey JW, Connell AJ, Li H, Giorgi EE, Song GS, Ding S, Finzi A, Newman A, Hernandez GE, Machiele E, Cain DW, Mansouri K, Lewis MG, Montefiori DC, Wiehe KJ, Alam SM, Teng IT, Kwong PD, Andrabi R, Verkoczy L, Burton DR, Korber BT, Saunders KO, Haynes BF, Edwards RJ, Shaw GM, and Hahn BH
- Subjects
- Humans, Animals, Mice, Broadly Neutralizing Antibodies, HIV Antibodies, Pan troglodytes metabolism, Macaca mulatta, Antibodies, Neutralizing, Epitopes, Glycoproteins, env Gene Products, Human Immunodeficiency Virus, HIV Infections, HIV-1
- Abstract
HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germ line-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-expressing knock-in mice and as chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) in rhesus macaques (RMs). Trimer immunization of knock-in mice induced V2-directed NAbs, indicating activation of V2-apex bNAb precursor-expressing mouse B cells. SCIV infection of RMs elicited high-titer viremia, potent autologous tier 2 neutralizing antibodies, and rapid sequence escape in the canonical V2-apex epitope. Six of seven animals also developed low-titer heterologous plasma breadth that mapped to the V2-apex. Antibody cloning from two of these animals identified multiple expanded lineages with long heavy chain third complementarity determining regions that cross-neutralized as many as 7 of 19 primary HIV-1 strains, but with low potency. Negative stain electron microscopy (NSEM) of members of the two most cross-reactive lineages confirmed V2 targeting but identified an angle of approach distinct from prototypical V2-apex bNAbs, with antibody binding either requiring or inducing an occluded-open trimer. Probing with conformation-sensitive, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency. IMPORTANCE An effective HIV-1 vaccination strategy will need to stimulate rare precursor B cells of multiple bNAb lineages and affinity mature them along desired pathways. Here, we searched for V2-apex germ line-targeting Envs among a large set of diverse primate lentiviruses and identified minimally modified versions of one chimpanzee SIV Env that bound several human V2-apex bNAb precursors and stimulated one of these in a V2-apex bNAb precursor-expressing knock-in mouse. We also generated chimeric simian-chimpanzee immunodeficiency viruses and showed that they elicit low-titer V2-directed heterologous plasma breadth in six of seven infected rhesus macaques. Characterization of this antibody response identified a new class of weakly cross-reactive neutralizing antibodies that target the V2-apex, but only in occluded-open Env trimers. The existence of this cryptic epitope, which in some Env backgrounds is immunodominant, needs to be considered in immunogen design.
- Published
- 2023
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21. Evasion of cGAS and TRIM5 defines pandemic HIV.
- Author
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Zuliani-Alvarez L, Govasli ML, Rasaiyaah J, Monit C, Perry SO, Sumner RP, McAlpine-Scott S, Dickson C, Rifat Faysal KM, Hilditch L, Miles RJ, Bibollet-Ruche F, Hahn BH, Boecking T, Pinotsis N, James LC, Jacques DA, and Towers GJ
- Subjects
- Animals, Humans, Phylogeny, Capsid metabolism, Nucleotidyltransferases genetics, Nucleotidyltransferases metabolism, Tripartite Motif Proteins genetics, Tripartite Motif Proteins metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Simian Immunodeficiency Virus metabolism, HIV-1 genetics, HIV Infections epidemiology, HIV Infections metabolism
- Abstract
Of the 13 known independent zoonoses of simian immunodeficiency viruses to humans, only one, leading to human immunodeficiency virus (HIV) type 1(M) has become pandemic, causing over 80 million human infections. To understand the specific features associated with pandemic human-to-human HIV spread, we compared replication of HIV-1(M) with non-pandemic HIV-(O) and HIV-2 strains in myeloid cell models. We found that non-pandemic HIV lineages replicate less well than HIV-1(M) owing to activation of cGAS and TRIM5-mediated antiviral responses. We applied phylogenetic and X-ray crystallography structural analyses to identify differences between pandemic and non-pandemic HIV capsids. We found that genetic reversal of two specific amino acid adaptations in HIV-1(M) enables activation of TRIM5, cGAS and innate immune responses. We propose a model in which the parental lineage of pandemic HIV-1(M) evolved a capsid that prevents cGAS and TRIM5 triggering, thereby allowing silent replication in myeloid cells. We hypothesize that this capsid adaptation promotes human-to-human spread through avoidance of innate immune response activation., (© 2022. The Author(s).)
- Published
- 2022
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22. Predictors of Nonseroconversion after SARS-CoV-2 Infection.
- Author
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Liu W, Russell RM, Bibollet-Ruche F, Skelly AN, Sherrill-Mix S, Freeman DA, Stoltz R, Lindemuth E, Lee FH, Sterrett S, Bar KJ, Erdmann N, Gouma S, Hensley SE, Ketas T, Cupo A, Cruz Portillo VM, Moore JP, Bieniasz PD, Hatziioannou T, Massey G, Minyard MB, Saag MS, Davis RS, Shaw GM, Britt WJ, Leal SM Jr, Goepfert P, and Hahn BH
- Subjects
- Antibody Formation, COVID-19 Serological Testing, Humans, Nasopharynx, SARS-CoV-2, Seroconversion, COVID-19 immunology
- Abstract
Not all persons recovering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection develop SARS-CoV-2-specific antibodies. We show that nonseroconversion is associated with younger age and higher reverse transcription PCR cycle threshold values and identify SARS-CoV-2 viral loads in the nasopharynx as a major correlate of the systemic antibody response.
- Published
- 2021
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23. SARS-CoV-2-specific circulating T follicular helper cells correlate with neutralizing antibodies and increase during early convalescence.
- Author
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Boppana S, Qin K, Files JK, Russell RM, Stoltz R, Bibollet-Ruche F, Bansal A, Erdmann N, Hahn BH, and Goepfert PA
- Subjects
- Adult, Aged, Antibody Specificity, Case-Control Studies, Coronavirus Nucleocapsid Proteins immunology, Female, Host Microbial Interactions immunology, Humans, Longitudinal Studies, Male, Middle Aged, Pandemics, Phosphoproteins immunology, Spike Glycoprotein, Coronavirus immunology, Time Factors, Viral Matrix Proteins immunology, Young Adult, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 immunology, COVID-19 virology, SARS-CoV-2 immunology, T Follicular Helper Cells immunology, T Follicular Helper Cells virology
- Abstract
T-cell immunity is likely to play a role in protection against SARS-CoV-2 by helping generate neutralizing antibodies. We longitudinally studied CD4 T-cell responses to the M, N, and S structural proteins of SARS-CoV-2 in 26 convalescent individuals. Within the first two months following symptom onset, a majority of individuals (81%) mounted at least one CD4 T-cell response, and 48% of individuals mounted detectable SARS-CoV-2-specific circulating T follicular helper cells (cTfh, defined as CXCR5+PD1+ CD4 T cells). SARS-CoV-2-specific cTfh responses across all three protein specificities correlated with antibody neutralization with the strongest correlation observed for S protein-specific responses. When examined over time, cTfh responses, particularly to the M protein, increased in convalescence, and robust cTfh responses with magnitudes greater than 5% were detected at the second convalescent visit, a median of 38 days post-symptom onset. CD4 T-cell responses declined but persisted at low magnitudes three months and six months after symptom onset. These data deepen our understanding of antigen-specific cTfh responses in SARS-CoV-2 infection, suggesting that in addition to S protein, M and N protein-specific cTfh may also assist in the development of neutralizing antibodies and that cTfh response formation may be delayed in SARS-CoV-2 infection., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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24. Modulating HIV-1 envelope glycoprotein conformation to decrease the HIV-1 reservoir.
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Rajashekar JK, Richard J, Beloor J, Prévost J, Anand SP, Beaudoin-Bussières G, Shan L, Herndler-Brandstetter D, Gendron-Lepage G, Medjahed H, Bourassa C, Gaudette F, Ullah I, Symmes K, Peric A, Lindemuth E, Bibollet-Ruche F, Park J, Chen HC, Kaufmann DE, Hahn BH, Sodroski J, Pazgier M, Flavell RA, Smith AB 3rd, Finzi A, and Kumar P
- Subjects
- Animals, Antibodies, Neutralizing immunology, Antibody-Dependent Cell Cytotoxicity, CD4 Antigens chemistry, CD4 Antigens metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, Cell Line, Epitopes immunology, Female, Glycoproteins chemistry, Glycoproteins immunology, HEK293 Cells, HIV Infections virology, HIV-1 chemistry, Humans, Immunoglobulin Fc Fragments immunology, Killer Cells, Natural immunology, Male, Mice, Mice, SCID, Models, Animal, Protein Conformation, Virus Replication drug effects, env Gene Products, Human Immunodeficiency Virus chemistry, Antibodies, Neutralizing therapeutic use, Antiviral Agents therapeutic use, HIV Infections drug therapy, HIV Infections immunology, HIV-1 drug effects, HIV-1 immunology, env Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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25. CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses.
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Russell RM, Bibollet-Ruche F, Liu W, Sherrill-Mix S, Li Y, Connell J, Loy DE, Trimboli S, Smith AG, Avitto AN, Gondim MVP, Plenderleith LJ, Wetzel KS, Collman RG, Ayouba A, Esteban A, Peeters M, Kohler WJ, Miller RA, François-Souquiere S, Switzer WM, Hirsch VM, Marx PA, Piel AK, Stewart FA, Georgiev AV, Sommer V, Bertolani P, Hart JA, Hart TB, Shaw GM, Sharp PM, and Hahn BH
- Subjects
- Alleles, Animals, CD4 Antigens chemistry, Evolution, Molecular, Gene Products, env chemistry, Humans, Protein Binding, Protein Domains, Acquired Immunodeficiency Syndrome genetics, CD4 Antigens genetics, Catarrhini genetics, Catarrhini virology, Genetic Variation, HIV, Simian Acquired Immunodeficiency Syndrome genetics, Simian Immunodeficiency Virus
- Abstract
Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of N -linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons ( Cercopithecus spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
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26. Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption.
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Gondim MVP, Sherrill-Mix S, Bibollet-Ruche F, Russell RM, Trimboli S, Smith AG, Li Y, Liu W, Avitto AN, DeVoto JC, Connell J, Fenton-May AE, Pellegrino P, Williams I, Papasavvas E, Lorenzi JCC, Salantes DB, Mampe F, Monroy MA, Cohen YZ, Heath S, Saag MS, Montaner LJ, Collman RG, Siliciano JM, Siliciano RF, Plenderleith LJ, Sharp PM, Caskey M, Nussenzweig MC, Shaw GM, Borrow P, Bar KJ, and Hahn BH
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- Antiviral Agents therapeutic use, CD4-Positive T-Lymphocytes, Humans, Viral Load, Virus Replication, HIV Infections drug therapy, HIV-1, Interferon Type I pharmacology
- Abstract
Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4
+ T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNβ that reduced viral replication in vitro by 50% (IC50 ) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4+ T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2021
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27. Recapitulation of HIV-1 Env-antibody coevolution in macaques leading to neutralization breadth.
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Roark RS, Li H, Williams WB, Chug H, Mason RD, Gorman J, Wang S, Lee FH, Rando J, Bonsignori M, Hwang KK, Saunders KO, Wiehe K, Moody MA, Hraber PT, Wagh K, Giorgi EE, Russell RM, Bibollet-Ruche F, Liu W, Connell J, Smith AG, DeVoto J, Murphy AI, Smith J, Ding W, Zhao C, Chohan N, Okumura M, Rosario C, Ding Y, Lindemuth E, Bauer AM, Bar KJ, Ambrozak D, Chao CW, Chuang GY, Geng H, Lin BC, Louder MK, Nguyen R, Zhang B, Lewis MG, Raymond DD, Doria-Rose NA, Schramm CA, Douek DC, Roederer M, Kepler TB, Kelsoe G, Mascola JR, Kwong PD, Korber BT, Harrison SC, Haynes BF, Hahn BH, and Shaw GM
- Subjects
- Animals, Binding Sites, CD4 Antigens immunology, Cryoelectron Microscopy, Epitopes immunology, HIV Envelope Protein gp120 genetics, HIV-1 genetics, Humans, Macaca mulatta, Molecular Mimicry immunology, Simian Immunodeficiency Virus genetics, Virus Replication, Biological Coevolution immunology, Broadly Neutralizing Antibodies chemistry, Broadly Neutralizing Antibodies genetics, Broadly Neutralizing Antibodies immunology, HIV Antibodies chemistry, HIV Antibodies genetics, HIV Antibodies immunology, HIV Envelope Protein gp120 immunology, HIV Infections immunology, HIV-1 immunology, Simian Immunodeficiency Virus immunology
- Abstract
Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins-when expressed by simian-human immunodeficiency viruses in rhesus macaques-elicited patterns of Env-antibody coevolution very similar to those in humans, including conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions, and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2 apex mode of recognition like that of human broadly neutralizing antibodies (bNAbs) PGT145 and PCT64-35S. Another rhesus antibody bound the CD4 binding site by CD4 mimicry, mirroring human bNAbs 8ANC131, CH235, and VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design., (Copyright © 2021, American Association for the Advancement of Science.)
- Published
- 2021
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28. SARS-CoV-2-specific peripheral T follicular helper cells correlate with neutralizing antibodies and increase during convalescence.
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Boppana S, Qin K, Files JK, Russell RM, Stoltz R, Bibollet-Ruche F, Bansal A, Erdmann N, Hahn BH, and Goepfert P
- Abstract
T-cell immunity is likely to play a role in protection against SARS-CoV-2 by helping generate neutralizing antibodies. We longitudinally studied CD4 T-cell responses to the M, N, and S structural proteins of SARS-CoV-2 in 21 convalescent individuals. Within the first two months following symptom onset, a majority of individuals (81%) mount at least one CD4 T-cell response, and 48% of individuals mount detectable SARS-CoV-2-specific peripheral T follicular helper cells (pTfh, defined as CXCR5+PD1+ CD4 T cells). SARS-CoV-2-specific pTfh responses across all three protein specificities correlate with antibody neutralization with the strongest correlation observed for S protein-specific responses. When examined over time, pTfh responses increase in frequency and magnitude in convalescence, and robust responses with magnitudes greater than 5% were detected only at the second convalescent visit, an average of 38 days post-symptom onset. These data deepen our understanding of antigen-specific pTfh responses in SARS-CoV-2 infection, suggesting that M and N protein-specific pTfh may also assist in the development of neutralizing antibodies and that pTfh response formation may be delayed in SARS-CoV-2 infection.
- Published
- 2020
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29. Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2.
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Hopfensperger K, Richard J, Stürzel CM, Bibollet-Ruche F, Apps R, Leoz M, Plantier JC, Hahn BH, Finzi A, Kirchhoff F, and Sauter D
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- CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, HEK293 Cells, HIV Infections immunology, HIV Infections virology, HIV-1 classification, HIV-1 immunology, HIV-2 immunology, Host-Pathogen Interactions immunology, Humans, Killer Cells, Natural immunology, T-Lymphocytes, Cytotoxic immunology, vif Gene Products, Human Immunodeficiency Virus immunology, Evolution, Molecular, HIV-1 genetics, HIV-2 genetics, HLA-C Antigens genetics, Human Immunodeficiency Virus Proteins genetics, Viral Regulatory and Accessory Proteins genetics, vif Gene Products, Human Immunodeficiency Virus genetics
- Abstract
HLA-C-mediated antigen presentation induces the killing of human immunodeficiency virus (HIV)-infected CD4
+ T cells by cytotoxic T lymphocytes (CTLs). To evade killing, many HIV-1 group M strains decrease HLA-C surface levels using their accessory protein Vpu. However, some HIV-1 group M isolates lack this activity, possibly to prevent the activation of natural killer (NK) cells. Analyzing diverse primate lentiviruses, we found that Vpu-mediated HLA-C downregulation is not limited to pandemic group M but is also found in HIV-1 groups O and P as well as several simian immunodeficiency viruses (SIVs). We show that Vpu targets HLA-C primarily at the protein level, independently of its ability to suppress NF-κB-driven gene expression, and that in some viral lineages, HLA-C downregulation may come at the cost of efficient counteraction of the restriction factor tetherin. Remarkably, HIV-2, which does not carry a vpu gene, uses its accessory protein Vif to decrease HLA-C surface expression. This Vif activity requires intact binding sites for the Cullin5/Elongin ubiquitin ligase complex but is separable from its ability to counteract APOBEC3G. Similar to HIV-1 Vpu, the degree of HIV-2 Vif-mediated HLA-C downregulation varies considerably among different virus isolates. In agreement with opposing selection pressures in vivo , we show that the reduction of HLA-C surface levels by HIV-2 Vif is accompanied by increased NK cell-mediated killing. In summary, our results highlight the complex role of HLA-C in lentiviral infections and demonstrate that HIV-1 and HIV-2 have evolved at least two independent mechanisms to decrease HLA-C levels on infected cells. IMPORTANCE Genome-wide association studies suggest that HLA-C expression is a major determinant of viral load set points and CD4+ T cell counts in HIV-infected individuals. On the one hand, efficient HLA-C expression enables the killing of infected cells by cytotoxic T lymphocytes (CTLs). On the other hand, HLA-C sends inhibitory signals to natural killer (NK) cells and enhances the infectivity of newly produced HIV particles. HIV-1 group M viruses modulate HLA-C expression using the accessory protein Vpu, possibly to balance CTL- and NK cell-mediated immune responses. Here, we show that the second human immunodeficiency virus, HIV-2, can use its accessory protein Vif to evade HLA-C-mediated restriction. Furthermore, our mutational analyses provide insights into the underlying molecular mechanisms. In summary, our results reveal how the two human AIDS viruses modulate HLA-C, a key component of the antiviral immune response., (Copyright © 2020 Hopfensperger et al.)- Published
- 2020
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30. Upregulation of BST-2 by Type I Interferons Reduces the Capacity of Vpu To Protect HIV-1-Infected Cells from NK Cell Responses.
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Prévost J, Pickering S, Mumby MJ, Medjahed H, Gendron-Lepage G, Delgado GG, Dirk BS, Dikeakos JD, Stürzel CM, Sauter D, Kirchhoff F, Bibollet-Ruche F, Hahn BH, Dubé M, Kaufmann DE, Neil SJD, Finzi A, and Richard J
- Subjects
- CD4-Positive T-Lymphocytes virology, Down-Regulation, GPI-Linked Proteins genetics, HEK293 Cells, HIV-1, Human Immunodeficiency Virus Proteins immunology, Humans, Immune Evasion, Receptors, Virus genetics, Receptors, Virus immunology, Signaling Lymphocytic Activation Molecule Family genetics, Signaling Lymphocytic Activation Molecule Family immunology, Transcriptional Activation, Up-Regulation, Viral Regulatory and Accessory Proteins immunology, Antigens, CD genetics, CD4-Positive T-Lymphocytes immunology, HIV Infections immunology, Human Immunodeficiency Virus Proteins genetics, Interferon Type I pharmacology, Killer Cells, Natural immunology, Viral Regulatory and Accessory Proteins genetics
- Abstract
The HIV-1 accessory protein Vpu enhances viral release by counteracting the restriction factor BST-2. Furthermore, Vpu promotes NK cell evasion by downmodulating cell surface NTB-A and PVR, known ligands of the NK cell receptors NTB-A and DNAM-1, respectively. While it has been established that Vpu's transmembrane domain (TMD) is required for the interaction and intracellular sequestration of BST-2, NTB-A, and PVR, it remains unclear how Vpu manages to target these proteins simultaneously. In this study, we show that upon upregulation, BST-2 is preferentially downregulated by Vpu over its other TMD substrates. We found that type I interferon (IFN)-mediated BST-2 upregulation greatly impairs the ability of Vpu to downregulate NTB-A and PVR. Our results suggest that occupation of Vpu by BST-2 affects its ability to downregulate other TMD substrates. Accordingly, knockdown of BST-2 increases Vpu's potency to downmodulate NTB-A and PVR in the presence of type I IFN treatment. Moreover, we show that expression of human BST-2, but not that of the macaque orthologue, decreases Vpu's capacity to downregulate NTB-A. Importantly, we show that type I IFNs efficiently sensitize HIV-1-infected cells to NTB-A- and DNAM-1-mediated direct and antibody-dependent NK cell responses. Altogether, our results reveal that type I IFNs decrease Vpu's polyfunctionality, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. IMPORTANCE The restriction factor BST-2 and the NK cell ligands NTB-A and PVR are among a growing list of membrane proteins found to be downregulated by HIV-1 Vpu. BST-2 antagonism enhances viral release, while NTB-A and PVR downmodulation contributes to NK cell evasion. However, it remains unclear how Vpu can target multiple cellular factors simultaneously. Here we provide evidence that under physiological conditions, BST-2 is preferentially targeted by Vpu over NTB-A and PVR. Specifically, we show that type I IFNs decrease Vpu's polyfunctionality by upregulating BST-2, thus reducing its capacity to protect HIV-1-infected cells from NK cell responses. This indicates that there is a hierarchy of Vpu substrates upon IFN treatment, revealing that for the virus, targeting BST-2 as part of its resistance to IFN takes precedence over evading NK cell responses. This reveals a potential weakness in HIV-1's immunoevasion mechanisms that may be exploited therapeutically to harness NK cell responses against HIV-1., (Copyright © 2019 Prévost et al.)
- Published
- 2019
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31. CD4 receptor diversity in chimpanzees protects against SIV infection.
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Bibollet-Ruche F, Russell RM, Liu W, Stewart-Jones GBE, Sherrill-Mix S, Li Y, Learn GH, Smith AG, Gondim MVP, Plenderleith LJ, Decker JM, Easlick JL, Wetzel KS, Collman RG, Ding S, Finzi A, Ayouba A, Peeters M, Leendertz FH, van Schijndel J, Goedmakers A, Ton E, Boesch C, Kuehl H, Arandjelovic M, Dieguez P, Murai M, Colin C, Koops K, Speede S, Gonder MK, Muller MN, Sanz CM, Morgan DB, Atencia R, Cox D, Piel AK, Stewart FA, Ndjango JN, Mjungu D, Lonsdorf EV, Pusey AE, Kwong PD, Sharp PM, Shaw GM, and Hahn BH
- Subjects
- Animals, CD4 Antigens immunology, CD4-Positive T-Lymphocytes immunology, Evolution, Molecular, Genetic Variation immunology, HIV genetics, HIV pathogenicity, Humans, Pan troglodytes genetics, Pan troglodytes immunology, Polysaccharides genetics, Polysaccharides immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus pathogenicity, Viral Envelope Proteins immunology, CD4 Antigens genetics, Simian Acquired Immunodeficiency Syndrome genetics, Simian Immunodeficiency Virus genetics, Viral Envelope Proteins genetics
- Abstract
Human and simian immunodeficiency viruses (HIV/SIVs) use CD4 as the primary receptor to enter target cells. Here, we show that the chimpanzee CD4 is highly polymorphic, with nine coding variants present in wild populations, and that this diversity interferes with SIV envelope (Env)-CD4 interactions. Testing the replication fitness of SIVcpz strains in CD4
+ T cells from captive chimpanzees, we found that certain viruses were unable to infect cells from certain hosts. These differences were recapitulated in CD4 transfection assays, which revealed a strong association between CD4 genotypes and SIVcpz infection phenotypes. The most striking differences were observed for three substitutions (Q25R, Q40R, and P68T), with P68T generating a second N-linked glycosylation site (N66) in addition to an invariant N32 encoded by all chimpanzee CD4 alleles. In silico modeling and site-directed mutagenesis identified charged residues at the CD4-Env interface and clashes between CD4- and Env-encoded glycans as mechanisms of inhibition. CD4 polymorphisms also reduced Env-mediated cell entry of monkey SIVs, which was dependent on at least one D1 domain glycan. CD4 allele frequencies varied among wild chimpanzees, with high diversity in all but the western subspecies, which appeared to have undergone a selective sweep. One allele was associated with lower SIVcpz prevalence rates in the wild. These results indicate that substitutions in the D1 domain of the chimpanzee CD4 can prevent SIV cell entry. Although some SIVcpz strains have adapted to utilize these variants, CD4 diversity is maintained, protecting chimpanzees against infection with SIVcpz and other SIVs to which they are exposed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)- Published
- 2019
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32. CHIIMP: An automated high-throughput microsatellite genotyping platform reveals greater allelic diversity in wild chimpanzees.
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Barbian HJ, Connell AJ, Avitto AN, Russell RM, Smith AG, Gundlapally MS, Shazad AL, Li Y, Bibollet-Ruche F, Wroblewski EE, Mjungu D, Lonsdorf EV, Stewart FA, Piel AK, Pusey AE, Sharp PM, and Hahn BH
- Abstract
Short tandem repeats (STRs), also known as microsatellites, are commonly used to noninvasively genotype wild-living endangered species, including African apes. Until recently, capillary electrophoresis has been the method of choice to determine the length of polymorphic STR loci. However, this technique is labor intensive, difficult to compare across platforms, and notoriously imprecise. Here we developed a MiSeq-based approach and tested its performance using previously genotyped fecal samples from long-term studied chimpanzees in Gombe National Park, Tanzania. Using data from eight microsatellite loci as a reference, we designed a bioinformatics platform that converts raw MiSeq reads into locus-specific files and automatically calls alleles after filtering stutter sequences and other PCR artifacts. Applying this method to the entire Gombe population, we confirmed previously reported genotypes, but also identified 31 new alleles that had been missed due to sequence differences and size homoplasy. The new genotypes, which increased the allelic diversity and heterozygosity in Gombe by 61% and 8%, respectively, were validated by replicate amplification and pedigree analyses. This demonstrated inheritance and resolved one case of an ambiguous paternity. Using both singleplex and multiplex locus amplification, we also genotyped fecal samples from chimpanzees in the Greater Mahale Ecosystem in Tanzania, demonstrating the utility of the MiSeq-based approach for genotyping nonhabituated populations and performing comparative analyses across field sites. The new automated high-throughput analysis platform (available at https://github.com/ShawHahnLab/chiimp) will allow biologists to more accurately and effectively determine wildlife population size and structure, and thus obtain information critical for conservation efforts.
- Published
- 2018
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33. Reply to Forni et al., "Multiple Selected Changes May Modulate the Molecular Interaction between Laverania RH5 and Primate Basigin".
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Plenderleith LJ, Liu W, MacLean OA, Li Y, Loy DE, Sundararaman SA, Bibollet-Ruche F, Learn GH, Hahn BH, and Sharp PM
- Subjects
- Animals, Pan troglodytes, Plasmodium falciparum, Primates, Basigin, Plasmodium
- Published
- 2018
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34. Loss of CXCR6 coreceptor usage characterizes pathogenic lentiviruses.
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Wetzel KS, Yi Y, Yadav A, Bauer AM, Bello EA, Romero DC, Bibollet-Ruche F, Hahn BH, Paiardini M, Silvestri G, Peeters M, and Collman RG
- Subjects
- Amino Acid Sequence, Animals, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cercocebus atys, Macaca mulatta, Phylogeny, Receptors, CCR5 genetics, Receptors, CXCR6 genetics, Sequence Homology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome metabolism, Virus Internalization, CD4-Positive T-Lymphocytes virology, Receptors, CCR5 metabolism, Receptors, CXCR6 metabolism, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus pathogenicity, Viral Load
- Abstract
Pandemic HIV-1 originated from the cross-species transmission of SIVcpz, which infects chimpanzees, while SIVcpz itself emerged following the cross-species transmission and recombination of monkey SIVs, with env contributed by the SIVgsn/mus/mon lineage that infects greater spot-nosed, mustached and mona monkeys. SIVcpz and HIV-1 are pathogenic in their respective hosts, while the phenotype of their SIVgsn/mus/mon ancestors is unknown. However, two well-studied SIV infected natural hosts, sooty mangabeys (SMs) and African green monkeys (AGMs), typically remain healthy despite high viral loads; these species express low levels of the canonical coreceptor CCR5, and recent work shows that CXCR6 is a major coreceptor for SIV in these hosts. It is not known what coreceptors were used by the precursors of SIVcpz, whether coreceptor use changed during emergence of the SIVcpz/HIV-1 lineage, and what T cell subsets express CXCR6 in natural hosts. Using species-matched coreceptors and CD4, we show here that SIVcpz uses only CCR5 for entry and, like HIV-1, cannot use CXCR6. In contrast, SIVmus efficiently uses both CXCR6 and CCR5. Coreceptor selectivity was determined by Env, with CXCR6 use abrogated by Pro326 in the V3 crown, which is absent in monkey SIVs but highly conserved in SIVcpz/HIV-1. To characterize which cells express CXCR6, we generated a novel antibody that recognizes CXCR6 of multiple primate species. Testing lymphocytes from SM, the best-studied natural host, we found that CXCR6 is restricted to CD4+ effector memory cells, and is expressed by a sub-population distinct from those expressing CCR5. Thus, efficient CXCR6 use, previously identified in SM and AGM infection, also characterizes a member of the SIV lineage that gave rise to SIVcpz/HIV-1. Loss of CXCR6 usage by SIVcpz may have altered its cell tropism, shifting virus from CXCR6-expressing cells that may support replication without disrupting immune function or homeostasis, towards CCR5-expressing cells with pathogenic consequences.
- Published
- 2018
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35. Adaptive Evolution of RH5 in Ape Plasmodium species of the Laverania Subgenus.
- Author
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Plenderleith LJ, Liu W, MacLean OA, Li Y, Loy DE, Sundararaman SA, Bibollet-Ruche F, Learn GH, Hahn BH, and Sharp PM
- Subjects
- Animals, Basigin metabolism, Binding Sites, Hominidae, Humans, Protein Binding, Protozoan Proteins metabolism, Selection, Genetic, Ape Diseases parasitology, Evolution, Molecular, Malaria parasitology, Malaria veterinary, Plasmodium genetics, Protozoan Proteins genetics
- Abstract
Plasmodium falciparum , the major cause of malaria morbidity and mortality in humans, has been shown to have emerged after cross-species transmission of one of six host-specific parasites (subgenus Laverania ) infecting wild chimpanzees ( Pan troglodytes ) and western gorillas ( Gorilla gorilla ). Binding of the parasite-encoded ligand RH5 to the host protein basigin is essential for erythrocyte invasion and has been implicated in host specificity. A recent study claimed to have found two amino acid changes in RH5 that "drove the host shift leading to the emergence of P. falciparum as a human pathogen." However, the ape Laverania data available at that time, which included only a single distantly related chimpanzee parasite sequence, were inadequate to justify any such conclusion. Here, we have investigated Laverania Rh5 gene evolution using sequences from all six ape parasite species. Searching for gene-wide episodic selection across the entire Laverania phylogeny, we found eight codons to be under positive selection, including three that correspond to contact residues known to form hydrogen bonds between P. falciparum RH5 and human basigin. One of these sites (residue 197) has changed subsequent to the transmission from apes to humans that gave rise to P. falciparum , suggesting a possible role in the adaptation of the gorilla parasite to the human host. We also found evidence that the patterns of nucleotide polymorphisms in P. falciparum are not typical of Laverania species and likely reflect the recent demographic history of the human parasite. IMPORTANCE A number of closely related, host-specific malaria parasites infecting wild chimpanzees and gorillas have recently been described. The most important cause of human malaria, Plasmodium falciparum , is now known to have resulted from a cross-species transmission of one of the gorilla parasites. Overcoming species-specific interactions between a parasite ligand, RH5, and its receptor on host cells, basigin, was likely an important step in the origin of the human parasite. We have investigated the evolution of the Rh5 gene and found evidence of adaptive changes during the diversification of the ape parasite species at sites that are known to form bonds with human basigin. One of these changes occurred at the origin of P. falciparum , implicating it as an important adaptation to the human host., (Copyright © 2018 Plenderleith et al.)
- Published
- 2018
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36. Effective treatment of SIVcpz-induced immunodeficiency in a captive western chimpanzee.
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Barbian HJ, Jackson-Jewett R, Brown CS, Bibollet-Ruche F, Learn GH, Decker T, Kreider EF, Li Y, Denny TN, Sharp PM, Shaw GM, Lifson J, Acosta EP, Saag MS, Bar KJ, and Hahn BH
- Subjects
- Animals, Anti-Retroviral Agents administration & dosage, Anti-Retroviral Agents blood, Antiretroviral Therapy, Highly Active adverse effects, CD4 Lymphocyte Count, Drug Resistance, Viral, Male, Mutation, RNA, Viral blood, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus genetics, Simian Immunodeficiency Virus physiology, Viral Load drug effects, Anti-Retroviral Agents therapeutic use, Ape Diseases drug therapy, Ape Diseases virology, Pan troglodytes virology, Simian Acquired Immunodeficiency Syndrome drug therapy, Simian Immunodeficiency Virus drug effects
- Abstract
Background: Simian immunodeficiency virus of chimpanzees (SIVcpz), the progenitor of human immunodeficiency virus type 1 (HIV-1), is associated with increased mortality and AIDS-like immunopathology in wild-living chimpanzees (Pan troglodytes). Surprisingly, however, similar findings have not been reported for chimpanzees experimentally infected with SIVcpz in captivity, raising questions about the intrinsic pathogenicity of this lentivirus., Findings: Here, we report progressive immunodeficiency and clinical disease in a captive western chimpanzee (P. t. verus) infected twenty years ago by intrarectal inoculation with an SIVcpz strain (ANT) from a wild-caught eastern chimpanzee (P. t. schweinfurthii). With sustained plasma viral loads of 10
5 to 106 RNA copies/ml for the past 15 years, this chimpanzee developed CD4+ T cell depletion (220 cells/μl), thrombocytopenia (90,000 platelets/μl), and persistent soft tissue infections refractory to antibacterial therapy. Combination antiretroviral therapy consisting of emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and dolutegravir (DTG) decreased plasma viremia to undetectable levels (<200 copies/ml), improved CD4+ T cell counts (509 cell/μl), and resulted in the rapid resolution of all soft tissue infections. However, initial lack of adherence and/or differences in pharmacokinetics led to low plasma drug concentrations, which resulted in transient rebound viremia and the emergence of FTC resistance mutations (M184V/I) identical to those observed in HIV-1 infected humans., Conclusions: These data demonstrate that SIVcpz can cause immunodeficiency and other hallmarks of AIDS in captive chimpanzees, including P. t. verus apes that are not naturally infected with this virus. Moreover, SIVcpz-associated immunodeficiency can be effectively treated with antiretroviral therapy, although sufficiently high plasma concentrations must be maintained to prevent the emergence of drug resistance. These findings extend a growing body of evidence documenting the immunopathogenicity of SIVcpz and suggest that experimentally infected chimpanzees may benefit from clinical monitoring and therapeutic intervention.- Published
- 2017
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37. BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity.
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Richard J, Prévost J, von Bredow B, Ding S, Brassard N, Medjahed H, Coutu M, Melillo B, Bibollet-Ruche F, Hahn BH, Kaufmann DE, Smith AB 3rd, Sodroski J, Sauter D, Kirchhoff F, Gee K, Neil SJ, Evans DT, and Finzi A
- Subjects
- Antigens, CD metabolism, CD4 Antigens metabolism, GPI-Linked Proteins deficiency, GPI-Linked Proteins genetics, GPI-Linked Proteins metabolism, HIV-1 genetics, Human Immunodeficiency Virus Proteins genetics, Human Immunodeficiency Virus Proteins metabolism, Humans, Immune Evasion, Interferon-beta pharmacology, Interleukins pharmacology, Jurkat Cells, Molecular Mimicry, Up-Regulation, Viral Regulatory and Accessory Proteins genetics, Viral Regulatory and Accessory Proteins metabolism, env Gene Products, Human Immunodeficiency Virus immunology, Antibody-Dependent Cell Cytotoxicity, Antigens, CD genetics, CD4 Antigens immunology, Epitopes immunology, HIV-1 immunology, env Gene Products, Human Immunodeficiency Virus genetics
- Abstract
Antibodies recognizing conserved CD4-induced (CD4i) epitopes on human immunodeficiency virus type 1 (HIV-1) Env and able to mediate antibody-dependent cellular cytotoxicity (ADCC) have been shown to be present in sera from most HIV-1-infected individuals. These antibodies preferentially recognize Env in its CD4-bound conformation. CD4 downregulation by Nef and Vpu dramatically reduces exposure of CD4i HIV-1 Env epitopes and therefore reduce the susceptibility of HIV-1-infected cells to ADCC mediated by HIV-positive (HIV+) sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4 mimetics (CD4mc) that are able to transition Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. However, HIV-1 developed additional mechanisms to avoid ADCC, including Vpu-mediated BST-2 antagonism, which decreases the overall amount of Env present at the cell surface. Accordingly, BST-2 upregulation in response to alpha interferon (IFN-α) was shown to increase the susceptibility of HIV-1-infected cells to ADCC despite the activity of Vpu. Here we show that BST-2 upregulation by IFN-β and interleukin-27 (IL-27) also increases the surface expression of Env and thus boosts the ability of CD4mc to sensitize HIV-1-infected cells to ADCC by sera from HIV-1-infected individuals. IMPORTANCE HIV-1 evolved sophisticated strategies to conceal Env epitopes from ADCC-mediating antibodies present in HIV+ sera. Vpu-mediated BST-2 downregulation was shown to decrease ADCC responses by limiting the amount of Env present at the cell surface. This effect of Vpu was shown to be attenuated by IFN-α treatment. Here we show that in addition to IFN-α, IFN-β and IL-27 also affect Vpu-mediated BST-2 downregulation and greatly enhance ADCC responses against HIV-1-infected cells in the presence of CD4mc. These findings may inform strategies aimed at HIV prevention and eradication., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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38. Efficient Vpu-Mediated Tetherin Antagonism by an HIV-1 Group O Strain.
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Mack K, Starz K, Sauter D, Langer S, Bibollet-Ruche F, Learn GH, Stürzel CM, Leoz M, Plantier JC, Geyer M, Hahn BH, and Kirchhoff F
- Subjects
- Antigens, CD, CD4-Positive T-Lymphocytes virology, Cell Line, GPI-Linked Proteins antagonists & inhibitors, Humans, NF-kappa B antagonists & inhibitors, HIV-1 immunology, HIV-1 physiology, Host-Pathogen Interactions, Human Immunodeficiency Virus Proteins metabolism, Viral Regulatory and Accessory Proteins metabolism, Virus Release
- Abstract
Simian immunodeficiency viruses (SIVs) use their Nef proteins to counteract the restriction factor tetherin. However, a deletion in human tetherin prevents antagonism by the Nef proteins of SIVcpz and SIVgor, which represent the ape precursors of human immunodeficiency virus type 1 (HIV-1). To promote virus release from infected cells, pandemic HIV-1 group M strains evolved Vpu as a tetherin antagonist, while the Nef protein of less widespread HIV-1 group O strains acquired the ability to target a region adjacent to this deletion. In this study, we identified an unusual HIV-1 group O strain (RBF206) that evolved Vpu as an effective antagonist of human tetherin. While both RBF206 Vpu and Nef exert anti-tetherin activity in transient-transfection assays, mainly Vpu promotes RBF206 release in infected CD4
+ T cells. Although mutations distinct from the adaptive changes observed in group M Vpus (M-Vpus) were critical for the acquisition of its anti-tetherin activity, RBF206 O-Vpu potently suppresses NF-κB activation and reduces CD4 cell surface expression. Interestingly, RBF206 Vpu counteracts tetherin in a largely species-independent manner, degrading both the long and short isoforms of human tetherin. Downmodulation of CD4, but not counteraction of tetherin, by RBF206 Vpu was dependent on the cellular ubiquitin ligase machinery. Our data present the first example of an HIV-1 group O Vpu that efficiently antagonizes human tetherin and suggest that counteraction by O-Nefs may be suboptimal. IMPORTANCE Previous studies showed that HIV-1 groups M and O evolved two alternative strategies to counteract the human ortholog of the restriction factor tetherin. While HIV-1 group M switched from Nef to Vpu due to a deletion in the cytoplasmic domain of human tetherin, HIV-1 group O, which lacks Vpu-mediated anti-tetherin activity, acquired a Nef protein that is able to target a region adjacent to the deletion. Here we report an unusual exception, identifying a strain of HIV-1 group O (RBF206) whose Vpu protein evolved an effective antagonism of human tetherin. Interestingly, the adaptive changes in RBF206 Vpu are distinct from those found in M-Vpus and mediate efficient counteraction of both the long and short isoforms of this restriction factor. Our results further illustrate the enormous flexibility of HIV-1 in counteracting human defense mechanisms., (Copyright © 2017 American Society for Microbiology.)- Published
- 2017
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39. Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness.
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Iyer SS, Bibollet-Ruche F, Sherrill-Mix S, Learn GH, Plenderleith L, Smith AG, Barbian HJ, Russell RM, Gondim MV, Bahari CY, Shaw CM, Li Y, Decker T, Haynes BF, Shaw GM, Sharp PM, Borrow P, and Hahn BH
- Subjects
- Female, Host-Pathogen Interactions, Humans, Male, Semen virology, Vaginal Douching, Virion, Virus Replication, HIV Infections immunology, HIV Infections transmission, HIV-1 physiology, Interferon Type I immunology
- Abstract
Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC
50 ) than did donor isolates, and their odds of replicating in CD4+ T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4+ T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response., Competing Interests: The authors declare no conflict of interest.- Published
- 2017
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40. The effect of HIV-1 Vif polymorphisms on A3G anti-viral activity in an in vivo mouse model.
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Cadena C, Stavrou S, Manzoni T, Iyer SS, Bibollet-Ruche F, Zhang W, Hahn BH, Browne EP, and Ross SR
- Subjects
- APOBEC-3G Deaminase genetics, Alleles, Animals, Disease Models, Animal, Friend murine leukemia virus genetics, Friend murine leukemia virus physiology, Humans, Mice, Mice, Transgenic, Mutation, Virus Replication, APOBEC-3G Deaminase metabolism, HIV Infections virology, HIV-1 genetics, Polymorphism, Genetic, vif Gene Products, Human Immunodeficiency Virus genetics
- Abstract
Humans encode seven APOBEC3 proteins (A-H), with A3G, 3F and 3H as the major factors restricting HIV-1 replication. HIV-1, however, encodes Vif, which counteracts A3 proteins by chaperoning them to the proteasome where they are degraded. Vif polymorphisms found in HIV-1s isolated from infected patients have varying anti-A3G potency when assayed in vitro, but there are few studies demonstrating this in in vivo models. Here, we created Friend murine leukemia viruses encoding vif alleles that were previously shown to differentially neutralize A3G in cell culture or that were originally found in primary HIV-1 isolates. Infection of transgenic mice expressing different levels of human A3G showed that these naturally occurring Vif variants differed in their ability to counteract A3G during in vivo infection, although the effects on viral replication were not identical to those seen in cultured cells. We also found that the polymorphic Vifs that attenuated viral replication reverted to wild type only in A3G transgenic mice. Finally, we found that the level of A3G-mediated deamination was inversely correlated with the level of viral replication. This animal model should be useful for studying the functional significance of naturally occurring vif polymorphisms, as well as viral evolution in the presence of A3G.
- Published
- 2016
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41. The Role of the Antiviral APOBEC3 Gene Family in Protecting Chimpanzees against Lentiviruses from Monkeys.
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Etienne L, Bibollet-Ruche F, Sudmant PH, Wu LI, Hahn BH, and Emerman M
- Subjects
- Animals, Blotting, Western, CD4-Positive T-Lymphocytes immunology, Cytidine Deaminase immunology, Genes, vif genetics, Haplorhini, Lentivirus genetics, Lentivirus Infections immunology, Molecular Sequence Data, Phylogeny, Polymerase Chain Reaction, Cytidine Deaminase genetics, Lentivirus Infections genetics, Pan troglodytes immunology, Pan troglodytes virology, Simian Immunodeficiency Virus genetics
- Abstract
Cross-species transmissions of viruses from animals to humans are at the origin of major human pathogenic viruses. While the role of ecological and epidemiological factors in the emergence of new pathogens is well documented, the importance of host factors is often unknown. Chimpanzees are the closest relatives of humans and the animal reservoir at the origin of the human AIDS pandemic. However, despite being regularly exposed to monkey lentiviruses through hunting, chimpanzees are naturally infected by only a single simian immunodeficiency virus, SIVcpz. Here, we asked why chimpanzees appear to be protected against the successful emergence of other SIVs. In particular, we investigated the role of the chimpanzee APOBEC3 genes in providing a barrier to infection by most monkey lentiviruses. We found that most SIV Vifs, including Vif from SIVwrc infecting western-red colobus, the chimpanzee's main monkey prey in West Africa, could not antagonize chimpanzee APOBEC3G. Moreover, chimpanzee APOBEC3D, as well as APOBEC3F and APOBEC3H, provided additional protection against SIV Vif antagonism. Consequently, lentiviral replication in primary chimpanzee CD4(+) T cells was dependent on the presence of a lentiviral vif gene that could antagonize chimpanzee APOBEC3s. Finally, by identifying and functionally characterizing several APOBEC3 gene polymorphisms in both common chimpanzees and bonobos, we found that these ape populations encode APOBEC3 proteins that are uniformly resistant to antagonism by monkey lentiviruses.
- Published
- 2015
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42. Neutralization properties of simian immunodeficiency viruses infecting chimpanzees and gorillas.
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Barbian HJ, Decker JM, Bibollet-Ruche F, Galimidi RP, West AP Jr, Learn GH, Parrish NF, Iyer SS, Li Y, Pace CS, Song R, Huang Y, Denny TN, Mouquet H, Martin L, Acharya P, Zhang B, Kwong PD, Mascola JR, Verrips CT, Strokappe NM, Rutten L, McCoy LE, Weiss RA, Brown CS, Jackson R, Silvestri G, Connors M, Burton DR, Shaw GM, Nussenzweig MC, Bjorkman PJ, Ho DD, Farzan M, and Hahn BH
- Subjects
- Animals, Gorilla gorilla, Humans, Inhibitory Concentration 50, Neutralization Tests, Pan troglodytes, Simian Immunodeficiency Virus isolation & purification, Antibodies, Neutralizing immunology, Cross Reactions, HIV Antibodies immunology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus immunology
- Abstract
Unlabelled: Broadly 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 troglodytes troglodytes) (SIVcpzPtt) and eastern (Pan troglodytes schweinfurthii) (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 SIVcpzPtt strains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Ig(mim2), 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., Importance: SIVcpz 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., (Copyright © 2015 Barbian et al.)
- Published
- 2015
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43. Nef proteins of epidemic HIV-1 group O strains antagonize human tetherin.
- Author
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Kluge SF, Mack K, Iyer SS, Pujol FM, Heigele A, Learn GH, Usmani SM, Sauter D, Joas S, Hotter D, Bibollet-Ruche F, Plenderleith LJ, Peeters M, Geyer M, Sharp PM, Fackler OT, Hahn BH, and Kirchhoff F
- Subjects
- Amino Acid Sequence, Antigens, CD metabolism, CD4-Positive T-Lymphocytes virology, Cell Line, Tumor, Endocytosis, Evolution, Molecular, GPI-Linked Proteins antagonists & inhibitors, GPI-Linked Proteins genetics, GPI-Linked Proteins metabolism, HEK293 Cells, HIV-1 classification, Humans, Molecular Sequence Data, Protein Conformation, Sequence Analysis, Sequence Deletion, Virion genetics, Virion metabolism, nef Gene Products, Human Immunodeficiency Virus genetics, Antigens, CD genetics, HIV-1 pathogenicity, nef Gene Products, Human Immunodeficiency Virus metabolism
- Abstract
Most simian immunodeficiency viruses use their Nef protein to antagonize the host restriction factor tetherin. A deletion in human tetherin confers Nef resistance, representing a hurdle to successful zoonotic transmission. HIV-1 group M evolved to utilize the viral protein U (Vpu) to counteract tetherin. Although HIV-1 group O has spread epidemically in humans, it has not evolved a Vpu-based tetherin antagonism. Here we show that HIV-1 group O Nef targets a region adjacent to this deletion to inhibit transport of human tetherin to the cell surface, enhances virion release, and increases viral resistance to inhibition by interferon-α. The Nef protein of the inferred common ancestor of group O viruses is also active against human tetherin. Thus, Nef-mediated antagonism of human tetherin evolved prior to the spread of HIV-1 group O and likely facilitated secondary virus transmission. Our results may explain the epidemic spread of HIV-1 group O., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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44. African origin of the malaria parasite Plasmodium vivax.
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Liu W, Li Y, Shaw KS, Learn GH, Plenderleith LJ, Malenke JA, Sundararaman SA, Ramirez MA, Crystal PA, Smith AG, Bibollet-Ruche F, Ayouba A, Locatelli S, Esteban A, Mouacha F, Guichet E, Butel C, Ahuka-Mundeke S, Inogwabini BI, Ndjango JB, Speede S, Sanz CM, Morgan DB, Gonder MK, Kranzusch PJ, Walsh PD, Georgiev AV, Muller MN, Piel AK, Stewart FA, Wilson ML, Pusey AE, Cui L, Wang Z, Färnert A, Sutherland CJ, Nolder D, Hart JA, Hart TB, Bertolani P, Gillis A, LeBreton M, Tafon B, Kiyang J, Djoko CF, Schneider BS, Wolfe ND, Mpoudi-Ngole E, Delaporte E, Carter R, Culleton RL, Shaw GM, Rayner JC, Peeters M, Hahn BH, and Sharp PM
- Subjects
- Africa, Animals, Asia, Evolution, Molecular, Phylogeny, Plasmodium vivax pathogenicity, Malaria physiopathology, Plasmodium vivax classification, Plasmodium vivax genetics
- Abstract
Plasmodium vivax is the leading cause of human malaria in Asia and Latin America but is absent from most of central Africa due to the near fixation of a mutation that inhibits the expression of its receptor, the Duffy antigen, on human erythrocytes. The emergence of this protective allele is not understood because P. vivax is believed to have originated in Asia. Here we show, using a non-invasive approach, that wild chimpanzees and gorillas throughout central Africa are endemically infected with parasites that are closely related to human P. vivax. Sequence analyses reveal that ape parasites lack host specificity and are much more diverse than human parasites, which form a monophyletic lineage within the ape parasite radiation. These findings indicate that human P. vivax is of African origin and likely selected for the Duffy-negative mutation. All extant human P. vivax parasites are derived from a single ancestor that escaped out of Africa.
- Published
- 2014
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45. Vif proteins from diverse primate lentiviral lineages use the same binding site in APOBEC3G.
- Author
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Letko M, Silvestri G, Hahn BH, Bibollet-Ruche F, Gokcumen O, Simon V, and Ooms M
- Subjects
- APOBEC-3G Deaminase, Animals, Binding Sites, DNA Mutational Analysis, Humans, Immunoprecipitation, Lentivirus isolation & purification, Molecular Sequence Data, Primates, Protein Binding, Proteolysis, Sequence Analysis, DNA, Cytidine Deaminase metabolism, Gene Products, vif metabolism, Host-Pathogen Interactions, Lentivirus physiology
- Abstract
APOBEC3G (A3G) is a cytidine deaminase that restricts human immunodeficiency virus type 1 (HIV-1) and other lentiviruses. Most of these viruses encode a Vif protein that directly binds A3G and leads to its proteasomal degradation. Both Vif proteins of HIV-1 and African green monkey simian immunodeficiency virus (SIVagm) bind residue 128 of A3G. However, this position does not control the A3G degradation by Vif variants derived from HIV-2 and SIVmac, which both originated from SIV of sooty mangabey monkeys (SIVsmm), suggesting that the A3G binding site for Vif proteins of the SIVsmm/HIV-2 lineage differs from that of HIV-1. To map the SIVsmm Vif binding site of A3G, we performed immunoprecipitations of individual A3G domains, Vif/A3G degradation assays and a detailed mutational analysis of human A3G. We show that A3G residue 129, but not the adjacent position 128, confers susceptibility to degradation by SIVsmm Vif. An artificial A3G mutant, the P129D mutant, was resistant to degradation by diverse Vifs from HIV-1, HIV-2, SIVagm, and chimpanzee SIV (SIVcpz), suggesting a conserved lentiviral Vif binding site. Gorilla A3G naturally contains a glutamine (Q) at position 129, which makes its A3G resistant to Vifs from diverse lineages. We speculate that gorilla A3G serves as a barrier against SIVcpz strains. In summary, we show that Vif proteins from distinct lineages bind to the same A3G loop, which includes positions 128 and 129. The multiple adaptations within this loop among diverse primates underscore the importance of counteracting A3G in lentiviral evolution.
- Published
- 2013
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46. The transmembrane domain of HIV-1 Vpu is sufficient to confer anti-tetherin activity to SIVcpz and SIVgor Vpu proteins: cytoplasmic determinants of Vpu function.
- Author
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Kluge SF, Sauter D, Vogl M, Peeters M, Li Y, Bibollet-Ruche F, Hahn BH, and Kirchhoff F
- Subjects
- Animals, Antigens, CD, Cell Line, GPI-Linked Proteins antagonists & inhibitors, Gorilla gorilla, HIV-1 genetics, Human Immunodeficiency Virus Proteins genetics, Humans, Pan troglodytes, Protein Structure, Tertiary, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Recombination, Genetic, Simian Immunodeficiency Virus genetics, Viral Regulatory and Accessory Proteins genetics, HIV-1 physiology, Human Immunodeficiency Virus Proteins metabolism, Simian Immunodeficiency Virus physiology, Viral Regulatory and Accessory Proteins metabolism, Virus Release
- Abstract
Background: The acquisition of effective Vpu-mediated anti-tetherin activity to promote virion release following transmission of SIVcpzPtt from central chimpanzees (Pan troglodytes troglodytes) to humans distinguishes pandemic HIV-1 group M strains from non-pandemic group N, O and P viruses and may have been a prerequisite for their global spread. Some functional motifs in the cytoplasmic region of HIV-1 M Vpus proposed to be important for anti-tetherin activity are more frequently found in the Vpu proteins of SIVcpzPtt than in those of SIVcpzPts infecting eastern chimpanzees (P. t. schweinfurthii), that have not been detected in humans, and SIVgor from gorillas, which is closely related to HIV-1 O and P. Thus, SIVcpzPtt strains may require fewer adaptive changes in Vpu than SIVcpzPts or SIVgor strains to counteract human tetherin., Results: To examine whether SIVcpzPtt may only need changes in the transmembrane domain (TMD) of Vpu to acquire anti-tetherin activity, whereas SIVcpzPts and SIVgor may also require changes in the cytoplasmic region, we analyzed chimeras between the TMD of an HIV-1 M Vpu and the cytoplasmic domains of SIVcpzPtt (n = 2), SIVcpzPts (n = 2) and SIVgor (n = 2) Vpu proteins. Unexpectedly, all of these chimeras were capable of counteracting human tetherin to enhance virion release, irrespective of the presence or absence of the putative adaptor protein binding sites and the DSGxxS β-TrCP binding motif reported to be critical for effective anti-tetherin activity of M Vpus. It was also surprising that in three of the six chimeras the gain of anti-tetherin function was associated with a loss of the CD4 degradation activity since this function was conserved among all parental HIV-1, SIVcpz and SIVgor Vpu proteins., Conclusions: Our results show that changes in the TMD of SIVcpzPtt, SIVcpzPts and SIVgor Vpus are sufficient to render them active against human tetherin. Thus, several previously described domains in the extracellular region of Vpu are not absolutely essential for tetherin antagonism but may be required for other Vpu functions.
- Published
- 2013
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47. Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein.
- Author
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Sauter D, Unterweger D, Vogl M, Usmani SM, Heigele A, Kluge SF, Hermkes E, Moll M, Barker E, Peeters M, Learn GH, Bibollet-Ruche F, Fritz JV, Fackler OT, Hahn BH, and Kirchhoff F
- Subjects
- Amino Acid Sequence, Binding Sites, Blotting, Western, Cells, Cultured, Flow Cytometry, GPI-Linked Proteins antagonists & inhibitors, GPI-Linked Proteins metabolism, HIV Infections metabolism, HIV-1 pathogenicity, Humans, Molecular Sequence Data, Protein Interaction Domains and Motifs, Sequence Homology, Amino Acid, Virus Release, Antigens, CD metabolism, HIV Infections virology, HIV-1 metabolism, Human Immunodeficiency Virus Proteins metabolism, Selection, Genetic, Viral Regulatory and Accessory Proteins metabolism
- Abstract
HIV-1 groups M and N emerged within the last century following two independent cross-species transmissions of SIVcpz from chimpanzees to humans. In contrast to pandemic group M strains, HIV-1 group N viruses are exceedingly rare, with only about a dozen infections identified, all but one in individuals from Cameroon. Poor adaptation to the human host may be responsible for this limited spread of HIV-1 group N in the human population. Here, we analyzed the function of Vpu proteins from seven group N strains from Cameroon, the place where this zoonosis originally emerged. We found that these N-Vpus acquired four amino acid substitutions (E15A, V19A and IV25/26LL) in their transmembrane domain (TMD) that allow efficient interaction with human tetherin. However, despite these adaptive changes, most N-Vpus still antagonize human tetherin only poorly and fail to down-modulate CD4, the natural killer (NK) cell ligand NTB-A as well as the lipid-antigen presenting protein CD1d. These functional deficiencies were mapped to amino acid changes in the cytoplasmic domain that disrupt putative adaptor protein binding sites and an otherwise highly conserved ßTrCP-binding DSGxxS motif. As a consequence, N-Vpus exhibited aberrant intracellular localization and/or failed to recruit the ubiquitin-ligase complex to induce tetherin degradation. The only exception was the Vpu of a group N strain recently discovered in France, but originally acquired in Togo, which contained intact cytoplasmic motifs and counteracted tetherin as effectively as the Vpus of pandemic HIV-1 M strains. These results indicate that HIV-1 group N Vpu is under strong host-specific selection pressure and that the acquisition of effective tetherin antagonism may lead to the emergence of viral variants with increased transmission fitness.
- Published
- 2012
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48. Epitope mapping of broadly neutralizing HIV-2 human monoclonal antibodies.
- Author
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Kong R, Li H, Georgiev I, Changela A, Bibollet-Ruche F, Decker JM, Rowland-Jones SL, Jaye A, Guan Y, Lewis GK, Langedijk JP, Hahn BH, Kwong PD, Robinson JE, and Shaw GM
- Subjects
- Amino Acid Sequence, Antibodies, Neutralizing immunology, Biotinylation, Enzyme-Linked Immunosorbent Assay methods, Epitopes chemistry, HIV Antibodies immunology, HIV Infections immunology, Humans, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Neutralization Tests methods, Peptides chemistry, Protein Binding, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Antibodies, Monoclonal chemistry, Epitope Mapping methods, HIV-2 chemistry
- Abstract
Recent studies have shown that natural infection by HIV-2 leads to the elicitation of high titers of broadly neutralizing antibodies (NAbs) against primary HIV-2 strains (T. I. de Silva, et al., J. Virol. 86:930-946, 2012; R. Kong, et al., J. Virol. 86:947-960, 2012; G. Ozkaya Sahin, et al., J. Virol. 86:961-971, 2012). Here, we describe the envelope (Env) binding and neutralization properties of 15 anti-HIV-2 human monoclonal antibodies (MAbs), 14 of which were newly generated from 9 chronically infected subjects. All 15 MAbs bound specifically to HIV-2 gp120 monomers and neutralized heterologous primary virus strains HIV-2(7312A) and HIV-2(ST). Ten of 15 MAbs neutralized a third heterologous primary virus strain, HIV-2(UC1). The median 50% inhibitory concentrations (IC(50)s) for these MAbs were surprisingly low, ranging from 0.007 to 0.028 μg/ml. Competitive Env binding studies revealed three MAb competition groups: CG-I, CG-II, and CG-III. Using peptide scanning, site-directed mutagenesis, chimeric Env constructions, and single-cycle virus neutralization assays, we mapped the epitope of CG-I antibodies to a linear region in variable loop 3 (V3), the epitope of CG-II antibodies to a conformational region centered on the carboxy terminus of V4, and the epitope(s) of CG-III antibodies to conformational regions associated with CD4- and coreceptor-binding sites. HIV-2 Env is thus highly immunogenic in vivo and elicits antibodies having diverse epitope specificities, high potency, and wide breadth. In contrast to the HIV-1 Env trimer, which is generally well shielded from antibody binding and neutralization, HIV-2 is surprisingly vulnerable to broadly reactive NAbs. The availability of 15 human MAbs targeting diverse HIV-2 Env epitopes can facilitate comparative studies of HIV/SIV Env structure, function, antigenicity, and immunogenicity.
- Published
- 2012
- Full Text
- View/download PDF
49. Eastern chimpanzees, but not bonobos, represent a simian immunodeficiency virus reservoir.
- Author
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Li Y, Ndjango JB, Learn GH, Ramirez MA, Keele BF, Bibollet-Ruche F, Liu W, Easlick JL, Decker JM, Rudicell RS, Inogwabini BI, Ahuka-Mundeke S, Leendertz FH, Reynolds V, Muller MN, Chancellor RL, Rundus AS, Simmons N, Worobey M, Shaw GM, Peeters M, Sharp PM, and Hahn BH
- Subjects
- Amino Acid Sequence, Animals, Antibodies chemistry, CD4-Positive T-Lymphocytes cytology, Democratic Republic of the Congo, Female, Genetic Variation, Genome, Geography, Humans, Likelihood Functions, Male, Molecular Sequence Data, Pan paniscus, Pan troglodytes, Phylogeny, Rwanda, Sequence Homology, Amino Acid, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus genetics, Uganda, Virion, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus immunology
- Abstract
Chimpanzees in west central Africa (Pan troglodytes troglodytes) are endemically infected with simian immunodeficiency viruses (SIVcpzPtt) that have crossed the species barrier to humans and gorillas on at least five occasions, generating pandemic and nonpandemic forms of human immunodeficiency virus type 1 (HIV-1) as well as gorilla SIV (SIVgor). Chimpanzees in east Africa (Pan troglodytes schweinfurthii) are also infected with SIVcpz; however, their viruses (SIVcpzPts) have never been found in humans. To examine whether this is due to a paucity of natural infections, we used noninvasive methods to screen wild-living eastern chimpanzees in the Democratic Republic of the Congo (DRC), Uganda, and Rwanda. We also screened bonobos (Pan paniscus) in the DRC, a species not previously tested for SIV in the wild. Fecal samples (n = 3,108) were collected at 50 field sites, tested for species and subspecies origin, and screened for SIVcpz antibodies and nucleic acids. Of 2,565 samples from eastern chimpanzees, 323 were antibody positive and 92 contained viral RNA. The antibody-positive samples represented 76 individuals from 19 field sites, all sampled north of the Congo River in an area spanning 250,000 km(2). In this region, SIVcpzPts was common and widespread, with seven field sites exhibiting infection rates of 30% or greater. The overall prevalence of SIVcpzPts infection was 13.4% (95% confidence interval, 10.7% to 16.5%). In contrast, none of the 543 bonobo samples from six sites was antibody positive. All newly identified SIVcpzPts strains clustered in strict accordance to their subspecies origin; however, they exhibited considerable genetic diversity, especially in protein domains known to be under strong host selection pressure. Thus, the absence of SIVcpzPts zoonoses cannot be explained by an insufficient primate reservoir. Instead, greater adaptive hurdles may have prevented the successful colonization of humans by P. t. schweinfurthii viruses.
- Published
- 2012
- Full Text
- View/download PDF
50. Reacquisition of Nef-mediated tetherin antagonism in a single in vivo passage of HIV-1 through its original chimpanzee host.
- Author
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Götz N, Sauter D, Usmani SM, Fritz JV, Goffinet C, Heigele A, Geyer M, Bibollet-Ruche F, Learn GH, Fackler OT, Hahn BH, and Kirchhoff F
- Subjects
- Amino Acid Substitution, Animals, Disease Models, Animal, HIV-1 growth & development, Humans, Mutant Proteins genetics, Mutant Proteins metabolism, Mutation, Missense, Pan troglodytes, Primate Diseases virology, nef Gene Products, Human Immunodeficiency Virus genetics, Antigens, CD immunology, HIV-1 immunology, Human Immunodeficiency Virus Proteins metabolism, Primate Diseases immunology, Viral Regulatory and Accessory Proteins metabolism, Virulence Factors metabolism, nef Gene Products, Human Immunodeficiency Virus metabolism
- Abstract
The interferon-induced host restriction factor tetherin poses a barrier for SIV transmission from primates to humans. After cross-species transmission, the chimpanzee precursor of pandemic HIV-1 switched from the accessory protein Nef to Vpu to effectively counteract human tetherin. As we report here, the experimental reintroduction of HIV-1 into its original chimpanzee host resulted in a virus that can use both Vpu and Nef to antagonize chimpanzee tetherin. Functional analyses demonstrated that alterations in and near the highly conserved ExxxLL motif in the C-terminal loop of Nef were critical for the reacquisition of antitetherin activity. Strikingly, just two amino acid changes allowed HIV-1 Nef to counteract chimpanzee tetherin and promote virus release. Our data demonstrate that primate lentiviruses can reacquire lost accessory gene functions during a single in vivo passage and suggest that other functional constraints keep Nef ready to regain antitetherin activity., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
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