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Article ; Online: Antibody-mediated immune exclusion of HIV.

Ruprecht, Ruth M / Lakhashe, Samir K

2017 Volume 12, Issue 3, Page(s) 222–228

Abstract: Purpose of review: Although approximately 90% of all HIV transmissions in humans occur through mucosal contact, the induction of mucosal anti-HIV immune responses has remained understudied. Here we summarize data demonstrating the powerful protection ... ...

Abstract	Purpose of review: Although approximately 90% of all HIV transmissions in humans occur through mucosal contact, the induction of mucosal anti-HIV immune responses has remained understudied. Here we summarize data demonstrating the powerful protection that is achievable at mucosal frontlines through virus-specific mucosal IgA alone or combined with IgG. Recent findings: Passive immunization with different monoclonal antibody subclasses but identical epitope specificity (the conserved V3-loop crown of HIV gp120) has revealed that the dimeric IgA1 (dIgA1) form with its open hinge can prevent simian-human immunodeficiency virus (SHIV) acquisition in rhesus macaques at a higher rate than dIgA2. Both dIgAs neutralized the challenge SHIV equally well. Protection was linked to better virion capture and inhibition of cell-free virus transcytosis by dIgA1. Synergistic interactions at the mucosal level between the IgG1 and dIgA2 versions of this monoclonal antibody yielded complete protection. Active vaccine strategies designed to induce mucosal IgA and systemic/mucosal IgG have given promising data. Summary: This review seeks to highlight the importance of mucosal IgAs in preventing virus acquisition. Passive immunization gave proof-of-concept for immune exclusion by mucosally administered monoclonal dIgAs. Unanswered questions remain regarding the interplay between mucosal IgA and other host immune defenses, including their induction with active immunization.
MeSH term(s)	Animals ; HIV Antibodies/immunology ; HIV Infections/immunology ; HIV Infections/virology ; HIV-1/immunology ; HIV-1/physiology ; Humans ; Immunity, Mucosal
Chemical Substances	HIV Antibodies
Language	English
Publishing date	2017-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2502511-9
ISSN	1746-6318 ; 1746-630X
ISSN (online)	1746-6318
ISSN	1746-630X
DOI	10.1097/COH.0000000000000369
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Article ; Online: Mucosal AIDS virus transmission is enhanced by antiviral IgG isolated early in infection.

Marasini, Bishal / Vyas, Hemant K / Lakhashe, Samir K / Hariraju, Dinesh / Akhtar, Akil / Ratcliffe, Sarah J / Ruprecht, Ruth M

AIDS (London, England)

2021 Volume 35, Issue 15, Page(s) 2423–2432

Abstract: Objective: Antibody-dependent enhancement (ADE) affects host-virus dynamics in fundamentally different ways: i) enhancement of initial virus acquisition, and/or ii) increased disease progression/severity. Here we address the question whether anti-HIV-1 ... ...

Abstract	Objective: Antibody-dependent enhancement (ADE) affects host-virus dynamics in fundamentally different ways: i) enhancement of initial virus acquisition, and/or ii) increased disease progression/severity. Here we address the question whether anti-HIV-1 antibodies can enhance initial infection. While cell-culture experiments hinted at this possibility, in-vivo proof remained elusive. Design: We used passive immunization in nonhuman primates challenged with simian-human immunodeficiency virus (SHIV), a chimera expressing HIV-1 envelope. We purified IgG from rhesus monkeys with early-stage SHIV infection - before cross-neutralizing anti-HIV-1 antibodies had developed - and screened for maximal complement-mediated antibody-dependent enhancement (C'-ADE) of viral replication with a SHIV strain phylogenetically distinct from that harbored by IgG donor macaques. IgG fractions with maximal C'-ADE but lacking neutralization were combined to yield enhancing anti-SHIV IgG (enSHIVIG). Results: We serially enrolled naive macaques (Group 1) to determine the minimal and 50% animal infectious doses required to establish persistent infection after intrarectal SHIV challenge. The first animal was inoculated with a 1 : 10 virus-stock dilution; after this animal's viral RNA load was >104copies/ml, the next macaque was challenged with 10x less virus, a process repeated until viremia no longer ensued. Group 2 was pretreated intravenously with enSHIVIG 24 h before SHIV challenge. Overall, Group 2 macaques required 3.4-fold less virus compared to controls (P = 0.002). This finding is consistent with enhanced susceptibility of the passively immunized animals to mucosal SHIV challenge. Conclusion: These passive immunization data give proof of IgG-mediated enhanced virus acquisition after mucosal exposure - a potential concern for antibody-based AIDS vaccine development.
MeSH term(s)	AIDS Vaccines ; Animals ; Antiviral Agents ; HIV Antibodies ; HIV Infections ; HIV-1 ; Immunoglobulin G ; Simian Acquired Immunodeficiency Syndrome ; Simian Immunodeficiency Virus
Chemical Substances	AIDS Vaccines ; Antiviral Agents ; HIV Antibodies ; Immunoglobulin G
Language	English
Publishing date	2021-08-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639076-6
ISSN	1473-5571 ; 0269-9370 ; 1350-2840
ISSN (online)	1473-5571
ISSN	0269-9370 ; 1350-2840
DOI	10.1097/QAD.0000000000003050
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Article ; Online: Cooperation Between Systemic and Mucosal Antibodies Induced by Virosomal Vaccines Targeting HIV-1 Env: Protection of Indian Rhesus Macaques Against Low-Dose Intravaginal SHIV Challenges.

Lakhashe, Samir K / Amacker, Mario / Hariraju, Dinesh / Vyas, Hemant K / Morrison, Kyle S / Weiner, Joshua A / Ackerman, Margaret E / Roy, Vicky / Alter, Galit / Ferrari, Guido / Montefiori, David C / Tomaras, Georgia D / Sawant, Sheetal / Yates, Nicole L / Gast, Chris / Fleury, Sylvain / Ruprecht, Ruth M

Frontiers in immunology

2022 Volume 13, Page(s) 788619

Abstract: A virosomal vaccine inducing systemic/mucosal anti-HIV-1 gp41 IgG/IgA had previously protected Chinese-origin rhesus macaques (RMs) against vaginal ... ...

Abstract	A virosomal vaccine inducing systemic/mucosal anti-HIV-1 gp41 IgG/IgA had previously protected Chinese-origin rhesus macaques (RMs) against vaginal SHIV
MeSH term(s)	AIDS Vaccines ; Animals ; Female ; HIV Seropositivity ; HIV-1 ; Humans ; Immunoglobulin A ; Immunoglobulin G ; Macaca mulatta ; Simian Immunodeficiency Virus ; Virosomes
Chemical Substances	AIDS Vaccines ; Immunoglobulin A ; Immunoglobulin G ; Virosomes
Language	English
Publishing date	2022-02-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.788619
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Article ; Online: Cooperation Between Systemic IgG1 and Mucosal Dimeric IgA2 Monoclonal Anti-HIV Env Antibodies: Passive Immunization Protects Indian Rhesus Macaques Against Mucosal SHIV Challenges.

Gong, Siqi / Lakhashe, Samir K / Hariraju, Dinesh / Scinto, Hanna / Lanzavecchia, Antonio / Cameroni, Elisabetta / Corti, Davide / Ratcliffe, Sarah J / Rogers, Kenneth A / Xiao, Peng / Fontenot, Jane / Villinger, François / Ruprecht, Ruth M

Frontiers in immunology

2021 Volume 12, Page(s) 705592

Abstract: Understanding the interplay between systemic and mucosal anti-HIV antibodies can provide important insights to develop new prevention strategies. We used passive ... ...

Abstract	Understanding the interplay between systemic and mucosal anti-HIV antibodies can provide important insights to develop new prevention strategies. We used passive immunization
MeSH term(s)	Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacology ; Antibodies, Neutralizing/immunology ; Antibodies, Neutralizing/pharmacology ; HIV Antibodies/immunology ; HIV Antibodies/pharmacology ; HIV-1/immunology ; Immunity, Mucosal/drug effects ; Immunization, Passive ; Macaca mulatta ; Pilot Projects ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Acquired Immunodeficiency Syndrome/prevention & control ; Simian Immunodeficiency Virus/immunology
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; HIV Antibodies
Language	English
Publishing date	2021-08-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.705592
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Article ; Online: Localization of infection in neonatal rhesus macaques after oral viral challenge.

Taylor, Roslyn A / McRaven, Michael D / Carias, Ann M / Anderson, Meegan R / Matias, Edgar / Araínga, Mariluz / Allen, Edward J / Rogers, Kenneth A / Gupta, Sandeep / Kulkarni, Viraj / Lakhashe, Samir / Lorenzo-Redondo, Ramon / Thomas, Yanique / Strickland, Amanda / Villinger, Francois J / Ruprecht, Ruth M / Hope, Thomas J

PLoS pathogens

2021 Volume 17, Issue 11, Page(s) e1009855

Abstract: Vertical transmission of human immunodeficiency virus (HIV) can occur in utero, during delivery, and through breastfeeding. We utilized Positron Emission Tomography (PET) imaging coupled with fluorescent microscopy of 64Cu-labeled photoactivatable-GFP- ... ...

Abstract	Vertical transmission of human immunodeficiency virus (HIV) can occur in utero, during delivery, and through breastfeeding. We utilized Positron Emission Tomography (PET) imaging coupled with fluorescent microscopy of 64Cu-labeled photoactivatable-GFP-HIV (PA-GFP-BaL) to determine how HIV virions distribute and localize in neonatal rhesus macaques two and four hours after oral viral challenge. Our results show that by four hours after oral viral exposure, HIV virions localize to and penetrate the rectal mucosa. We also used a dual viral challenge with a non-replicative viral vector and a replication competent SHIV-1157ipd3N4 to examine viral transduction and dissemination at 96 hours. Our data show that while SHIV-1157ipd3N4 infection can be found in the oral cavity and upper gastrointestinal (GI) tract, the small and large intestine contained the largest number of infected cells. Moreover, we found that T cells were the biggest population of infected immune cells. Thus, thanks to these novel technologies, we are able to visualize and delineate of viral distribution and infection throughout the entire neonatal GI tract during acute viral infection.
MeSH term(s)	Animals ; Animals, Newborn ; Copper Radioisotopes/analysis ; Gastrointestinal Tract/virology ; HIV Infections/virology ; HIV-1/isolation & purification ; Humans ; Macaca mulatta ; Positron Emission Tomography Computed Tomography ; Simian Acquired Immunodeficiency Syndrome/virology ; Simian Immunodeficiency Virus/isolation & purification ; T-Lymphocytes/virology ; Viral Load
Chemical Substances	Copper Radioisotopes ; Copper-64
Language	English
Publishing date	2021-11-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1009855
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Article ; Online: No acquisition: a new ambition for HIV vaccine development?

Lakhashe, Samir K / Silvestri, Guido / Ruprecht, Ruth M

Current opinion in virology

2011 Volume 1, Issue 4, Page(s) 246–253

Abstract: Development of a safe and effective prophylactic HIV-1 vaccine presents unique challenges. The pessimism following the failure of two HIV-1 vaccine concepts in clinical trials, HIV-1 gp120 and an adenovirus-based approach to induce only cellular immune ... ...

Abstract	Development of a safe and effective prophylactic HIV-1 vaccine presents unique challenges. The pessimism following the failure of two HIV-1 vaccine concepts in clinical trials, HIV-1 gp120 and an adenovirus-based approach to induce only cellular immune responses, has been replaced by cautious optimism engendered by the RV144 trial outcome, the isolation of several new broadly reactive neutralizing monoclonal antibodies, and recent primate model data indicating prevention of viral acquisition by active or passive immunization. Intense efforts are underway to optimize immunogen design, adjuvants, and the tools for preclinical evaluation of candidate vaccines in primates, where correlates of protection can be examined in detail - as proof-of-concept for clinical trials.
MeSH term(s)	AIDS Vaccines/genetics ; AIDS Vaccines/immunology ; Animals ; Clinical Trials as Topic ; Drug Design ; HIV Infections/immunology ; HIV Infections/prevention & control ; HIV Infections/virology ; HIV-1/genetics ; HIV-1/immunology ; Humans
Chemical Substances	AIDS Vaccines
Language	English
Publishing date	2011-03-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2011.07.005
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Article ; Online: Bimodal AIDS vaccine approach: induction of cellular as well as humoral immunity can protect from systemic infection.

Rasmussen, Robert A / Lakhashe, Samir K / Ruprecht, Ruth M

Vaccine

2010 Volume 28 Suppl 2, Page(s) B25–31

Abstract: HIV clade C (HIV-C) strains comprise approximately 56% of all HIV infections worldwide, and AIDS vaccines intended for global use must protect against this subtype. Our vaccine strategy has been to induce balanced antiviral immunity consisting of both ... ...

Abstract	HIV clade C (HIV-C) strains comprise approximately 56% of all HIV infections worldwide, and AIDS vaccines intended for global use must protect against this subtype. Our vaccine strategy has been to induce balanced antiviral immunity consisting of both neutralizing antibody and cell-mediated immune responses, an approach we tested in primates. As reported earlier, after isolating recently transmitted HIV-C strains from Zambian infants, we used env from one such virus, HIV1084i, to generate a multimeric gp160 immunogen. From another virus, isolated from a different child of the same mother-infant cohort, we cloned env to generate a recombinant simian-human immunodeficiency virus (SHIV), which was adapted to rhesus monkeys to yield SHIV-1157ip. Infant macaques were immunized with recombinant viral proteins, including multimeric HIV-C Env 1084i. To test whether cross-protection could be achieved, we mismatched HIV-C Env immunogens and challenge virus env. All vaccinated and control monkeys were exposed orally to low-dose SHIV-1157ip. Animals with no or only transient infection were rechallenged intrarectally with a high dose of R5 SHIV-1157ipd3N4, a "late", animal-evolved variant of SHIV-1157ip. Compared to controls, the vaccinees had significantly lower peak viral RNA loads, and one vaccinee remained completely virus-free, even in lymphoid tissues. Data from our novel heterologous mucosal challenge model and our protein-only immunogens imply that significant protection against heterologous viruses circulating in the local community may be achievable with a strategy that seeks to simultaneously induce cellular immunity as well as neutralizing antibody responses.
MeSH term(s)	AIDS Vaccines/immunology ; Amino Acid Sequence ; Animals ; Animals, Newborn ; Antibodies, Neutralizing/blood ; Antibodies, Neutralizing/immunology ; HIV Antibodies/blood ; HIV Antibodies/immunology ; HIV Envelope Protein gp160/immunology ; HIV Infections/immunology ; HIV Infections/prevention & control ; Immunity, Cellular ; Immunity, Humoral ; Macaca mulatta ; Molecular Sequence Data ; Recombinant Proteins/immunology ; Viral Load
Chemical Substances	AIDS Vaccines ; Antibodies, Neutralizing ; HIV Antibodies ; HIV Envelope Protein gp160 ; Recombinant Proteins
Language	English
Publishing date	2010-05-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2009.10.131
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Article ; Online: Modified Adenovirus Prime-Protein Boost Clade C HIV Vaccine Strategy Results in Reduced Viral DNA in Blood and Tissues Following Tier 2 SHIV Challenge.

Frontiers in immunology

2021 Volume 11, Page(s) 626464

Abstract: Designing immunogens and improving delivery methods eliciting protective immunity is a paramount goal of HIV vaccine development. A comparative vaccine challenge study was performed in rhesus macaques using clade C HIV Envelope (Env) and SIV Gag antigens. ...

Abstract	Designing immunogens and improving delivery methods eliciting protective immunity is a paramount goal of HIV vaccine development. A comparative vaccine challenge study was performed in rhesus macaques using clade C HIV Envelope (Env) and SIV Gag antigens. One group was vaccinated using co-immunization with DNA Gag and Env expression plasmids cloned from a single timepoint and trimeric Env gp140 glycoprotein from one of these clones (DNA+Protein). The other group was a prime-boost regimen composed of two replicating simian (SAd7) adenovirus-vectored vaccines expressing Gag and one Env clone from the same timepoint as the DNA+Protein group paired with the same Env gp140 trimer (SAd7+Protein). The env genes were isolated from a single pre-peak neutralization timepoint approximately 1 year post infection in CAP257, an individual with a high degree of neutralization breadth. Both DNA+Protein and SAd7+Protein vaccine strategies elicited significant Env-specific T cell responses, lesser Gag-specific responses, and moderate frequencies of Env-specific T
MeSH term(s)	AIDS Vaccines/immunology ; AIDS Vaccines/pharmacology ; Adenoviridae ; Animals ; DNA, Viral/blood ; DNA, Viral/immunology ; HIV Antibodies/blood ; HIV Antibodies/immunology ; HIV Infections/blood ; HIV Infections/immunology ; HIV Infections/prevention & control ; Immunization, Secondary ; Immunoglobulin A/blood ; Immunoglobulin A/immunology ; Immunoglobulin G/blood ; Immunoglobulin G/immunology ; Macaca mulatta ; Male
Chemical Substances	AIDS Vaccines ; DNA, Viral ; HIV Antibodies ; Immunoglobulin A ; Immunoglobulin G
Language	English
Publishing date	2021-02-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.626464
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Article: Characterization of B/C recombinants of near full-length HIV type 1 from northeastern India with mosaics identical to ARE195FL but with a different ancestral origin.

Lakhashe, Samir / Tripathy, Srikanth / Paranjape, Ramesh / Bhattacharya, Jayanta

AIDS research and human retroviruses

2008 Volume 24, Issue 1, Page(s) 92–99

Abstract: We have characterized near full-length genomes of three B/C recombinants of HIV-1 from the northeastern state of India. The recombinant viruses showed a backbone of subtype C virus with a single insertion of the subtype B genome in the envelope region. ... ...

Abstract	We have characterized near full-length genomes of three B/C recombinants of HIV-1 from the northeastern state of India. The recombinant viruses showed a backbone of subtype C virus with a single insertion of the subtype B genome in the envelope region. While all of them were distinct from B/C recombinants CRF_07 and CRF_08 circulating in China and CRF_04BR137 circulating in Brazil, two of them presented with break-points identical to the Argentinean B/C recombinant ARE195FL. However, neighbor-joining analysis followed by phylogenetic clustering showed that gp120 belonging to subtype B of all the recombinants clustered with Thai B sequences, while subtype C gag clustered with an Indian subtype C sequence, suggesting a unique ancestral origin of these recombinants.
MeSH term(s)	Evolution, Molecular ; Gene Products, gag/genetics ; Genome, Viral ; HIV Envelope Protein gp120/genetics ; HIV Infections/virology ; HIV-1/classification ; HIV-1/genetics ; HIV-1/isolation & purification ; Humans ; India ; Molecular Sequence Data ; Mosaicism ; Phylogeny ; Recombination, Genetic ; Sequence Analysis, DNA
Chemical Substances	Gene Products, gag ; HIV Envelope Protein gp120
Language	English
Publishing date	2008-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639130-8
ISSN	1931-8405 ; 0889-2229
ISSN (online)	1931-8405
ISSN	0889-2229
DOI	10.1089/aid.2007.0214
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Article: Evidence of a novel B/C recombinant exhibiting unique breakpoints of near full-length HIV type 1 genome from Northeastern India.

Lakhashe, Samir / Tripathy, Srikanth / Paranjape, Ramesh / Bhattacharya, Jayanta

AIDS research and human retroviruses

2008 Volume 24, Issue 2, Page(s) 229–234

Abstract: Despite the predominance of the HIV-1 clade C in India, the presence of other subtypes and recombinants has been reported. Here we report the identification of a novel HIV-1 B/C recombinant isolated from Northeast India and characterized near full length ...

Abstract	Despite the predominance of the HIV-1 clade C in India, the presence of other subtypes and recombinants has been reported. Here we report the identification of a novel HIV-1 B/C recombinant isolated from Northeast India and characterized near full length genome of the recombinant virus. Bootscan analysis of the nearly full-length genome showed a unique mosaic structure consisting of a subtype B backbone with three subtype C genome insertions. Breakpoint analyses revealed insertion of fragments belonging to subtype C at positions 1853-2223 in gag and 3025-3759 and 3998-5073 in pol. Phylogenetic analysis revealed that the segments of subtype B clustered with sequences of subtype B viruses reported from Thailand whereas segments of subtype C clustered with sequences of subtype C viruses reported from India. We report the mosaic structure that is distinct to HIV-1 B/C recombinant viruses reported to date.
MeSH term(s)	Cluster Analysis ; Genome, Viral ; Genotype ; HIV Infections/virology ; HIV-1/classification ; HIV-1/genetics ; HIV-1/isolation & purification ; Humans ; INDEL Mutation ; India ; Phylogeny ; Recombination, Genetic ; Sequence Analysis, DNA
Language	English
Publishing date	2008-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639130-8
ISSN	1931-8405 ; 0889-2229
ISSN (online)	1931-8405
ISSN	0889-2229
DOI	10.1089/aid.2007.0229
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