204 results on '"Kalyanaraman VS"'
Search Results
2. Non-neutralizing antibodies and vaccine-induced protection
- Author
-
Demberg, Thorsten, primary, Florese, Ruth H, additional, Gomez-Roman, V Raul, additional, Larsen, Kay, additional, Van Rompay, Koen KA, additional, Marthas, Marta L, additional, Venzon, David, additional, Kalyanaraman, VS, additional, Pal, Ranajit, additional, Barnett, Susan W, additional, Cafaro, Aurelio, additional, Ensoli, Barbara, additional, and Robert-Guroff, Marjiorie, additional
- Published
- 2006
- Full Text
- View/download PDF
3. Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor- alpha secretion
- Author
-
Oyaizu, N, primary, McCloskey, TW, additional, Than, S, additional, Hu, R, additional, Kalyanaraman, VS, additional, and Pahwa, S, additional
- Published
- 1994
- Full Text
- View/download PDF
4. Effect of human immunodeficiency virus type-1 envelope glycoprotein gp160 on cytokine production from cord-blood T cells
- Author
-
Than, S, primary, Oyaizu, N, additional, Pahwa, RN, additional, Kalyanaraman, VS, additional, and Pahwa, S, additional
- Published
- 1994
- Full Text
- View/download PDF
5. Accelerated apoptosis in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus type-1 infected patients and in CD4 cross-linked PBMCs from normal individuals
- Author
-
Oyaizu, N, primary, McCloskey, TW, additional, Coronesi, M, additional, Chirmule, N, additional, Kalyanaraman, VS, additional, and Pahwa, S, additional
- Published
- 1993
- Full Text
- View/download PDF
6. Effect of human immunodeficiency virus-1 envelope glycoprotein on in vitro hematopoiesis of umbilical cord blood
- Author
-
Sugiura, K, primary, Oyaizu, N, additional, Pahwa, R, additional, Kalyanaraman, VS, additional, and Pahwa, S, additional
- Published
- 1992
- Full Text
- View/download PDF
7. Inhibition of normal B-cell function by human immunodeficiency virus envelope glycoprotein, gp120
- Author
-
Chirmule, N, primary, Oyaizu, N, additional, Kalyanaraman, VS, additional, and Pahwa, S, additional
- Published
- 1992
- Full Text
- View/download PDF
8. Inhibition of functional properties of tetanus antigen-specific T-cell clones by envelope glycoprotein GP120 of human immunodeficiency virus
- Author
-
Chirmule, N, primary, Kalyanaraman, VS, additional, Oyaizu, N, additional, Slade, HB, additional, and Pahwa, S, additional
- Published
- 1990
- Full Text
- View/download PDF
9. Serological confirmation of human T-lymphotropic virus type I infection in healthy blood and plasma donors
- Author
-
Anderson, DW, Epstein, JS, Lee, TH, Lairmore, MD, Saxinger, C, Kalyanaraman, VS, Slamon, D, Parks, W, Poiesz, BJ, and Pierik, LT
- Abstract
We wished to develop criteria for serological confirmation of human T- lymphotropic virus type I (HTLV-I) infection in healthy donors. Selected serum or plasma samples reactive by HTLV-I enzyme immunosorbent assay or gel-agglutination assays with at least one viral- specific band on Western immunoblot (WIB) were tested in six laboratories by four WIBs and four radioimmunoprecipitation assays (RIPAs) for antibodies to HTLV-I proteins encoded by gag (p19 and p24), env (gp46 and/or gp61), and tax (p40x) genes. One hundred forty-two donor sera were obtained from 38 Japanese, 69 American, and 35 Caribbean blood or plasma donors. Among these samples, WIB assays appeared more sensitive to p24 antibodies, whereas RIPAs were significantly more sensitive to gp61 antibodies. All sera (137) with gp61 antibodies had p24 antibodies. Of the 137 sera positive for p24 and gp61 antibodies, p19 antibodies were detected in 129 sera, and p40x antibodies were detected in 108. In sera with p19 antibodies and antibodies to env- or tax-encoded proteins, p24 antibodies were always present. Antibodies to p40x were not found in the absence of gp61 antibodies. Virological evidence of infection was found in seven American donors by lymphocyte coculture (one HTLV-I, one HTLV-II) or by polymerase chain reaction (three HTLV-I, two HTLV-II). Sera from all seven donors showed p24 and gp46 and/or gp61 antibodies. We suggest that seroreactivity to both p24 and gp46 and/or gp61 by WIB or RIPA or both are suitable criteria to confirm but not to distinguish HTLV-I and HTLV-II infections.
- Published
- 1989
- Full Text
- View/download PDF
10. Transformed T lymphocytes infected by a novel isolate of human T cell leukemia virus type II
- Author
-
Chorba, TL, Brynes, R, Kalyanaraman, VS, Telfer, M, Ramsey, R, Mawle, A, Palmer, EL, Chen, AT, Feorino, P, and Evatt, BL
- Abstract
Human T cell leukemia virus type II (HTLV-II) has been isolated from a patient (Mo) with features of leukemic reticuloendotheliosis (LRE) and from a patient with acquired immunodeficiency syndrome (AIDS). We have obtained another isolate of HTLV-II from a patient (CM) with severe hemophilia A, pancytopenia, and a 14-year history of staphylococcal and candidal infections but no evidence of T cell leukemia/lymphoma, AIDS, or LRE. Fresh mononuclear cells and cultured lymphocytes from CM express retroviral antigens indistinguishable by molecular criteria from HTLV-IIMo. Leukocyte cultures from CM yield hyperdiploid (48,XY, +2, +19) continuous lymphoid lines; human fetal cord blood lymphocytes (CBL) are transformed by cocultivation with these CM cell cultures but retain normal cytogenetic constitution. Electron microscopic examination of the CM cultures and transformed CBL reveals budding of extracellular viral particles, intracellular tubuloreticular structures, and viral particles contained within intracellular vesicles. CM cell cultures and the transformed CBL do not require exogenous interleukin 2, have T cell cytochemical features and mature T helper phenotypes, and exhibit minimal T helper and profound T suppressor activity on pokeweed mitogen-stimulated differentiation of normal B cells. These characteristics, which are similar to those observed with the first HTLV-II isolate, may represent properties of all HTLV-II-infected T cells.
- Published
- 1985
- Full Text
- View/download PDF
11. Screening tests for blood donors presumed to have transmitted the acquired immunodeficiency syndrome
- Author
-
McDougal, JS, Jaffe, HW, Cabridilla, CD, Sarngadharan, MG, Nicholson, JK, Kalyanaraman, VS, Schable, CA, Kilbourne, B, Evatt, BL, and Gallo, RC
- Abstract
We investigated 18 sets of blood donors from 12 to 50 months after they donated blood to recipients who subsequently developed the acquired immunodeficiency syndrome (AIDS). Within each donor set, only one donor was suspected of having transmitted the disease (ie, member of an AIDS risk group). The other donors (n = 189) were not risk group members and served as controls. A number of laboratory tests distinguished suspected from nonsuspected donors, including determination of T helper/T suppressor cell ratio, antibody to hepatitis B core antigen, and immune complexes, but none of these was as sensitive and specific as tests for antibody to the human retrovirus, HTLV-III/LAV.
- Published
- 1985
- Full Text
- View/download PDF
12. Unsung Hero Robert C. Gallo
- Author
-
Abbadessa, G, Accolla, R, Aiuti, F, Albini, A, Aldovini, A, Alfano, M, Antonelli, G, Bartholomew, C, Bentwich, Z, Bertazzoni, U, Berzofsky, Ja, Biberfeld, P, Boeri, E, Buonaguro, L, Buonaguro, Fm, Bukrinsky, M, Burny, A, Caruso, A, Cassol, S, Chandra, P, CECCHERINI NELLI, L, CHIECO BIANCHI, L, Clerici, M, COLOMBINI HATCH, S, Giuli, De, Morghen, C, DE MARIA, A, DE ROSSI, A, Dierich, M, DELLA FAVERA, R, Dolei, A, Douek, D, Erfle, V, Felber, B, Fiorentini, S, Franchini, G, Gershoni, Jm, Gotch, F, Green, P, Greene, Wc, Hall, W, Haseltine, W, Jacobson, S, Kallings, Lo, Kalyanaraman, Vs, Katinger, H, Khalili, K, Klein, G, Klein, E, Klotman, M, Klotman, P, Kotler, M, Kurth, R, Lafeuillade, A, LA PLACA, M, Lewis, J, Lillo, F, Lisziewicz, J, Lomonico, A, Lopalco, L, Lori, F, Lusso, P, Macchi, B, Malim, M, Margolis, L, Markham, Pd, Mcclure, M, Miller, N, Mingari, Mc, Moretta, L, Noonan, D, O'Brien, S, Okamoto, T, Pal, R, Palese, P, Panet, A, Pantaleo, G, Pavlakis, G, Pistello, M, Plotkin, S, Poli, G, Pomerantz, R, Radaelli, A, Robertguroff, M, Roederer, M, Sarngadharan, Mg, Schols, D, Secchiero, P, Shearer, G, Siccardi, A, Stevenson, M, Svoboda, J, Tartaglia, J, Torelli, G, Tornesello, Ml, Tschachler, E, Vaccarezza, Mauro, Vallbracht, A, VAN LUNZEN, J, Varnier, O, Vicenzi, E, Von, Melchner, H, Witz, I, Zagury, D, Zagury, Jf, Zauli, G, Zipeto, D., Abbadessa G, Accolla A, Aiuti F, Albini A, Aldovini A, Alfano M, Antonelli G, Bartholomew C, Bentwich Z, Bertazzoni U, Berzofski JA, Biberfeld P, Boeri E, Buonaguro L, Buonaguro FM, Bukrinsky M, Burny A, Caruso A, Cassol S, Chandra P, Ceccherini-Nelli L, Chieco-Bianchi L, Clerici M, Colombini-Hatc S, De Giuli Morghen C, De Maria A, De Rossi A, Dierich M, Della-Favera R, Dolei A, Douek D, Erfle V, Felber B, Fiorentini S, Franchini G, Gershoni JM, Gotch F, Green P, Greene WC, Hall W, Haseltine W, Jacobson S, Kallings LO, Kalianaraman VS, Katinger H, Khalili K, Klein G, Klein E, Klotman M, Klotman P, Kotler M, Kurth R, Lafeuillade A, La Placa M, Lewis J, Lillo F, Lisziewicz J, Lomonico A, Lopalco L, Lori F, Lusso P, Macchi B, malim M, margolis L, Markham PD, McClure M, Miller N, Mingari MC, Moretta L, Noonan D, O'Brien S, Okamoto T, Pal R, Palese P, Panet A, Pantaleo G, Pavlakis J, Pistello M, Plotkin S, Poli G, Pomerantz R, Radaelli A, Robert-Guroff M, Roederer M, Sarnagadharan MG, Schols D, Secchiero P, Shearer G, Siccardi A, Stevenson M, Svoboda J, Tartaglia J, Torelli G, Tornesello ML, Tschachler E, Vaccarezza M, Vallbracht A, Van Lunzen J, Varnier O, Vicenzi E, Von Melchner H, Witz I, Zagury D, Zagury JF, Zauli G, Zipeto D., Abbadessa, Giovanni, Accolla, Roberto, Aiuti, Fernando, Albini, Adriana, Aldovini, Anna, Alfano, Massimo, Antonelli, Guido, Bartholomew, Courtenay, Bentwich, Zvi, Bertazzoni, Umberto, Berzofsky Jay, A., Biberfeld, Peter, Boeri, Enzo, Buonaguro, Luigi, Buonaguro Franco, M., Bukrinsky, Michael, Burny, Arsene, Caruso, Arnaldo, Cassol, Sharon, Chandra, Prakash, Ceccherini Nelli, Luca, Chieco Bianchi, Luigi, Clerici, Mario, Colombini Hatch, Sandra, Morghen Carlo De, Giuli, De Maria, Andrea, De Rossi, Anita, Dierich, Manfred, Della Favera, Riccardo, Dolei, Antonina, Douek, Daniel, Erfle, Volker, Felber, Barbara, Fiorentini, Simona, Franchini, Genoveffa, Gershoni Jonathan, M., Gotch, France, Green, Patrick, Greene Warner, C., Hall, William, Haseltine, William, Jacobson, Stephen, Kallings Lars, O., Kalyanaraman Vaniambadi, S., Katinger, Hermann, Khalili, Kamel, Klein, George, Klein, Eva, Klotman, Mary, Klotman, Paul, Kotler, Moshe, Kurth, Reinhard, Lafeuillade, Alain, La Placa, Michelangelo, Lewis, Jonathan, Lillo, Flavia, Lisziewicz, Julianna, Lomonico, Anita, Lopalco, Lucia, Lori, Franco, Lusso, Paolo, Macchi, Beatrice, Malim, Michael, Margolis, Leonid, Markham Phillip, D., Mcclure, Myra, Miller, Nancy, Mingari Maria, C., Moretta, Lorenzo, Noonan, Dougla, O'Brien, Steve, Okamoto, Takashi, Pal, Ranajit, Palese, Peter, Panet, Amo, Pantaleo, Giuseppe, Pavlakis, George, Pistello, Mauro, Plotkin, Stanley, Poli, Guido, Pomerantz, Roger, Radaelli, Antonia, Robert Guroff, Marjorie, Roederer, Mario, Sarngadharan Mangalasseril, G., Schols, Dominique, Secchiero, Paola, Shearer, Gene, Siccardi, Antonio, Stevenson, Mario, Svoboda, Jan, Tartaglia, Jim, Torelli, Giuseppe, Tornesello Maria, Lina, Tschachler, Erwin, Vaccarezza, Mauro, Vallbracht, Angelika, Van Lunzen, Jan, Varnier, Oliviero, Vicenzi, Elisa, Von Melchner, Harald, Witz, Isaac, Zagury, Daniel, Zagury Jean, Francoi, Zauli, Giorgio, and Zipeto, Donato
- Subjects
History ,education ,Immunology ,Acquired Immunodeficiency Syndrome ,HIV-1 ,20th Century ,21st Century ,Humans ,Nobel Prize ,United States ,NO ,HIV Research ,Acquired immunodeficiency syndrome (AIDS) ,medicine ,HERO ,health care economics and organizations ,Multidisciplinary ,integumentary system ,Philosophy ,medicine.disease ,humanities ,AIDS ,Harm ,Classics - Abstract
Awarding the Nobel prize in physiology or medicine to Francoise Barre-Sinoussi and Luc Montagnier for the discovery of HIV-1, the causative agent of AIDS ([1][1]), is timely given the harm that the virus continues to inflict on the people of the world. While these awardees fully deserve the award
13. Landscape of humoral immune responses against SARS-CoV-2 in patients with COVID-19 disease and the value of antibody testing.
- Author
-
Mahalingam S, Peter J, Xu Z, Bordoloi D, Ho M, Kalyanaraman VS, Srinivasan A, and Muthumani K
- Abstract
A new pandemic is ongoing in several parts of the world. The agent responsible is the newly emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The symptoms associated with this virus are known as the coronavirus disease-2019 (COVID-19). In this review, we summarize the published data on virus specific antibodies in hospitalized patients with COVID-19 disease, patients recovered from the disease and the individuals who are asymptomatic with SARS-CoV-2 infections. The review highlights the following: i) an adjunct role of antibody tests in the diagnosis of COVID-19 in combination with RT-PCR; ii) status of antibodies from COVID-19 convalescent patients to select donors for plasma therapy; iii) the potential confounding effects of other coronaviruses, measles, mumps and rubella in antibody testing due to homology of certain viral genes; and iv) the role of antibody testing for conducting surveillance in populations, incidence estimation, contact tracing and epidemiologic studies., (© 2021 The Authors.)
- Published
- 2021
- Full Text
- View/download PDF
14. Preexisting vs. de novo antibodies against SARS-CoV-2 in individuals without or with virus infection: impact on antibody therapy, vaccine research and serological testing.
- Author
-
Muthumani K, Xu Z, Jeong M, Maslow JN, Kalyanaraman VS, and Srinivasan A
- Abstract
The causative agent of the ongoing pandemic in the world is SARS-CoV-2. The research on SARS-CoV-2 has progressed with lightning speed on various fronts, including clinical research and treatment, virology, epidemiology, drug development, and vaccine research. Recent studies reported that sera from healthy individuals, who were confirmed negative for SARS-CoV-2 by RT-PCR method, tested positive for antibodies against spike and nucleocapsid proteins of SARS-CoV-2. Further, such antibodies also exhibited neutralizing activity against the virus. These observations have prompted us to prepare a commentary on this topic. While the preexisting antibodies are likely to protect against SARS-CoV-2 infection, they may also complicate serological testing results. Another unknown is the influence of preexisting antibodies on immune responses in individuals receiving vaccines against SARS-CoV-2. The commentary identifies the potential limitations with the serological tests based on spike and nucleocapsid proteins as these tests may overestimate the seroprevalence due to cross-reactive antibodies. The inclusion of tests specific to SARS-CoV-2 (such as RBD of spike protein) could overcome these limitations., Competing Interests: Competing interestsThe authors declare no competing financial interest., (© The Author(s) 2021.)
- Published
- 2021
- Full Text
- View/download PDF
15. DNA prime/protein boost vaccination elicits robust humoral response in rhesus macaques using oligomeric simian immunodeficiency virus envelope and Advax delta inulin adjuvant.
- Author
-
Menon V, Ayala VI, Rangaswamy SP, Kalisz I, Whitney S, Galmin L, Ashraf A, LaBranche C, Montefiori D, Petrovsky N, Kalyanaraman VS, and Pal R
- Subjects
- AIDS Vaccines, Adjuvants, Immunologic administration & dosage, Animals, Antibodies, Neutralizing immunology, DNA, Viral administration & dosage, DNA, Viral genetics, HIV Antibodies immunology, HIV Envelope Protein gp120 administration & dosage, HIV Envelope Protein gp120 genetics, HIV Infections prevention & control, HIV Infections virology, HIV-1 genetics, HIV-1 immunology, Humans, Immunity, Humoral, Immunization, Secondary, Inulin administration & dosage, Macaca mulatta, Rabbits, SAIDS Vaccines administration & dosage, SAIDS Vaccines genetics, Simian Immunodeficiency Virus genetics, Vaccination, Antibodies, Viral immunology, DNA, Viral immunology, HIV Envelope Protein gp120 immunology, HIV Infections immunology, SAIDS Vaccines immunology, Simian Immunodeficiency Virus immunology
- Abstract
The partial success of the RV144 trial underscores the importance of envelope-specific antibody responses for an effective HIV-1 vaccine. Oligomeric HIV-1 envelope proteins delivered with a potent adjuvant are expected to elicit strong antibody responses with broad neutralization specificity. To test this hypothesis, two SIV envelope proteins were formulated with delta inulin-based adjuvant (Advax) and used to immunize nonhuman primates. Oligomeric gp140-gp145 from SIVmac251 and SIVsmE660 was purified to homogeneity. Oligomers showed high-affinity interaction with CD4 and were highly immunogenic in rabbits, inducing Tier 2 SIV-neutralizing antibodies. The immunogenicity of an oligomeric Env DNA prime and protein boost together with Advax was evaluated in Chinese rhesus macaques. DNA administration elicited antibodies to both envelopes, and titres were markedly enhanced following homologous protein boosts via intranasal and intramuscular routes. Strong antibody responses were detected against the V1 and V2 domains of gp120. During peak immune responses, a low to moderate level of neutralizing activity was detected against Tier 1A/1B SIV isolates, with a moderate level noted against a Tier 2 isolate. Increased serum antibody affinity to SIVmac251 gp140 and generation of Env-specific memory B cells were observed in the immunized macaques. Animals were subjected to low-dose intravaginal challenge with SIVmac251 one week after the last protein boost. One out of three immunized animals was protected from infection. Although performed with a small number of macaques, this study demonstrates the utility of oligomeric envelopes formulated with Advax in eliciting broad antibody responses with the potential to provide protection against SIV transmission.
- Published
- 2017
- Full Text
- View/download PDF
16. Characterization of protective immune response elicited by a trimeric envelope protein from an Indian clade C HIV-1 isolate in rhesus macaques.
- Author
-
Menon V, Priya RS, Labranche C, Montefiori D, Mahalingam S, Kalyanaraman VS, and Pal R
- Subjects
- Animals, Molecular Sequence Data, Monkey Diseases virology, Sequence Analysis, DNA, Viral Envelope Proteins metabolism, HIV-1 physiology, Macaca mulatta, Monkey Diseases immunology, Viral Envelope Proteins genetics
- Abstract
Background: Recent preclinical studies have demonstrated the use of properly folded trimeric HIV-1 envelope proteins as immunogen for eliciting protecting immune response in macaques., Methods: Trimeric gp145 protein of Indian clade C HIV-1 (93IN101) was characterized for antigenicity by evaluating its binding to sCD4, and several monoclonal antibodies to HIV-1 by bio-layer interferometry. Ten macaques were immunized four times with purified gp145 in adjuplex adjuvant, and serum antibodies were characterized for binding to gp145 and neutralization. Immunized macaques were subjected to weekly low-dose vaginal challenge with SHIV1157-ipEL-p for 8 weeks., Results: Env protein elicited strong antibody response in macaques. Following challenge, seven of ten immunized macaques resisted challenge, while six of eight control animals were infected., Conclusions: Env proteins from a clade C Indian isolate can elicit protective immune response and therefore may be a candidate for inclusion in a multiclade-based HIV-1 vaccine., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2015
- Full Text
- View/download PDF
17. Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge.
- Author
-
Tuero I, Mohanram V, Musich T, Miller L, Vargas-Inchaustegui DA, Demberg T, Venzon D, Kalisz I, Kalyanaraman VS, Pal R, Ferrari MG, LaBranche C, Montefiori DC, Rao M, Vaccari M, Franchini G, Barnett SW, and Robert-Guroff M
- Subjects
- Animals, Antibodies, Viral blood, Antibodies, Viral immunology, Female, Immunity, Cellular immunology, Immunity, Mucosal immunology, Macaca mulatta, Male, Rectum, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus immunology, B-Lymphocytes immunology, Intestinal Mucosa immunology, SAIDS Vaccines immunology, Sex Factors, Simian Acquired Immunodeficiency Syndrome immunology
- Abstract
Many viral infections, including HIV, exhibit sex-based pathogenic differences. However, few studies have examined vaccine-related sex differences. We compared immunogenicity and protective efficacy of monomeric SIV gp120 with oligomeric SIV gp140 in a pre-clinical rhesus macaque study and explored a subsequent sex bias in vaccine outcome. Each immunization group (16 females, 8 males) was primed twice mucosally with replication-competent Ad-recombinants encoding SIVsmH4env/rev, SIV239gag and SIV239nefΔ1-13 and boosted twice intramuscularly with SIVmac239 monomeric gp120 or oligomeric gp140 in MF59 adjuvant. Controls (7 females, 5 males) received empty Ad and MF59. Up to 9 weekly intrarectal challenges with low-dose SIVmac251 were administered until macaques became infected. We assessed vaccine-induced binding, neutralizing, and non-neutralizing antibodies, Env-specific memory B cells and plasmablasts/plasma cells (PB/PC) in bone marrow and rectal tissue, mucosal Env-specific antibodies, and Env-specific T-cells. Post-challenge, only one macaque (gp140-immunized) remained uninfected. However, SIV acquisition was significantly delayed in vaccinated females but not males, correlated with Env-specific IgA in rectal secretions, rectal Env-specific memory B cells, and PC in rectal tissue. These results extend previous correlations of mucosal antibodies and memory B cells with protective efficacy. The gp140 regimen was more immunogenic, stimulating elevated gp140 and cyclic V2 binding antibodies, ADCC and ADCP activities, bone marrow Env-specific PB/PC, and rectal gp140-specific IgG. However, immunization with gp120, the form of envelope immunogen used in RV144, the only vaccine trial to show some efficacy, provided more significant acquisition delay. Further over 40 weeks of follow-up, no gp120 immunized macaques met euthanasia criteria in contrast to 7 gp140-immunized and 2 control animals. Although males had higher binding antibodies than females, ADCC and ADCP activities were similar. The complex challenge outcomes may reflect differences in IgG subtypes, Fc glycosylation, Fc-R polymorphisms, and/or the microbiome, key areas for future studies. This first demonstration of a sex-difference in SIV vaccine-induced protection emphasizes the need for sex-balancing in vaccine trials. Our results highlight the importance of mucosal immunity and memory B cells at the SIV exposure site for protection.
- Published
- 2015
- Full Text
- View/download PDF
18. Antigenicity and immunogenicity of a trimeric envelope protein from an Indian clade C HIV-1 isolate.
- Author
-
Sneha Priya R, Veena M, Kalisz I, Whitney S, Priyanka D, LaBranche CC, Sri Teja M, Montefiori DC, Pal R, Mahalingam S, and Kalyanaraman VS
- Subjects
- Animals, Binding Sites, CHO Cells, Circular Dichroism, Cricetinae, Cricetulus, Enzyme-Linked Immunosorbent Assay, HEK293 Cells, Humans, Viral Envelope Proteins metabolism, HIV Antigens immunology, HIV-1 immunology, Viral Envelope Proteins immunology
- Abstract
Human immunodeficiency virus type 1 (HIV-1) isolates from India mainly belong to clade C and are quite distinct from clade C isolates from Africa in terms of their phylogenetic makeup, serotype, and sensitivity to known human broadly neutralizing monoclonal antibodies. Because many of these properties are associated with the envelope proteins of HIV-1, it is of interest to study the envelope proteins of Indian clade C isolates as part of the ongoing efforts to develop a vaccine against HIV-1. To this end, we purified trimeric uncleaved gp145 of a CCR5 tropic Indian clade C HIV-1 (93IN101) from the conditioned medium of 293 cells. The purified protein was shown to be properly folded with stable structure by circular dichroism. Conformational integrity was further demonstrated by its high affinity binding to soluble CD4, CD4 binding site antibodies such as b12 and VRC01, quaternary epitope-specific antibody PG9, and CD4-induced epitope-specific antibody 17b. Sera from rabbits immunized with gp145 elicited high titer antibodies to various domains of gp120 and neutralized a broad spectrum of clade B and clade C HIV-1 isolates. Similar to other clade B and clade C envelope immunogens, most of the Tier 1 neutralizing activity could be absorbed with the V3-specific peptide. Subsequent boosting of these rabbits with a clade B HIV-1 Bal gp145 resulted in an expanded breadth of neutralization of HIV-1 isolates. The present study strongly supports the inclusion of envelopes from Indian isolates in a future mixture of HIV-1 vaccines., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2015
- Full Text
- View/download PDF
19. Impact of antibody quality and anamnestic response on viremia control post-challenge in a combined Tat/Env vaccine regimen in rhesus macaques.
- Author
-
Demberg T, Brocca-Cofano E, Kuate S, Aladi S, Vargas-Inchaustegui DA, Venzon D, Kalisz I, Kalyanaraman VS, Lee EM, Pal R, DiPasquale J, Ruprecht RM, Montefiori DC, Srivastava I, Barnett SW, and Robert-Guroff M
- Subjects
- Adjuvants, Immunologic administration & dosage, Alum Compounds administration & dosage, Animals, Antibodies, Neutralizing blood, Gene Products, env immunology, Gene Products, tat immunology, Humans, Macaca mulatta, SAIDS Vaccines administration & dosage, Simian Immunodeficiency Virus immunology, Antibodies, Viral blood, Immunologic Memory, SAIDS Vaccines immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome virology, Viremia prevention & control
- Abstract
Previously, priming rhesus macaques with Adenovirus type 5 host range mutant-recombinants encoding Tat and Env and boosting with Tat and Env protein in MPL-SE controlled chronic viremia by 4 logs following homologous intravenous SHIV89.6P challenge. Here we evaluated Tat, Env, and Tat/Env regimens for immunogenicity and protective efficacy using clade C Env, alum adjuvant, and a heterologous intrarectal SHIV1157ipd3N4 challenge. Despite induction of strong cellular and humoral immunity, Tat/Env group T and B-cell memory responses were not significantly enhanced over Tat- or Env-only groups. Lack of viremia control post-challenge was attributed to lower avidity Env antibodies and no anamnestic ADCC response or SHIV1157ipd3N4 neutralizing antibody development post-challenge. Poor biologic activity of the Tat immunogen may have impaired Tat immunity. In the absence of sterilizing immunity, strong anamnestic responses to heterologous virus can help control viremia. Both antibody breadth and optimal adjuvanticity are needed to elicit high-quality antibody for protective efficacy., (Published by Elsevier Inc.)
- Published
- 2013
- Full Text
- View/download PDF
20. Dynamics of memory B-cell populations in blood, lymph nodes, and bone marrow during antiretroviral therapy and envelope boosting in simian immunodeficiency virus SIVmac251-infected rhesus macaques.
- Author
-
Demberg T, Brocca-Cofano E, Xiao P, Venzon D, Vargas-Inchaustegui D, Lee EM, Kalisz I, Kalyanaraman VS, Dipasquale J, McKinnon K, and Robert-Guroff M
- Subjects
- Analysis of Variance, Animals, Anti-Retroviral Agents immunology, B-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, Flow Cytometry, Linear Models, Lymph Nodes cytology, Lymph Nodes immunology, Male, Membrane Glycoproteins administration & dosage, Plasma Cells cytology, Plasma Cells metabolism, Simian Acquired Immunodeficiency Syndrome drug therapy, Viral Envelope Proteins administration & dosage, Viral Load, Anti-Retroviral Agents therapeutic use, B-Lymphocytes immunology, Bone Marrow Cells immunology, Immunologic Memory immunology, Macaca mulatta, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology
- Abstract
Human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection causes B-cell dysregulation and the loss of memory B cells in peripheral blood mononuclear cells (PBMC). These effects are not completely reversed by antiretroviral treatment (ART). To further elucidate B-cell changes during chronic SIV infection and treatment, we investigated memory B-cell subpopulations and plasma cells/plasmablasts (PC/PB) in blood, bone marrow, and lymph nodes of rhesus macaques during ART and upon release from ART. Macaques previously immunized with SIV recombinants and the gp120 protein were included to assess the effects of prior vaccination. ART was administered for 11 weeks, with or without gp120 boosting at week 9. Naïve and resting, activated, and tissue-like memory B cells and PC/PB were evaluated by flow cytometry. Antibody-secreting cells (ASC) and serum antibody titers were assessed. No lasting changes in B-cell memory subpopulations occurred in bone marrow and lymph nodes, but significant decreases in numbers of activated memory B cells and increases in numbers of tissue-like memory B cells persisted in PBMC. Macaque PC/PB were found to be either CD27(+) or CD27(-) and therefore were defined as CD19(+) CD38(hi) CD138(+). The numbers of these PC/PB were transiently increased in both PBMC and bone marrow following gp120 boosting of the unvaccinated and vaccinated macaque groups. Similarly, ASC numbers in PBMC and bone marrow of the two macaque groups also transiently increased following envelope boosting. Nevertheless, serum binding titers against SIVgp120 remained unchanged. Thus, even during chronic SIV infection, B cells respond to antigen, but long-term memory does not develop, perhaps due to germinal center destruction. Earlier and/or prolonged treatment to allow the generation of virus-specific long-term memory B cells should benefit ART/therapeutic vaccination regimens.
- Published
- 2012
- Full Text
- View/download PDF
21. Replicating adenovirus-simian immunodeficiency virus (SIV) recombinant priming and envelope protein boosting elicits localized, mucosal IgA immunity in rhesus macaques correlated with delayed acquisition following a repeated low-dose rectal SIV(mac251) challenge.
- Author
-
Xiao P, Patterson LJ, Kuate S, Brocca-Cofano E, Thomas MA, Venzon D, Zhao J, DiPasquale J, Fenizia C, Lee EM, Kalisz I, Kalyanaraman VS, Pal R, Montefiori D, Keele BF, and Robert-Guroff M
- Subjects
- Adenoviruses, Human genetics, Animals, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Antibody Specificity, Cytokines metabolism, Female, Gene Products, env genetics, Humans, Immunity, Mucosal, Immunologic Memory, Macaca mulatta, Male, Molecular Sequence Data, Simian Immunodeficiency Virus genetics, T-Lymphocytes immunology, Vaccines, Synthetic genetics, Viremia immunology, Adenoviruses, Human immunology, Gene Products, env immunology, Immunoglobulin A, Secretory immunology, Simian Immunodeficiency Virus immunology, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic immunology
- Abstract
We have shown that sequential replicating adenovirus type 5 host range mutant human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) recombinant priming delivered first intranasally (i.n.) plus orally and then intratracheally (i.t.), followed by envelope protein boosting, elicits broad cellular immunity and functional, envelope-specific serum and mucosal antibodies that correlate with protection from high-dose SIV and simian/human immunodeficiency virus (SHIV) challenges in rhesus macaques. Here we extended these studies to compare the standard i.n./i.t. regimen with additional mucosal administration routes, including sublingual, rectal, and vaginal routes. Similar systemic cellular and humoral immunity was elicited by all immunization routes. Central and effector memory T cell responses were also elicited by the four immunization routes in bronchoalveolar lavage fluid and jejunal, rectal, and vaginal tissue samples. Cellular responses in vaginal tissue were more compartmentalized, being induced primarily by intravaginal administration. In contrast, all immunization routes elicited secretory IgA (sIgA) responses at multiple mucosal sites. Following a repeated low-dose intrarectal (i.r.) challenge with SIV(mac251) at a dose transmitting one or two variants, protection against acquisition was not achieved except in one macaque in the i.r. immunized group. All immunized macaques exhibited reduced peak viremia compared to that of controls, correlated inversely with prechallenge serum antienvelope avidity, antibody-dependent cellular cytotoxicity (ADCC) titers, and percent antibody-dependent cell-mediated viral inhibition. Both antibody avidity and ADCC titers were correlated with the number of exposures required for infection. Notably, we show for the first time a significant correlation of vaccine-induced sIgA titers in rectal secretions with delayed acquisition. Further investigation of the characteristics and properties of the sIgA should elucidate the mechanism leading to this protective effect.
- Published
- 2012
- Full Text
- View/download PDF
22. Mechanism of host cell MAPK/ERK-2 incorporation into lentivirus particles: characterization of the interaction between MAPK/ERK-2 and proline-rich-domain containing capsid region of structural protein Gag.
- Author
-
Gupta P, Singhal PK, Rajendrakumar P, Padwad Y, Tendulkar AV, Kalyanaraman VS, Schmidt RE, Srinivasan A, and Mahalingam S
- Subjects
- Amino Acid Sequence, Conserved Sequence genetics, DNA Replication, HIV-1 physiology, HeLa Cells, Humans, Molecular Sequence Data, Mutation genetics, Protein Binding, Simian Immunodeficiency Virus physiology, Structure-Activity Relationship, Virus Assembly physiology, Capsid chemistry, Gene Products, gag chemistry, Gene Products, gag metabolism, Lentivirus metabolism, Mitogen-Activated Protein Kinase 1 metabolism, Proline-Rich Protein Domains, Virion metabolism
- Abstract
The characteristic event that follows infection of a cell by retroviruses Including human immunodeficiency virus (HIV)/ simian immunodeficiency virus (SIV) is the formation of a reverse transcription complex in which viral nucleic acids are synthesized. Nuclear transport of newly synthesized viral DNA requires phosphorylation of proteins in the reverse transcription complex by virion-associated cellular kinases. Recently, we demonstrated that disruption of cellular mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 2 (ERK-2) incorporation into SIV virions inhibits virus replication in nonproliferating target cells, indicating that MAPK/ERK-2 plays an important role in HIV /SIV replication. The mechanism of incorporation of MAPK/ERK-2 into virus particles is not defined. In this regard, we hypothesized that a likely interaction of MAPK/ERK-2 with Gag(p55) may enable its packaging into virus particles. In the present investigation, we provided evidence for the first time that MAPK/ERK-2 interacts with the structural Gag polyprotein p55 using a combination of mutagenesis and protein-protein interaction analysis. We further show that MAPK/ERK-2 interacts specifically with the poly-proline motif present in the capsid region of Gag(p55). Utilizing virus-like particles directed by Gag, we have shown that the exchange of conserved proline residues within capsid of Gag(p55) resulted in impaired incorporation of MAPK/ERK-2. In addition, the deletion of a domain comprising amino acids 201 to 255 within host cell MAPK/ERK-2 abrogates its interaction with Gag(p55). The relevance of the poly-proline motif is further evident by its conservation in diverse retroviruses, as noted from the sequence analysis and structural modeling studies of predicted amino acid sequences of the corresponding Gag proteins. Collectively, these data suggest that the interaction of MAPK/ERK-2 with Gag polyprotein results in its incorporation into virus particles and may be essential for retroviral replication., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
23. Rapid SIV Env-specific mucosal and serum antibody induction augments cellular immunity in protecting immunized, elite-controller macaques against high dose heterologous SIV challenge.
- Author
-
Patterson LJ, Daltabuit-Test M, Xiao P, Zhao J, Hu W, Wille-Reece U, Brocca-Cofano E, Kalyanaraman VS, Kalisz I, Whitney S, Lee EM, Pal R, Montefiori DC, Dandekar S, Seder R, Roederer M, Wiseman RW, Hirsch V, and Robert-Guroff M
- Subjects
- Animals, Antibodies, Neutralizing immunology, Jejunum virology, Lymph Nodes virology, Macaca mulatta, Serum immunology, T-Lymphocytes immunology, Viremia prevention & control, Antibodies, Viral immunology, Immunity, Cellular, Immunity, Mucosal, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus immunology
- Abstract
Three Indian rhesus macaques, Ad-SIV primed/protein boosted and exposed twice to high-dose mucosal SIV(mac251) challenges, exhibited elite control of viremia over 6.5 years. They were negative for host factors associated with control of SIV infection. After a third intrarectal challenge with SIV(smE660), all controlled viremia, with one (macaque #5) maintaining undetectable viremia in blood. Acquisition was not blocked, but virus was contained in the jejunum and draining lymph nodes. Polyfunctional memory T cell responses and high-titered neutralizing and non-neutralizing serum and mucosal antibodies were present before and maintained post-challenge. The level of protection seen for animal #5 was predicted from analyses of gene transcription in jejunum 2 weeks post-challenge. Macaques #7 and #9, exhibiting lower pre-challenge cellular and humoral immunity, partially controlled the SIV(smE660) challenge. Initial vaccine-induced control by macaque #5 extended to the SIV(smE660) challenge due to multiple immune mechanisms that were boosted and augmented by cryptic SIV exposure., (Published by Elsevier Inc.)
- Published
- 2011
- Full Text
- View/download PDF
24. Unsung hero Robert C. Gallo.
- Author
-
Abbadessa G, Accolla R, Aiuti F, Albini A, Aldovini A, Alfano M, Antonelli G, Bartholomew C, Bentwich Z, Bertazzoni U, Berzofsky JA, Biberfeld P, Boeri E, Buonaguro L, Buonaguro FM, Bukrinsky M, Burny A, Caruso A, Cassol S, Chandra P, Ceccherini-Nelli L, Chieco-Bianchi L, Clerici M, Colombini-Hatch S, de Giuli Morghen C, de Maria A, de Rossi A, Dierich M, Della-Favera R, Dolei A, Douek D, Erfle V, Felber B, Fiorentini S, Franchini G, Gershoni JM, Gotch F, Green P, Greene WC, Hall W, Haseltine W, Jacobson S, Kallings LO, Kalyanaraman VS, Katinger H, Khalili K, Klein G, Klein E, Klotman M, Klotman P, Kotler M, Kurth R, Lafeuillade A, La Placa M, Lewis J, Lillo F, Lisziewicz J, Lomonico A, Lopalco L, Lori F, Lusso P, Macchi B, Malim M, Margolis L, Markham PD, McClure M, Miller N, Mingari MC, Moretta L, Noonan D, O'Brien S, Okamoto T, Pal R, Palese P, Panet A, Pantaleo G, Pavlakis G, Pistello M, Plotkin S, Poli G, Pomerantz R, Radaelli A, Robertguroff M, Roederer M, Sarngadharan MG, Schols D, Secchiero P, Shearer G, Siccardi A, Stevenson M, Svoboda J, Tartaglia J, Torelli G, Tornesello ML, Tschachler E, Vaccarezza M, Vallbracht A, van Lunzen J, Varnier O, Vicenzi E, von Melchner H, Witz I, Zagury D, Zagury JF, Zauli G, and Zipeto D
- Subjects
- Acquired Immunodeficiency Syndrome diagnosis, Acquired Immunodeficiency Syndrome virology, History, 20th Century, History, 21st Century, Humans, United States, Acquired Immunodeficiency Syndrome history, HIV-1 growth & development, HIV-1 isolation & purification, Nobel Prize
- Published
- 2009
- Full Text
- View/download PDF
25. Correlation of vaccine-elicited systemic and mucosal nonneutralizing antibody activities with reduced acute viremia following intrarectal simian immunodeficiency virus SIVmac251 challenge of rhesus macaques.
- Author
-
Hidajat R, Xiao P, Zhou Q, Venzon D, Summers LE, Kalyanaraman VS, Montefiori DC, and Robert-Guroff M
- Subjects
- Animals, Bronchoalveolar Lavage Fluid immunology, Immunoglobulin A analysis, Macaca mulatta, Male, Rectum immunology, T-Lymphocytes, Cytotoxic immunology, HIV Antibodies analysis, HIV Antibodies blood, Immunity, Mucosal, SAIDS Vaccines immunology, Simian Immunodeficiency Virus immunology, Viremia prevention & control
- Abstract
Cell-mediated immunity and neutralizing antibodies contribute to control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection, but the role of nonneutralizing antibodies is not defined. Previously, we reported that sequential oral/oral or intranasal/oral (I/O) priming with replication-competent adenovirus type 5 host range mutant (Ad5hr)-SIV recombinants, followed by intramuscular envelope protein boosting, elicited systemic and mucosal cellular immunity and exhibited equivalent, significant reductions of chronic viremia after rectal SIV(mac251) challenge. However, I/O priming gave significantly better control of acute viremia. Here, systemic and mucosal humoral immunity were investigated for potential correlates with the acute challenge outcome. Strong serum binding but nonneutralizing antibody responses against SIV(mac251) were induced in both groups. Antibody responses appeared earlier and overall were higher in the I/O group. Reduced acute viremia was significantly correlated with higher serum binding titer, stronger antibody-dependent cellular cytotoxicity activity, and peak prechallenge and 2-week-postchallenge antibody-dependent cell-mediated viral inhibition (ADCVI). The I/O group consistently displayed greater anti-envelope immunoglobulin A (IgA) antibody responses in bronchoalveolar lavage and a stronger rectal anti-envelope IgA anamnestic response 2 weeks postchallenge. Pre- and postchallenge rectal secretions inhibited SIV transcytosis across epithelial cells. The inhibition was significantly higher in the I/O group, although a significant correlation with reduced acute viremia was not reached. Overall, the replicating Ad5hr-SIV priming/envelope boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities. The pattern of elevated immune responses in the I/O group is consistent with its better control of acute viremia mediated, at least in part, by ADCVI activity and transcytosis inhibition.
- Published
- 2009
- Full Text
- View/download PDF
26. Sequential priming with simian immunodeficiency virus (SIV) DNA vaccines, with or without encoded cytokines, and a replicating adenovirus-SIV recombinant followed by protein boosting does not control a pathogenic SIVmac251 mucosal challenge.
- Author
-
Demberg T, Boyer JD, Malkevich N, Patterson LJ, Venzon D, Summers EL, Kalisz I, Kalyanaraman VS, Lee EM, Weiner DB, and Robert-Guroff M
- Subjects
- Adenoviridae genetics, Animals, Cytokines immunology, Immunization, Secondary, Leukocytes, Mononuclear immunology, Macaca mulatta, Plasmids, Simian Immunodeficiency Virus immunology, Vaccines, Subunit administration & dosage, Vaccines, Subunit immunology, Viral Load, Viremia prevention & control, Adjuvants, Immunologic administration & dosage, Cytokines administration & dosage, SAIDS Vaccines administration & dosage, SAIDS Vaccines immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Vaccines, DNA administration & dosage, Vaccines, DNA immunology
- Abstract
Previously, combination DNA/nonreplicating adenovirus (Ad)- or poxvirus-vectored vaccines have strongly protected against SHIV(89.6P), DNAs expressing cytokines have modulated immunity elicited by DNA vaccines, and replication-competent Ad-recombinant priming and protein boosting has strongly protected against simian immunodeficiency virus (SIV) challenge. Here we evaluated a vaccine strategy composed of these promising components. Seven rhesus macaques per group were primed twice with multigenic SIV plasmid DNA with or without interleukin-12 (IL-12) DNA or IL-15 DNA. After a multigenic replicating Ad-SIV immunization, all groups received two booster immunizations with SIV gp140 and SIV Nef protein. Four control macaques received control DNA plasmids, empty Ad vector, and adjuvant. All vaccine components were immunogenic, but the cytokine DNAs had little effect. Macaques that received IL-15-DNA exhibited higher peak anti-Nef titers, a more rapid anti-Nef anamnestic response postchallenge, and expanded CD8(CM) T cells 2 weeks postchallenge compared to the DNA-only group. Other immune responses were indistinguishable between groups. Overall, no protection against intrarectal challenge with SIV(mac251) was observed, although immunized non-Mamu-A*01 macaques as a group exhibited a statistically significant 1-log decline in acute viremia compared to non-Mamu-A*01 controls. Possible factors contributing to the poor outcome include administration of cytokine DNAs to sites different from the Ad recombinants (intramuscular and intratracheal, respectively), too few DNA priming immunizations, a suboptimal DNA delivery method, failure to ensure delivery of SIV and cytokine plasmids to the same cell, and instability and short half-life of the IL-15 component. Future experiments should address these issues to determine if this combination approach is able to control a virulent SIV challenge.
- Published
- 2008
- Full Text
- View/download PDF
27. A comprehensive analysis of the naturally occurring polymorphisms in HIV-1 Vpr: potential impact on CTL epitopes.
- Author
-
Srinivasan A, Ayyavoo V, Mahalingam S, Kannan A, Boyd A, Datta D, Kalyanaraman VS, Cristillo A, Collman RG, Morellet N, Sawaya BE, and Murali R
- Subjects
- Amino Acid Sequence, Gene Products, vpr genetics, Gene Products, vpr immunology, HIV Infections virology, HIV-1 immunology, Humans, Molecular Sequence Data, Sequence Alignment, Epitopes, T-Lymphocyte immunology, Gene Products, vpr chemistry, Genes, vpr, HIV Infections immunology, HIV-1 genetics, Polymorphism, Genetic, T-Lymphocytes, Cytotoxic immunology
- Abstract
The enormous genetic variability reported in HIV-1 has posed problems in the treatment of infected individuals. This is evident in the form of HIV-1 resistant to antiviral agents, neutralizing antibodies and cytotoxic T lymphocytes (CTLs) involving multiple viral gene products. Based on this, it has been suggested that a comprehensive analysis of the polymorphisms in HIV proteins is of value for understanding the virus transmission and pathogenesis as well as for the efforts towards developing anti-viral therapeutics and vaccines. This study, for the first time, describes an in-depth analysis of genetic variation in Vpr using information from global HIV-1 isolates involving a total of 976 Vpr sequences. The polymorphisms at the individual amino acid level were analyzed. The residues 9, 33, 39, and 47 showed a single variant amino acid compared to other residues. There are several amino acids which are highly polymorphic. The residues that show ten or more variant amino acids are 15, 16, 28, 36, 37, 48, 55, 58, 59, 77, 84, 86, 89, and 93. Further, the variant amino acids noted at residues 60, 61, 34, 71 and 72 are identical. Interestingly, the frequency of the variant amino acids was found to be low for most residues. Vpr is known to contain multiple CTL epitopes like protease, reverse transcriptase, Env, and Gag proteins of HIV-1. Based on this, we have also extended our analysis of the amino acid polymorphisms to the experimentally defined and predicted CTL epitopes. The results suggest that amino acid polymorphisms may contribute to the immune escape of the virus. The available data on naturally occurring polymorphisms will be useful to assess their potential effect on the structural and functional constraints of Vpr and also on the fitness of HIV-1 for replication.
- Published
- 2008
- Full Text
- View/download PDF
28. Comparative study of Tat vaccine regimens in Mauritian cynomolgus and Indian rhesus macaques: influence of Mauritian MHC haplotypes on susceptibility/resistance to SHIV(89.6P) infection.
- Author
-
Florese RH, Wiseman RW, Venzon D, Karl JA, Demberg T, Larsen K, Flanary L, Kalyanaraman VS, Pal R, Titti F, Patterson LJ, Heath MJ, O'Connor DH, Cafaro A, Ensoli B, and Robert-Guroff M
- Subjects
- Animals, Macaca fascicularis, Macaca mulatta, Viral Load, Viremia, AIDS Vaccines immunology, Disease Susceptibility, Haplotypes, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class II genetics, Simian Acquired Immunodeficiency Syndrome prevention & control, tat Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Protection afforded by HIV Tat-based vaccines has differed in Indian rhesus and Mauritian cynomolgus macaques. We evaluated native Tat and Ad-HIVtat priming/Tat-boosting regimens in both species. Both vaccines were immunogenic. Only the Ad-tat regimen modestly reduced acute viremia in rhesus macaques after SHIV(89.6P) challenge. Confounding variables uncovered in Mauritian macaques included significant associations of susceptibility to infection with MHC class IB and class II H2 and H5 haplotypes, and resistance to infection with class IB haplotypes H3 and H6. Although protection here was limited, Tat-based vaccines incorporating other HIV components have shown greater efficacy. Combination strategies should be further explored.
- Published
- 2008
- Full Text
- View/download PDF
29. Replicating adenovirus HIV/SIV recombinant priming alone or in combination with a gp140 protein boost results in significant control of viremia following a SHIV89.6P challenge in Mamu-A*01 negative rhesus macaques.
- Author
-
Patterson LJ, Beal J, Demberg T, Florese RH, Malkevich N, Venzon D, Aldrich K, Richardson E, Kalyanaraman VS, Kalisz I, Lee EM, Montefiori DC, Robey FA, and Robert-Guroff M
- Subjects
- AIDS Vaccines administration & dosage, AIDS Vaccines immunology, Adenoviridae genetics, Animals, HIV Antibodies blood, HIV Infections prevention & control, HIV-1 genetics, HIV-1 pathogenicity, Histocompatibility Antigens Class I metabolism, Humans, Immunization, Immunization, Secondary, Macaca mulatta, Male, Recombination, Genetic, SAIDS Vaccines administration & dosage, SAIDS Vaccines immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus genetics, Simian Immunodeficiency Virus pathogenicity, Simian Immunodeficiency Virus radiation effects, T-Lymphocytes immunology, Virus Replication, env Gene Products, Human Immunodeficiency Virus administration & dosage, Adenoviridae physiology, Genetic Vectors, HIV-1 immunology, Simian Immunodeficiency Virus immunology, Viremia prevention & control, env Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Previously, replicating adenovirus type 5 host range (Ad5hr)-HIV/SIV recombinant priming in combination with SIV envelope boosting, resulted in significant, durable protection in 39% of rhesus macaques after SIVmac251 challenge. Both Env-specific antibody mediating ADCC, and cellular immunity correlated with protection. Here we evaluate the relative immunogenicities of novel HIV proteins and their contribution to protection in a SHIV89.6P model. All groups were primed with Ad-HIVenv89.6P, SIVgag239, and SIVnef239 recombinants. One group was not boosted, one received HIV89.6Pgp140DeltaCFI protein, and one a novel HIV-1 poly-peptide "peptomer". The HIV89.6Pgp140DeltaCFI protein in adjuvant strongly boosted Env-specific antibody and memory T cell responses in blood and tissue, resulting in significant reductions in acute and set point viremia. Macaques not boosted, showed a significant reduction in set point viremia, a full 32 weeks after the last Ad priming immunization. The HIV peptomer-boosted group showed a trend toward chronic viremia reduction, but was not protected.
- Published
- 2008
- Full Text
- View/download PDF
30. Comparative evaluation of oral and intranasal priming with replication-competent adenovirus 5 host range mutant (Ad5hr)-simian immunodeficiency virus (SIV) recombinant vaccines on immunogenicity and protective efficacy against SIV(mac251).
- Author
-
Zhou Q, Hidajat R, Peng B, Venzon D, Aldrich MK, Richardson E, Lee EM, Kalyanaraman VS, Grimes G, Gómez-Román VR, Summers LE, Malkevich N, and Robert-Guroff M
- Subjects
- Administration, Intranasal, Administration, Oral, Animals, Cells, Cultured, Feces virology, Humans, Immunologic Memory immunology, Integrins metabolism, Interferon-gamma metabolism, Leukocytes cytology, Leukocytes immunology, Leukocytes metabolism, Macaca mulatta, Male, Mutation genetics, Recombinant Proteins genetics, Recombinant Proteins immunology, Recombinant Proteins metabolism, SAIDS Vaccines administration & dosage, Tablets, Vaccines, Synthetic, Adenoviridae genetics, DNA Replication genetics, SAIDS Vaccines immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus genetics, Simian Immunodeficiency Virus immunology
- Abstract
Oral, replication-competent Ad-HIV vaccines are advancing to human trials. Previous evaluation of protective efficacy in non-human primates has primarily followed upper respiratory tract administrations. Here we compared sequential oral (O/O) versus intranasal/oral (I/O) priming of rhesus macaques with Ad5 host range mutant-SIV recombinants expressing SIV env/rev, gag, and nef genes followed by boosting with SIV gp120 protein. Cellular immune responses in PBMC were stronger and more frequent after I/O administration. Both groups developed mucosal immunity, including memory cells in bronchial alveolar lavage, and gut-homing receptors on PBMC. Following intrarectal SIV(mac251) challenge, both groups exhibited equivalent, significant protection and robust post-challenge cellular immunity. Our results illustrate the promise of oral replication-competent Ad-recombinant vaccines. Pre-challenge PBMC ELISPOT and proliferative responses did not predict protection in the O/O group, highlighting the need for simple, non-invasive methods to reliably assess mucosal immunity.
- Published
- 2007
- Full Text
- View/download PDF
31. HIV-1 prophylactic vaccine comprised of topical DermaVir prime and protein boost elicits cellular immune responses and controls pathogenic R5 SHIV162P3.
- Author
-
Cristillo AD, Lisziewicz J, He L, Lori F, Galmin L, Trocio JN, Unangst T, Whitman L, Hudacik L, Bakare N, Whitney S, Restrepo S, Suschak J, Ferrari MG, Chung HK, Kalyanaraman VS, Markham P, and Pal R
- Subjects
- AIDS Vaccines therapeutic use, Animals, Codon, Cytokines analysis, Cytokines immunology, Disease Models, Animal, Flow Cytometry, Genes, env, HIV Envelope Protein gp120 immunology, HIV-1 pathogenicity, Immunization, Secondary, Macaca mulatta, Mice, Simian Immunodeficiency Virus immunology, T-Lymphocytes, Cytotoxic immunology, Th1 Cells immunology, Th2 Cells microbiology, AIDS Vaccines immunology, Acquired Immunodeficiency Syndrome immunology, HIV-1 immunology
- Abstract
Topical DNA vaccination (DermaVir) facilitates antigen presentation to naive T cells. DermaVir immunization in mice, using HIV-1 Env and Gag, elicited cellular immune responses. Boosting with HIV-1 gp120 Env and p41 Gag augmented Th1 cytokine levels. Intramuscular DNA administration was less efficient in priming antigen-specific cytokine production and memory T cells. In rhesus macaques, DermaVir immunization induced Gag- and Env-specific Th1 and Th2 cytokines and generation of memory T cells. Boosting of DermaVir-primed serum antibody levels was noted following gp140(SHIV89.6P)/p27(SIV) immunization. Rectal challenge with pathogenic R5-tropic SHIV162P3 resulted in control of plasma viremia (4/5 animals) that was reflected in jejunum, colon and mesenteric lymph nodes. An inverse correlation was found between Gag- and Env-specific central memory T cell responses on the day of challenge and plasma viremia at set point. Overall, the topical DermaVir/protein vaccination yields central memory T cell responses and facilitates control of pathogenic SHIV infection.
- Published
- 2007
- Full Text
- View/download PDF
32. A replication-competent adenovirus-human immunodeficiency virus (Ad-HIV) tat and Ad-HIV env priming/Tat and envelope protein boosting regimen elicits enhanced protective efficacy against simian/human immunodeficiency virus SHIV89.6P challenge in rhesus macaques.
- Author
-
Demberg T, Florese RH, Heath MJ, Larsen K, Kalisz I, Kalyanaraman VS, Lee EM, Pal R, Venzon D, Grant R, Patterson LJ, Korioth-Schmitz B, Buzby A, Dombagoda D, Montefiori DC, Letvin NL, Cafaro A, Ensoli B, and Robert-Guroff M
- Subjects
- Animals, Antibodies, Viral immunology, Antibodies, Viral pharmacology, Gene Products, env genetics, Gene Products, env immunology, Gene Products, tat genetics, Gene Products, tat immunology, HIV genetics, Immunologic Memory immunology, Lymphocytes drug effects, Lymphocytes immunology, Macaca mulatta, tat Gene Products, Human Immunodeficiency Virus, Adenoviridae genetics, Gene Products, env metabolism, Gene Products, tat metabolism, HIV immunology, HIV metabolism, Simian Immunodeficiency Virus physiology, Virus Replication
- Abstract
We previously demonstrated that replication-competent adenovirus (Ad)-simian immunodeficiency virus (SIV) recombinant prime/protein boost regimens elicit potent immunogenicity and strong, durable protection of rhesus macaques against SIV(mac251). Additionally, native Tat vaccines have conferred strong protection against simian/human immunodeficiency virus SHIV(89.6P) challenge of cynomolgus monkeys, while native, inactivated, or vectored Tat vaccines have failed to elicit similar protective efficacy in rhesus macaques. Here we asked if priming rhesus macaques with replicating Ad-human immunodeficiency virus (HIV) tat and boosting with the Tat protein would elicit protection against SHIV(89.6P). We also evaluated a Tat/Env regimen, adding an Ad-HIV env recombinant and envelope protein boost to test whether envelope antibodies would augment acute-phase protection. Further, expecting cellular immunity to enhance chronic viremia control, we tested a multigenic group: Ad-HIV tat, -HIV env, -SIV gag, and -SIV nef recombinants and Tat, Env, and Nef proteins. All regimens were immunogenic. A hierarchy was observed in enzyme-linked immunospot responses (with the strongest response for Env, followed by Gag, followed by Nef, followed by Tat) and antibody titers (with the highest titer for Env, followed by Tat, followed by Nef, followed by Gag). Following intravenous SHIV(89.6P) challenge, all macaques became infected. Compared to controls, no protection was seen in the Tat-only group, confirming previous reports for rhesus macaques. However, the multigenic group blunted acute viremia by approximately 1 log (P = 0.017), and both the multigenic and Tat/Env groups reduced chronic viremia by 3 and 4 logs, respectively, compared to controls (multigenic, P = 0.0003; Tat/Env, P < 0.0001). The strikingly greater reduction in the Tat/Env group than in the multigenic group (P = 0.014) was correlated with Tat and Env binding antibodies. Since prechallenge anti-Env antibodies lacked SHIV(89.6P)-neutralizing activity, other functional anti-Env and anti-Tat activities are under investigation, as is a possible synergy between the Tat and Env immunogens.
- Published
- 2007
- Full Text
- View/download PDF
33. An adenovirus-based HIV subtype B prime/boost vaccine regimen elicits antibodies mediating broad antibody-dependent cellular cytotoxicity against non-subtype B HIV strains.
- Author
-
Gómez-Román VR, Florese RH, Peng B, Montefiori DC, Kalyanaraman VS, Venzon D, Srivastava I, Barnett SW, and Robert-Guroff M
- Subjects
- AIDS Vaccines administration & dosage, Adenoviridae genetics, Animals, Cross Reactions, Drug Evaluation, Preclinical, Genetic Vectors immunology, HIV Antibodies blood, HIV Envelope Protein gp120 immunology, HIV Infections immunology, HIV Infections prevention & control, HIV-1 classification, HIV-1 genetics, Neutralization Tests, Pan troglodytes, Recombinant Proteins immunology, Vaccines, Synthetic immunology, Viral Vaccines administration & dosage, AIDS Vaccines immunology, HIV Antibodies immunology, HIV-1 immunology, Immunization, Secondary
- Abstract
Although HIV subtype B predominates in North America and Western Europe, most HIV infections worldwide are non-subtype B. Globally effective AIDS vaccines need to elicit broad immunity against multiple HIV strains. In this study, 10 chimpanzees were intranasally primed sequentially with adenovirus type 5 (Ad5)- and Ad7-HIVMNenv/rev recombinants and boosted twice intramuscularly with heterologous oligomeric HIVSF162 gp140DeltaV2 protein in MF59 adjuvant. Sera were evaluated for binding, neutralizing, and antibody-dependent cellular cytotoxicity (ADCC) against HIV clades A, B, C, and CRF01_AE. The vaccine regimen elicited high-titered HIV subtype A, B, C and CRF01_AE gp120-binding antibodies. Sera from 7 of 10 vaccinated chimpanzees cross-neutralized the heterologous South African subtype C primary HIVTV-1 isolate. Significant cross-clade neutralization against other subtype A, C and E isolates was not observed. Sera from all animals mediated ADCC of cells coated with gp120 from HIV subtypes A and B. Nine of 10 animals also exhibited ADCC activity against HIV subtype C and CRF01_AE gp120-coated targets. This subtype B Ad-HIV recombinant prime/envelope protein boost regimen is a promising approach for eliciting broad ADCC activity against diverse HIV clades. Incorporating additional non-subtype B envelope genes and protein boosts in a multivalent strategy may be required to elicit broader neutralizing antibodies against non-subtype B HIV strains.
- Published
- 2006
- Full Text
- View/download PDF
34. Coadsorption of HIV-1 p24 and gp120 proteins to surfactant-free anionic PLA nanoparticles preserves antigenicity and immunogenicity.
- Author
-
Lamalle-Bernard D, Munier S, Compagnon C, Charles MH, Kalyanaraman VS, Delair T, Verrier B, and Ataman-Onal Y
- Subjects
- Adsorption, Animals, Anions, Antibody Specificity, Binding, Competitive, Enzyme-Linked Immunosorbent Assay, Epitopes immunology, Escherichia coli genetics, Female, Immunization, Lactic Acid, Mice, Mice, Inbred BALB C, Molecular Weight, Nanostructures, Particle Size, Polyglycolic Acid, Polylactic Acid-Polyglycolic Acid Copolymer, Polymers, Recombinant Proteins administration & dosage, Recombinant Proteins immunology, Thermodynamics, AIDS Vaccines administration & dosage, AIDS Vaccines immunology, HIV Core Protein p24 administration & dosage, HIV Core Protein p24 immunology, HIV Envelope Protein gp120 administration & dosage, HIV Envelope Protein gp120 immunology
- Abstract
Biodegradable micro- or nanoparticles with surface adsorbed antigens represent a promising method for in vivo delivery of vaccines. Most vaccines, licensed or under development, are based on combined delivery of multiple antigens. Thus, we investigated the feasibility of combining two vaccine antigens, HIV-1 p24 and gp120 proteins, on the surface of surfactant-free anionic PLA nanoparticles obtained by an improved solvent diffusion method. The analysis of adsorption isotherms has shown that both proteins had similar and high affinities for the nanoparticles. Coadsorption of p24 and gp120 onto the same PLA particle was evidenced by sandwich ELISA, using antibodies directed against one protein for particle capture and the other one for detection. To assess structural integrity, the antigenicity of free and PLA-adsorbed antigens was compared by competition ELISA, using a set of 6 anti-p24 and 7 anti-gp120 antibodies, as well as soluble CD4. The antigenicity of proteins on the nanoparticle surface was well preserved, adsorbed either individually or in combination. Furthermore, both antigens maintained their immunogenicity, since high antibody titres (10(6) for p24 and 10(5) for gp120) were elicited in mice with monovalent and divalent PLA formulations. Taken together our results show that development of multivalent vaccines based on anionic PLA nanoparticles is possible. Moreover, coadsorption of a ligand for cell-specific targeting or of an immunostimulatory molecule will further extend the field of application of delivery systems based on charged micro- and nanoparticles.
- Published
- 2006
- Full Text
- View/download PDF
35. Evaluation of passively transferred, nonneutralizing antibody-dependent cellular cytotoxicity-mediating IgG in protection of neonatal rhesus macaques against oral SIVmac251 challenge.
- Author
-
Florese RH, Van Rompay KK, Aldrich K, Forthal DN, Landucci G, Mahalanabis M, Haigwood N, Venzon D, Kalyanaraman VS, Marthas ML, and Robert-Guroff M
- Subjects
- Administration, Oral, Animals, Animals, Newborn, Drug Evaluation, Preclinical, Immunoglobulin G chemistry, Macaca mulatta, Simian Acquired Immunodeficiency Syndrome prevention & control, Antibody-Dependent Cell Cytotoxicity immunology, Immunization, Passive, Immunoglobulin G administration & dosage, Immunoglobulin G physiology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Immunodeficiency Virus immunology
- Abstract
Previously, Ab-dependent cellular cytotoxicity (ADCC) was significantly correlated with reduced acute viremia upon intrarectal SIVmac251 challenge of immunized rhesus macaques. To directly assess ADCC protective efficacy, six neonatal macaques were infused s.c. with immune IgG (220 mg/kg) purified from the immunized animals and positive for ADCC and Ab-dependent cell-mediated viral inhibition (ADCVI) activities. Six neonates received control IgG. The neonates were challenged twice orally with 10(5) 50% inhibiting tissue culture-infective dose of SIVmac251 2 days post-IgG infusion. At challenge, plasma of neonates that received immune IgG did not neutralize SIVmac251 but had geometric mean ADCC titers of 48,130 and 232,850 against SIVmac251 -infected and gp120-coated targets, respectively. Peak ADCVI activity varied from 62 to 81%. ADCC activity declined with the 2-wk IgG half-life but was boosted at wk 4, together with de novo ADCC-mediating Abs in controls, by postchallenge viremia. ADCVI activity was similarly induced. No protection, assessed by viral burdens, CD4 counts, and time to euthanasia was observed. Possible factors contributing to the discrepancy between the previous correlation and lack of protection here include: the high oral challenge dose compared with the 400-fold lower intrarectal dose; the challenge route with regard to viral dissemination and distribution of infused IgG; insufficient NK effector activity and/or poor functionality in newborns; insufficient immune IgG; and the possibility that the previous correlation of ADCC with protection was augmented by cellular immune responses also present at challenge. Future studies should explore additional challenge routes in juvenile macaques using higher amounts of potent IgG preparations.
- Published
- 2006
- Full Text
- View/download PDF
36. Durable protection of rhesus macaques immunized with a replicating adenovirus-SIV multigene prime/protein boost vaccine regimen against a second SIVmac251 rectal challenge: role of SIV-specific CD8+ T cell responses.
- Author
-
Malkevitch NV, Patterson LJ, Aldrich MK, Wu Y, Venzon D, Florese RH, Kalyanaraman VS, Pal R, Lee EM, Zhao J, Cristillo A, and Robert-Guroff M
- Subjects
- Adenoviridae immunology, Administration, Rectal, Animals, Immunity, Cellular, Immunization, Secondary, Macaca mulatta, RNA, Viral analysis, Recombinant Fusion Proteins immunology, SAIDS Vaccines genetics, SAIDS Vaccines immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome virology, Simian Immunodeficiency Virus isolation & purification, Time Factors, Vaccination, Vaccines, Synthetic administration & dosage, Viremia, Virus Replication, Adenoviridae genetics, CD8-Positive T-Lymphocytes immunology, SAIDS Vaccines administration & dosage, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus immunology
- Abstract
Previously, priming with replication-competent adenovirus-SIV multigenic vaccines and boosting with envelope subunits strongly protected 39% of rhesus macaques against rectal SIV(mac251) challenge. To evaluate protection durability, eleven of the protected and two SIV-infected unimmunized macaques that controlled viremia were re-challenged rectally with SIV(mac251). Strong protection was observed in 8/11 vaccinees, including two exhibiting <50 SIV RNA copies. Decreased viremia compared to naïve controls was observed in the other three. The SIV-infected unimmunized macaques modestly controlled viremia but exhibited CD4 counts < or =200, unlike the protected macaques. Durable protection was associated with significantly increased SIV-specific ELISPOT responses and lymphoproliferative responses to p27 at re-challenge. After CD8 depletion, 2 of 8 re-challenged, protected vaccinees maintained <50 SIV RNA copies; SIV RNA emerged in 6. Re-appearance of CD8 cells and restoration of SIV-specific cellular immunity coincided with viremia suppression. Overall, cellular immunity induced by vaccination and/or low-level, inapparent viremia post-first SIV(mac251) challenge, was associated with durable protection against re-challenge.
- Published
- 2006
- Full Text
- View/download PDF
37. Subunit recombinant vaccine protects against monkeypox.
- Author
-
Heraud JM, Edghill-Smith Y, Ayala V, Kalisz I, Parrino J, Kalyanaraman VS, Manischewitz J, King LR, Hryniewicz A, Trindade CJ, Hassett M, Tsai WP, Venzon D, Nalca A, Vaccari M, Silvera P, Bray M, Graham BS, Golding H, Hooper JW, and Franchini G
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Viral biosynthesis, Antibodies, Viral blood, Antigens, Viral administration & dosage, Antigens, Viral genetics, Antigens, Viral immunology, DNA, Viral administration & dosage, DNA, Viral immunology, Disease Models, Animal, Macaca mulatta, Molecular Sequence Data, Mpox (monkeypox) immunology, Monkeypox virus genetics, Smallpox Vaccine adverse effects, Smallpox Vaccine immunology, Vaccines, Subunit administration & dosage, Vaccines, Subunit genetics, Vaccines, Subunit immunology, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, Viral Vaccines genetics, Mpox (monkeypox) prevention & control, Monkeypox virus immunology, Viral Vaccines administration & dosage, Viral Vaccines immunology
- Abstract
The smallpox vaccine Dryvax, a live vaccinia virus (VACV), protects against smallpox and monkeypox, but is contraindicated in immunocompromised individuals. Because Abs to VACV mediate protection, a live virus vaccine could be substituted by a safe subunit protein-based vaccine able to induce a protective Ab response. We immunized rhesus macaques with plasmid DNA encoding the monkeypox orthologs of the VACV L1R, A27L, A33R, and B5R proteins by the intradermal and i.m. routes, either alone or in combination with the equivalent recombinant proteins produced in Escherichia coli. Animals that received only DNA failed to produce high titer Abs, developed innumerable skin lesions after challenge, and died in a manner similar to placebo controls. By contrast, the animals vaccinated with proteins developed moderate to severe disease (20-155 skin lesions) but survived. Importantly, those immunized with DNA and boosted with proteins had mild disease with 15 or fewer lesions that resolved within days. DNA/protein immunization elicited Th responses and binding Ab titers to all four proteins that correlated negatively with the total lesion number. The sera of the immunized macaques recognized a limited number of linear B cell epitopes that are highly conserved among orthopoxviruses. Their identification may guide future efforts to develop simpler, safer, and more effective vaccines for monkeypox and smallpox.
- Published
- 2006
- Full Text
- View/download PDF
38. Polyvalent HIV-1 Env vaccine formulations delivered by the DNA priming plus protein boosting approach are effective in generating neutralizing antibodies against primary human immunodeficiency virus type 1 isolates from subtypes A, B, C, D and E.
- Author
-
Wang S, Pal R, Mascola JR, Chou TH, Mboudjeka I, Shen S, Liu Q, Whitney S, Keen T, Nair BC, Kalyanaraman VS, Markham P, and Lu S
- Subjects
- Animals, Female, HIV Antibodies blood, Immunoglobulin G blood, Immunoglobulin G immunology, Neutralization Tests, Rabbits, AIDS Vaccines classification, AIDS Vaccines immunology, DNA, Viral immunology, HIV Antibodies immunology, HIV Envelope Protein gp120 immunology, HIV Infections immunology, HIV Infections prevention & control
- Abstract
A major challenge in developing an HIV-1 vaccine is to identify immunogens and their delivery methods that can elicit broad neutralizing antibodies against primary isolates of different genetic subtypes. Recently, we demonstrated that priming with DNA vaccines expressing primary HIV-1 envelope glycoprotein (Env) followed by recombinant Env protein boosting was successful in generating positive neutralizing antibody responses against a clade B primary HIV-1 isolate, JR-FL, that was not easily neutralized. In the current study, we examined whether the DNA priming plus recombinant protein boosting approach delivering a polyvalent primary Env formulation was able to generate neutralizing antibodies against primary HIV-1 viral isolates from various genetic subtypes. New Zealand White rabbits were first immunized with DNA vaccines expressing one, three or eight primary HIV-1 gp120 antigens delivered by a gene gun followed by recombinant gp120 protein boosting. Neutralizing antibody responses were examined by two independently executed neutralization assays: the first one was a single round infection neutralization assay against a panel of 10 primary HIV-1 isolates of subtypes A, B, C and E and the second one used the PhenoSense assay against a panel of 12 pseudovirues expressing primary HIV-1 Env antigens from subtypes A, B, C, D and E as well as 2 pseudoviruses expressing the Env antigens from MN and NL4-3 viruses. Rabbit sera immunized with the DNA priming plus protein boosting approach, but not DNA vaccine alone or Env protein alone, were capable of neutralizing 7 of 10 viruses in the first assay and 12 of 14 viruses in the second assay. More importantly, sera immunized with the polyvalent Env antigens were able to neutralize a significantly higher percentage of viruses than the sera immunized with the monovalent antigens. Our results suggest that DNA priming followed by recombinant Env protein boosting can be used to deliver polyvalent Env-antigen-based HIV-1 vaccines to elicit neutralizing antibody responses against viruses with diverse genetic sequence variations.
- Published
- 2006
- Full Text
- View/download PDF
39. Immunization of rhesus macaques with a polyvalent DNA prime/protein boost human immunodeficiency virus type 1 vaccine elicits protective antibody response against simian human immunodeficiency virus of R5 phenotype.
- Author
-
Pal R, Kalyanaraman VS, Nair BC, Whitney S, Keen T, Hocker L, Hudacik L, Rose N, Mboudjeka I, Shen S, Wu-Chou TH, Montefiori D, Mascola J, Markham P, and Lu S
- Subjects
- AIDS Vaccines genetics, Animals, Antibodies, Viral biosynthesis, Gene Products, gag, HIV Envelope Protein gp120 genetics, HIV Envelope Protein gp120 immunology, HIV-1 genetics, Humans, Immunity, Cellular, Immunization Schedule, Immunization, Secondary, Macaca mulatta, Neutralization Tests, Phenotype, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus classification, Simian Immunodeficiency Virus pathogenicity, Vaccines, DNA genetics, Vaccines, Subunit administration & dosage, Vaccines, Subunit genetics, AIDS Vaccines administration & dosage, HIV-1 immunology, Simian Immunodeficiency Virus immunology, Vaccines, DNA administration & dosage
- Abstract
The immunogenicity of a poylvalent HIV-1 vaccine comprised of Env antigens from primary R5 isolates was evaluated in rhesus macaques. DNA vaccines encoding four Env antigens from multiple HIV-1 subtypes and HIV-1 Gag antigen from a single subtype elicited a persistent level of binding antibodies to gp120 from multiple HIV-1 isolates that were markedly enhanced following boosting with homologous gp120 proteins in QS-21 adjuvant irrespective of the route of DNA immunization. These sera neutralized homologous and, to a lesser degree, heterologous HIV-1 isolates. Four of the six immunized animals were completely protected following rectal challenge with a SHIV encoding Env from HIV-1(Ba-L), whereas the virus load was reduced in the remaining animals compared to naïve controls. Hence priming with DNA encoding Env antigens from multiple HIV-1 clades followed by boosting with homologous Env proteins elicits anti-HIV-1 immune responses capable of protecting macaques against mucosal transmission of R5 tropic SHIV isolate.
- Published
- 2006
- Full Text
- View/download PDF
40. Systemic immunization with an ALVAC-HIV-1/protein boost vaccine strategy protects rhesus macaques from CD4+ T-cell loss and reduces both systemic and mucosal simian-human immunodeficiency virus SHIVKU2 RNA levels.
- Author
-
Pal R, Venzon D, Santra S, Kalyanaraman VS, Montefiori DC, Hocker L, Hudacik L, Rose N, Nacsa J, Edghill-Smith Y, Moniuszko M, Hel Z, Belyakov IM, Berzofsky JA, Parks RW, Markham PD, Letvin NL, Tartaglia J, and Franchini G
- Subjects
- Animals, HIV Antibodies blood, HIV-1 isolation & purification, Immunization, Secondary, Macaca mulatta, Research Design, Simian Immunodeficiency Virus isolation & purification, Viral Load, Viremia prevention & control, AIDS Vaccines immunology, CD4 Lymphocyte Count, HIV-1 immunology, RNA, Viral analysis, Simian Immunodeficiency Virus immunology
- Abstract
Transmission of human immunodeficiency virus type 1 (HIV-1) occurs primarily via the mucosal route, suggesting that HIV-1 vaccines may need to elicit mucosal immune responses. Here, we investigated the immunogenicity and relative efficacy of systemic immunization with two human ALVAC-HIV-1 recombinant vaccines expressing Gag, Pol, and gp120 (vCP250) or Gag, Pol, and gp160 (vCP1420) in a prime-boost protocol with their homologous vaccine native Env proteins. The relative efficacy was measured against a high-dose mucosal exposure to the pathogenic neutralization-resistant variant SHIV(KU2) (simian-human immunodeficiency virus). Systemic immunization with both vaccine regimens decreased viral load levels not only in blood but unexpectedly also in mucosal sites and protected macaques from peripheral CD4+ T-cell loss. This protective effect was stronger when the gp120 antigen was included in the vaccine. Inclusion of recombinant Tat protein in the boosting phase along with the Env protein did not contribute further to the preservation of CD4+ T cells. Thus, systemic immunization with ALVAC-HIV-1 vaccine candidates elicits anti-HIV-1 immune responses able to contain virus replication also at mucosal sites in macaques.
- Published
- 2006
- Full Text
- View/download PDF
41. Preclinical evaluation of cellular immune responses elicited by a polyvalent DNA prime/protein boost HIV-1 vaccine.
- Author
-
Cristillo AD, Wang S, Caskey MS, Unangst T, Hocker L, He L, Hudacik L, Whitney S, Keen T, Chou TH, Shen S, Joshi S, Kalyanaraman VS, Nair B, Markham P, Lu S, and Pal R
- Subjects
- AIDS Vaccines genetics, Animals, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cytokines metabolism, Gene Products, env genetics, Gene Products, env immunology, Gene Products, gag genetics, Gene Products, gag immunology, HIV Antibodies blood, Humans, Immunity, Cellular, Immunization, Immunization Schedule, Macaca mulatta, Mice, Mice, Inbred BALB C, Th1 Cells immunology, AIDS Vaccines administration & dosage, AIDS Vaccines immunology, HIV Infections immunology, HIV-1 immunology, Immunization, Secondary methods, Vaccines, DNA administration & dosage, Vaccines, DNA immunology
- Abstract
While DNA vaccines have been shown to prime cellular immune responses, levels are often low in nonhuman primates or humans. Hence, efforts have been directed toward boosting responses by combining DNA with different vaccination modalities. To this end, a polyvalent DNA prime/protein boost vaccine, consisting of codon optimized HIV-1 env (A, B, C, E) and gag (C) and homologous gp120 proteins in QS-21, was evaluated in rhesus macaques and BALB/c mice. Humoral and cellular responses, detected following DNA immunization, were increased following protein boost in macaques and mice. In dissecting cellular immune responses in mice, protein-enhanced responses were found to be mediated by CD4+ and CD8+ T cells with a Th1 cytokine bias. Our study reveals that, in addition to augmenting humoral responses, protein boosting of DNA-primed animals augments cellular immune responses mediated by CD8+ CTL, CD4+ T-helper cells and Th1 cytokines; thus, offering much promise in controlling HIV-1 in vaccinees.
- Published
- 2006
- Full Text
- View/download PDF
42. Definitive toxicology and biodistribution study of a polyvalent DNA prime/protein boost human immunodeficiency virus type 1 (HIV-1) vaccine in rabbits.
- Author
-
Pal R, Yu Q, Wang S, Kalyanaraman VS, Nair BC, Hudacik L, Whitney S, Keen T, Hung CL, Hocker L, Kennedy JS, Markham P, and Lu S
- Subjects
- AIDS Vaccines metabolism, AIDS Vaccines toxicity, Animals, Immunization Schedule, Plasmids, Rabbits, Tissue Distribution, Vaccines, DNA metabolism, Vaccines, DNA toxicity, AIDS Vaccines immunology, HIV Envelope Protein gp120 immunology, HIV-1 immunology, Vaccines, DNA immunology
- Abstract
A toxicity and immunogenicity study, evaluating the safety of a polyvalent DNA prime/protein boost HIV-1 vaccine (DP6-001), was examined in rabbits. Animals were primed with a cocktail of six different DNA plasmids expressing five HIV-1 env genes and one gag gene followed by boosting with five gp120 proteins homologous to the DNA vaccines. The vaccine was shown to be immunogenic as evident from the induction of high-titered anti-Env and anti-Gag antibodies. There was an absence of detectable adverse effects on key toxicology parameters. Although plasmids persisted in the injection sites following single administration for 64 days, no evidence of integration into the host genomic DNA was observed. These studies demonstrate that a novel polyvalent DNA prime/protein boost vaccine lacks signs of toxicity and DNA integration in a rabbit model, and immunogenicity and toxicology data support clinical testing of the vaccine in humans.
- Published
- 2006
- Full Text
- View/download PDF
43. Enhanced cellular immunity to SIV Gag following co-administration of adenoviruses encoding wild-type or mutant HIV Tat and SIV Gag.
- Author
-
Zhao J, Voltan R, Peng B, Davis-Warren A, Kalyanaraman VS, Alvord WG, Aldrich K, Bernasconi D, Buttò S, Cafaro A, Ensoli B, and Robert-Guroff M
- Subjects
- AIDS Vaccines administration & dosage, AIDS Vaccines genetics, AIDS Vaccines immunology, Adenoviridae genetics, Adenoviridae immunology, Animals, Antibodies, Viral biosynthesis, Base Sequence, DNA, Recombinant genetics, Female, Genes, gag, Genes, tat, Genetic Vectors, HIV Antibodies biosynthesis, Humans, Immunity, Cellular, Immunization, Interferon-gamma biosynthesis, Macaca mulatta, Mice, Mice, Inbred BALB C, Mutation, T-Lymphocytes immunology, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, tat Gene Products, Human Immunodeficiency Virus, Gene Products, gag genetics, Gene Products, gag immunology, Gene Products, tat genetics, Gene Products, tat immunology, HIV-1 genetics, HIV-1 immunology, Simian Immunodeficiency Virus genetics, Simian Immunodeficiency Virus immunology
- Abstract
Among candidate antigens for human immunodeficiency virus (HIV) prophylactic vaccines, the regulatory protein Tat is a critical early target, but has a potential for immune suppression. Adenovirus (Ad) recombinants encoding wild-type HIV Tat (Tat-wt) and a transdominant negative mutant HIV Tat (Tat22) were constructed and administered to mice separately or together with Ad-SIVgag. Immunogenicity and effects on immune responses to the co-administered Gag immunogen were evaluated. Wild-type and mutant Tat recombinants elicited similar Tat-specific cellular and humoral immune responses. Co-administration of either Tat immunogen with Ad-SIVgag induced modest but significant enhancement of Gag-specific interferon-gamma secreting T cells and lymphoproliferative responses. Neither the Ad-recombinant encoding Tat-wt nor Tat22 suppressed induction of anti-Tat or anti-Gag antibodies. Based on the immune responses observed in mice, both recombinants appear to be suitable vaccine candidates. Their contribution to protective efficacy remains to be determined in a non-human primate model.
- Published
- 2005
- Full Text
- View/download PDF
44. Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy.
- Author
-
Popovic M, Tenner-Racz K, Pelser C, Stellbrink HJ, van Lunzen J, Lewis G, Kalyanaraman VS, Gallo RC, and Racz P
- Subjects
- Enzyme-Linked Immunosorbent Assay, HIV Antibodies metabolism, HIV Infections drug therapy, HIV-1 genetics, Humans, Immunohistochemistry, In Situ Hybridization, Neutralization Tests, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Antiretroviral Therapy, Highly Active, Glycoproteins metabolism, HIV Infections metabolism, HIV-1 metabolism, Lymph Nodes metabolism, RNA, Viral metabolism, Viral Structural Proteins metabolism
- Abstract
Here we report a long-term persistence of HIV-1 structural proteins and glycoproteins in germinal centers (GCs) of lymph nodes (LNs) in the absence of detectable virus replication in patients under highly active antiretroviral therapy (HAART). The persistence of viral structural proteins and glycoproteins in GCs was accompanied by specific antibody responses to HIV-1. Seven patients during the chronic phase of HIV-1 infection were analyzed for the presence of the capsid protein (HIV-1p24), matrix protein (HIV-1p17), and envelope glycoproteins (HIV-1gp120/gp41), as well as for viral RNA (vRNA) in biopsy specimens from LNs obtained before initiation of therapy and during HAART that lasted from 5 to 13 months. In parallel, these patients were also monitored for viremia and specific anti-HIV-1 antibody responses to structural proteins and glycoproteins both before and during treatment. Before-therapy viral levels, as determined by RT-PCR, ranged from 3 x 10(3) to 6.3 x 10(5) copies of vRNA per ml, whereas during treatment, vRNA was under detectable levels (<25 copies per ml). The pattern of vRNA detection in peripheral blood was concordant with in situ hybridization results of LN specimens. Before treatment, vRNA associated with follicular dendritic cells (FDCs) was readily detected in GCs of LNs of the patients, whereas during therapy, vRNA was consistently absent in the GCs of LN biopsies of treated patients. In contrast to vRNA hybridization results, viral structural proteins and glycoproteins, evaluated by immunohistochemical staining, were present and persisted in the GC light zone of LNs in abundant amounts not only before initiation of therapy but also during HAART, when no vRNA was detected in GCs. Consistent with immunohistochemical findings, specific antibody responses to HIV-1p17, -p24, and -gp120/gp41, as evaluated by ELISA and virus neutralization, persisted in patients under therapy for up to 13 months of follow-up. The implications of these findings are discussed in relation to HIV-1 persistence in infected individuals and the potential role of chronic antigenic stimulation by the deposited structural proteins in GCs for AIDS-associated B cell malignancies.
- Published
- 2005
- Full Text
- View/download PDF
45. Polyvalent DNA prime and envelope protein boost HIV-1 vaccine elicits humoral and cellular responses and controls plasma viremia in rhesus macaques following rectal challenge with an R5 SHIV isolate.
- Author
-
Pal R, Wang S, Kalyanaraman VS, Nair BC, Whitney S, Keen T, Hocker L, Hudacik L, Rose N, Cristillo A, Mboudjeka I, Shen S, Wu-Chou TH, Montefiori D, Mascola J, Lu S, and Markham P
- Subjects
- Animals, Antibodies, Viral blood, Enzyme-Linked Immunosorbent Assay veterinary, Genes, gag genetics, Genes, gag immunology, HIV Envelope Protein gp120 genetics, HIV Envelope Protein gp120 immunology, Interferon-gamma immunology, Lentiviruses, Primate immunology, Monocytes immunology, Neutralization Tests veterinary, Simian Acquired Immunodeficiency Syndrome immunology, Viremia veterinary, AIDS Vaccines immunology, HIV-1 immunology, Macaca mulatta, Monkey Diseases immunology, Monkey Diseases virology, Simian Acquired Immunodeficiency Syndrome prevention & control
- Abstract
Immunization of macaques with multivalent DNA encoding gp120 genes from HIV-1 subtypes A, B, C and E and a gag gene followed by boosting with homologous gp120 proteins elicited strong anti-gp120 antibodies capable of neutralizing homologous and to a lesser degree heterologous HIV-1 isolates. Both Env- and Gag-specific cell mediated immune (CMI) responses were detected in the immunized animals. Following rectal challenge with an SHIV isolate encoding HIV-1(Ba-L)env, plasma viremia in the infected immunized animals was significantly lower than that observed in the naïve animals. Further, one of six immunized animals was completely protected whereas all six naïve animals were infected. These results demonstrate that a vaccine based on priming with a polyvalent DNA vaccine from multiple HIV-1 subtypes followed by boosting with homologous Env proteins elicits anti-HIV-1 immune responses capable of controlling rectal transmission of SHIV(Ba-L).
- Published
- 2005
- Full Text
- View/download PDF
46. Replicating rather than nonreplicating adenovirus-human immunodeficiency virus recombinant vaccines are better at eliciting potent cellular immunity and priming high-titer antibodies.
- Author
-
Peng B, Wang LR, Gómez-Román VR, Davis-Warren A, Montefiori DC, Kalyanaraman VS, Venzon D, Zhao J, Kan E, Rowell TJ, Murthy KK, Srivastava I, Barnett SW, and Robert-Guroff M
- Subjects
- Adenoviridae physiology, Animals, Antibody-Dependent Cell Cytotoxicity, Genetic Vectors, Immunization, Lymphocyte Activation, Pan troglodytes, Research Design, AIDS Vaccines immunology, Adenoviridae genetics, HIV Antibodies blood, Vaccines, Synthetic immunology, Virus Replication
- Abstract
A major challenge in combating the human immunodeficiency virus (HIV) epidemic is the development of vaccines capable of inducing potent, persistent cellular immunity and broadly reactive neutralizing antibody responses to HIV type 1 (HIV-1). We report here the results of a preclinical trial using the chimpanzee model to investigate a combination vaccine strategy involving sequential priming immunizations with different serotypes of adenovirus (Ad)/HIV-1(MN)env/rev recombinants and boosting with an HIV envelope subunit protein, oligomeric HIV(SF162) gp140deltaV2. The immunogenicities of replicating and nonreplicating Ad/HIV-1(MN)env/rev recombinants were compared. Replicating Ad/HIV recombinants were better at eliciting HIV-specific cellular immune responses and better at priming humoral immunity against HIV than nonreplicating Ad-HIV recombinants carrying the same gene insert. Enhanced cellular immunity was manifested by a greater frequency of HIV envelope-specific gamma interferon-secreting peripheral blood lymphocytes and better priming of T-cell proliferative responses. Enhanced humoral immunity was seen in higher anti-envelope binding and neutralizing antibody titers and better induction of antibody-dependent cellular cytotoxicity. More animals primed with replicating Ad recombinants mounted neutralizing antibodies against heterologous R5 viruses after one or two booster immunizations with the mismatched oligomeric HIV-1(SF162) gp140deltaV2 protein. These results support continued development of the replicating Ad-HIV recombinant vaccine approach and suggest that the use of replicating vectors for other vaccines may prove fruitful.
- Published
- 2005
- Full Text
- View/download PDF
47. Protection against mucosal simian immunodeficiency virus SIV(mac251) challenge by using replicating adenovirus-SIV multigene vaccine priming and subunit boosting.
- Author
-
Patterson LJ, Malkevitch N, Venzon D, Pinczewski J, Gómez-Román VR, Wang L, Kalyanaraman VS, Markham PD, Robey FA, and Robert-Guroff M
- Subjects
- Animals, Antibodies, Viral immunology, Female, Interferon-gamma immunology, Interferon-gamma metabolism, Male, Research Design, SAIDS Vaccines administration & dosage, SAIDS Vaccines genetics, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome virology, Vaccines, DNA administration & dosage, Vaccines, DNA genetics, Vaccines, DNA immunology, Vaccines, Subunit administration & dosage, Vaccines, Subunit genetics, Vaccines, Subunit immunology, Viral Load, Viremia immunology, Viremia prevention & control, Adenoviridae genetics, Immunity, Mucosal immunology, Immunization, Secondary, Macaca mulatta immunology, SAIDS Vaccines immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus immunology
- Abstract
Whereas several recent AIDS vaccine strategies have protected rhesus macaques against a pathogenic simian/human immunodeficiency virus (SHIV)(89.6P) challenge, similar approaches have provided only modest, transient reductions in viral burden after challenge with virulent, pathogenic SIV, which is more representative of HIV infection of people. We show here that priming with replicating adenovirus recombinants encoding SIV env/rev, gag, and/or nef genes, followed by boosting with SIV gp120 or an SIV polypeptide mimicking the CD4 binding region of the envelope, protects rhesus macaques from intrarectal infection with the highly pathogenic SIV(mac251). Using trend analysis, significant reductions in acute-phase and set point viremia were correlated with anti-gp120 antibody and cellular immune responses, respectively. Within immunization groups exhibiting significant protection, a subset (39%) of macaques have exhibited either no viremia, cleared viremia, or controlled viremia at the threshold of detection, now more than 40 weeks postchallenge. This combination prime-boost strategy, utilizing replication competent adenovirus, is a promising alternative for HIV vaccine development.
- Published
- 2004
- Full Text
- View/download PDF
48. Evaluation of combination DNA/replication-competent Ad-SIV recombinant immunization regimens in rhesus macaques.
- Author
-
Malkevitch N, Rohne D, Pinczewski J, Aldrich K, Kalyanaraman VS, Letvin NL, and Robert-Guroff M
- Subjects
- Adenoviridae genetics, Animals, Antibodies, Viral biosynthesis, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Female, Genetic Vectors, Immunity, Cellular, Immunity, Mucosal, Interferon-gamma biosynthesis, Macaca mulatta, Male, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, SAIDS Vaccines genetics, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus genetics, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic genetics, Viral Envelope Proteins genetics, Viral Envelope Proteins immunology, SAIDS Vaccines administration & dosage, Simian Immunodeficiency Virus immunology
- Abstract
Combination vaccine regimens in which priming with recombinant DNA is followed by boosting with recombinant viral vectors have been shown in previous studies to effectively enhance cellular immunity. However, no information exists concerning possible synergy of the cellular immune response when DNA immunization is followed by administration of a recombinant vector able to replicate. As our approach makes use of replication-competent Ad HIV and SIV recombinants, we performed a pilot experiment in six rhesus macaques in which we compared immunogenicity resulting from priming with one or two DNA recombinants encoding the SIVsmH4 env and rev genes with that elicited by a single replication-competent Ad5hr-SIV env/rev priming immunization. All macaques were subsequently administered an Ad5hr-SIV env/rev booster immunization followed by two immunizations with SIV gp120 protein. The choice of the env gene as target immunogen allowed comparison of induced cellular immune responses as well as binding and neutralizing antibodies elicited in serum and mucosal secretions. We report here that all immunized monkeys developed strong cellular immunity to the SIV envelope as shown by secretion of interferon-gamma, lysis of envelope-expressing target cells, and/or proliferation in response to gp120 or inactivated SIV. Similarly, all macaques developed anti-gp120 binding antibodies and neutralizing antibodies in serum and IgG and IgA binding antibodies in mucosal secretions. We did not observe consistently enhanced immune responses in any immunization group. We conclude that two sequential immunizations with the same replication-competent Ad5hr-SIV recombinant is as effective as priming with one or two recombinant DNA vaccines followed by a single Ad5hrSIV recombinant immunization.
- Published
- 2004
- Full Text
- View/download PDF
49. Boosting of SIV-specific immune responses in rhesus macaques by repeated administration of Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinants.
- Author
-
Zhao J, Lou Y, Pinczewski J, Malkevitch N, Aldrich K, Kalyanaraman VS, Venzon D, Peng B, Patterson LJ, Edghill-Smith Y, Woodward R, Pavlakis GN, and Robert-Guroff M
- Subjects
- Animals, Blotting, Western, Cell Division, Cryopreservation, Enzyme-Linked Immunosorbent Assay, Female, Immunization, Secondary, Interferon-gamma biosynthesis, Interferon-gamma genetics, Macaca mulatta, Neutralization Tests, T-Lymphocytes immunology, Vaccines, Synthetic immunology, Gene Products, gag immunology, Gene Products, rev immunology, Simian Immunodeficiency Virus immunology, Viral Envelope Proteins immunology, Viral Vaccines administration & dosage, Viral Vaccines immunology
- Abstract
Previous non-human primate studies have shown replication competent adenovirus (Ad) HIVenv/rev and SIVenv/rev recombinants to be promising vaccine candidates. To broaden induced immunity in rhesus macaques, an Ad type 5 host range (Ad5hr) mutant vector with an inserted SIV gag gene was added to the vaccine regimen. Immunity to the encoded SIV Env, Rev, and Gag gene products was evaluated following two immunizations with the same recombinants. The vaccines were administered intranasally plus orally via stomach tube at weeks 0 and 12. The recombinants replicated well in the upper respiratory tract but poorly in the gut, suggesting enteric-coated capsules might improve oral delivery to the intestine. SIV-specific cellular immunity was induced in all 16 immunized macaques. Fourteen exhibited positive interferon-gamma (IFN-gamma) ELISPOT responses, and nine, including two lacking IFN-gamma responses, exhibited SIV-specific T-cell proliferative activity. IFN-gamma secreting peripheral blood mononuclear cells (PBMCs) in response to SIV Gag, Env, and Rev peptides were induced in 73, 53, and 27% of macaques, respectively, and were boosted two- to four-fold by the second immunization. A persistent response to Gag was evident at least 10 weeks thereafter. p11C tetramer staining confirmed elicitation of SIV Gag-specific CD8+ T-cells in Mamu-A*01 macaques. Proliferative responses were more frequent after the second immunization, and binding antibody titers to SIV gp120 were significantly boosted by the immunization regimen. We conclude that a second administration of recombinants based in the same Ad5hr vector can effectively boost immunity to inserted gene products, obviating development of several recombinants in different Ad serotypes for multiple immunizations.
- Published
- 2003
- Full Text
- View/download PDF
50. Improved protection of rhesus macaques against intrarectal simian immunodeficiency virus SIV(mac251) challenge by a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen.
- Author
-
Zhao J, Pinczewski J, Gómez-Román VR, Venzon D, Kalyanaraman VS, Markham PD, Aldrich K, Moake M, Montefiori DC, Lou Y, Pavlakis GN, and Robert-Guroff M
- Subjects
- Administration, Rectal, Animals, Antibodies, Viral blood, Female, Gene Products, env genetics, Gene Products, env immunology, Gene Products, gag genetics, Gene Products, gag immunology, Gene Products, rev genetics, Gene Products, rev immunology, Immunity, Mucosal, Immunization, Immunization, Secondary, Macaca mulatta, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, RNA, Viral blood, Recombination, Genetic, SAIDS Vaccines genetics, SAIDS Vaccines immunology, Simian Immunodeficiency Virus genetics, Simian Immunodeficiency Virus physiology, Vaccines, Synthetic, Viral Envelope Proteins genetics, Viral Envelope Proteins immunology, Viral Proteins genetics, Viral Proteins immunology, Virus Replication, Adenoviridae genetics, SAIDS Vaccines administration & dosage, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus immunology
- Abstract
In this study we investigated the ability of a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen to induce protective immunity in rhesus macaques against pathogenic simian immunodeficiency virus(mac251). Immunization of macaques by two sequential administrations of the same recombinants by the same route resulted in boosting and persistence of SIV-specific cellular immune responses for 42 weeks past the initial immunization. Anti-SIV gp120 immunoglobulin G (IgG) and IgA antibodies were induced in secretory fluids, and all macaques exhibited serum neutralizing antibody activity. After intrarectal SIV(mac251) challenge, all of the macaques became infected. However, relative protection, as assessed by statistically significant lower SIV viral loads in plasma at both acute infection and set point, was observed in 8 out of 12 immunized non-Mamu-A(*)01 animals. Elevated mean cellular immune responses to Gag and Env, neutralizing antibody activity, and IgG and IgA binding antibody levels were observed in the eight protected macaques. Statistically significant correlations with protective outcome were observed for cellular immune responses to SIV Env and Gag and for SIV gp120-specific IgG antibodies in nasal and vaginal fluids. Two macaques that exhibited the greatest and most persistent viremia control also exhibited strong CD8(+) T-cell antiviral activity. The results suggest that a spectrum of immune responses may be necessary for adequate control of viral replication and disease progression and highlight a potential role for nonneutralizing antibodies at mucosal sites.
- Published
- 2003
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.