A crucial element in the development of effective prophylactic strategies for AIDS is an experimental animal model in which the course of immunodeficiency virus infection parallels the pathogenesis of the human disease. SIV infection of macaques is a relevant model since it induces an immunodeficiency syndrome in infected macaques that is remarkably similar to human AIDS. Our studies have focused on the use of the highly attenuated modified vaccinia virus Ankara to express SIV proteins. Immunization with MVA-SIV recombinants resulted in a reduction in setpoint plasma viral load that was associated with prolonged survival. Vaccination was associated with better preservation of memory CD4+ T cells that in turn correlated with titers of neutralizing antibodies to the challenge virus prior to challenge suggesting an important role for NAb and Envelope immunogens in this model.
The purpose of our current vaccine studies has been to use a prime-boost strategy to generate antibody that will neutralize the pathogenic SIVsmE660 and study the role of this antibody in the SIV model. Similar studies using SIVmac239 have been hampered due to the neutralization resistance associated with its envelope glycoprotein.
We generated a MVA recombinant that expresses the less neutralization-resistant SIVsmE543-3 envelope and a plasmid of the codon-optimized gp140 that we used to generate recombinant trimeric envelope. A cohort of 24 rhesus macaques (6 per group) were immunized with either: A) Trimer, B) MVA-nonrecombinant, C) Two MVA-Env primes, + two trimer boosts and D) MVA-Env plus trimer co-administered 4 times. All were given with adjuvant (AbISCO-100). All SIV Env immunized animals developed neutralizing antibodies to SIVsmE660 but only weak and partial neutralization of SIVsmE543. They were challenged intrarectally with a single dose of SIVsmE660, 4 months following the last immunization. A delay and blunting of viremia was observed in 50% of animals that received the prime boost regimen with one animal not apparently infected (Group C). However a macaque each from Groups B and D also remained uninfected. All uninfected animals were rechallenged with the same IR dose of SIVsmE660. We are currently evaluating vaccine-induced cellular immune responses and breadth and titers of neutralizing antibody to determine immune correlates of the partial protection observed. We developed a panel of chimeric E660 clones expressing a range of late stage envelopes with varying sensitivity to neutralization. We are currently screening immune and post challenge sera for neutralizing antibodies in order to define immune correlates of the partial protection we observed We collaborated with a number of groups on vaccine studies using SIVsmE543 immunogens or SIVsmE660 challenge viruses including: 1) Dr. Barbara Felber and George Pavlakis at the NCI, 2) Dr. Harriet Robinson at Emory and 3) Dr. Dan Barouch (Harvard) and Nelson Michael (WRAIR). In this latter study, MVA and adenovirus expressing SIVsmE543-3 gag-pol and env were combined as immunogens. This strategy led of a delay in acquisition of infection by the heterologous SIVmac251 despite the fact that high titers of tier 2 neutralizing antibodies were not generated by this strategy. DEVELOPMENT OF ALTERNATIVE CHALLENGE STRAINS. The development and characterization of alternative to the major SIVmac239/2251 and SIVsmE660 challenge strains are required for studies evaluating the role of neutralizing antibody in protection. We wish to develop and characterize additional strains of SIV that are more sensitive to neutralization and that can model the Tier2 type sensitivity of primary HIV isolates. We are evaluating two full length infectious clones of SIVsmE660. These both replicate efficiently in macaque PBMC in vivo, are sensitive to neutralization and replicate efficiently in rhesus macaques in vivo. As described in the pathogenesis project (AI000370) these clones are still sensitive to TRIM restriction and recent studies from the Watkins and Letvin labs suggest that TRIM5 polymorphisms and in particular expression of the restrictive TRIM-TFP allele contributes to protection in low dose SIVsmE660 challenge models. Therefore we have generated minimal point mutants in CA that are now resistant to TRIM restriction that will be evaluated in vivo. These clones would be ideal source of challenge strains that should avoid TRIM restriction as a confounding factor in low dose E660 challenge models. In addition, we have generated clones with a more neutralization resistant phenotype that is intermediate between the original E660 clones and 543-3 that may better model the phenotype of primary HIV-1 strains.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Singh, Shakti; Ramírez-Salazar, Eric G; Doueiri, Rami et al. (2018) Control of Heterologous Simian Immunodeficiency Virus SIVsmE660 Infection by DNA and Protein Coimmunization Regimens Combined with Different Toll-Like-Receptor-4-Based Adjuvants in Macaques. J Virol 92:
Hessell, Ann J; Jaworski, J Pablo; Epson, Erin et al. (2016) Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques. Nat Med 22:362-8
Huang, Jinghe; Kang, Byong H; Ishida, Elise et al. (2016) Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth. Immunity 45:1108-1121
Wu, Fan; Ourmanov, Ilnour; Riddick, Nadeene et al. (2015) TRIM5? restriction affects clinical outcome and disease progression in simian immunodeficiency virus-infected rhesus macaques. J Virol 89:2233-40
Fukazawa, Yoshinori; Lum, Richard; Okoye, Afam A et al. (2015) B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat Med 21:132-9
Teigler, Jeffrey E; Phogat, Sanjay; Franchini, Genoveffa et al. (2014) The canarypox virus vector ALVAC induces distinct cytokine responses compared to the vaccinia virus-based vectors MVA and NYVAC in rhesus monkeys. J Virol 88:1809-14
Patel, Vainav; Jalah, Rashmi; Kulkarni, Viraj et al. (2013) DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge. Proc Natl Acad Sci U S A 110:2975-80
Kuwata, Takeo; Takaki, Kaori; Yoshimura, Kazuhisa et al. (2013) Conformational epitope consisting of the V3 and V4 loops as a target for potent and broad neutralization of simian immunodeficiency viruses. J Virol 87:5424-36
Barouch, Dan H; Liu, Jinyan; Li, Hualin et al. (2012) Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature 482:89-93
Patterson, L Jean; Daltabuit-Test, Mara; Xiao, Peng et al. (2011) Rapid SIV Env-specific mucosal and serum antibody induction augments cellular immunity in protecting immunized, elite-controller macaques against high dose heterologous SIV challenge. Virology 411:87-102

Showing the most recent 10 out of 17 publications