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The search for a safe and effective AIDS vaccine is both a fascinating intellectual challenge and an important biomedical problem. HIV has evolved sophisticated mechanisms of immune evasion that will ultimately need to be overcome in designing an effective vaccine. A successful vaccine will also need to achieve lasting protective immunity against naturally transmitted HIV field isolates with extraordinary genetic and antigenic diversity.
Our research focuses on novel AIDS vaccine approaches, viral pathogenesis and mechanisms of immune evasion using simian immunodeficiency virus (SIV) infection of rhesus macaques as an animal model. SIV causes AIDS in infected macaques with a course of disease progression that closely resembles HIV infection of humans. SIV infection of macaques is therefore a valuable model for AIDS vaccine development and for studies of lentiviral pathogenesis.
We have devised a genetic system for producing strains of SIV, and potentially HIV, that are limited to a single cycle of infection. This system is based on a unique combination of mutations specifically designed to prevent the recovery of replication-competent viruses by recombination or nucleotide reversion. Unlike previous lentiviral vectors, single-cycle SIV (scSIV) produced by this approach is capable of expressing eight of the nine viral gene products and scSIV infected cells release immature virus particles that are unable to complete subsequent rounds of infection. In preliminary studies, rhesus macaques immunized with scSIV had transient viral loads in plasma and made antibody and T cell responses to multiple viral antigens. After challenging with a strain of SIV that is notoriously difficult to control by vaccination, scSIV-immunized animals were better able to control virus replication than unvaccinated control animals. Additional modifications to enhance the potential immunogenicity of scSIV and improved immunization regimens are now being evaluated to more fully explore the extent of protection that may be achieved by this new vaccine approach.
Single-cycle SIV also affords a unique opportunity to study aspects of viral pathogenesis that are difficult to address using replication-competent viruses. Current projects in the lab are aimed using scSIV as a tool to study the earliest stages of virus transmission across mucosal barriers and how defined sequence changes in envelope that affect cellular tropism influence the dynamics of productive infection in animals. Additional studies are aimed at understanding how the SIV Nef protein contributes to the evasion of both virus-specific cytotoxic T lymphocyte and natural killer cell responses.
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References:
DeGottardi MQ, Lew SK, Piatak M, Jia B, Fend Y, Lee SJ, Brenchley JM, Douek DC, Kodama T, Lifson JD, Evans DT. Comparison of plasma viremia and antibody responses in macaques inoculated with envelope variants of single-cycle SIV differing in infectivity and cellular tropism. J Virol 2008;82:321-334.
DeGottardi MQ, Specht A, Metcalf B, Kaur A, Kirchhoff F, and Evans DT. Selective downregulation of rhesus macaque and sooty mangabey major histocompatibility complex class I molecules by Nef alleles of simian immunodeficiency virus and human immunodeficiency virus type 2. J Virol 2008;82:3139-3164.
Evans DT, Bricker JE, Sanford HB, Lang S, Carville A, Richardson BA, Piatak M, Lifson JD, Mansfield KG, Desrosiers RC. Immunization of macaques with single-cycle SIV stimulates diverse virus-specific immune responses and reduces viral loads after challenge with SIVmac239. J Virol 2005; 79:7707-7720.
Evans DT, Bricker JE, Desrosiers RC. A novel approach for producing lentiviruses that are limited to a single cycle of infection. J Virol 2004; 78:11715-25.
Evans DT, O’Connor DH, Jing P, Dzuris JL, Sydney J, Da Silva J, Allen TM, Horton H, Venham JE, Rudersdorf RA, Vogel T, Pauza CD, Bontrop RE, DeMars R, Sette A, Hughes AL, Watkins DI. Virus-specific CTL responses select for for amino acid variation in simian immunodeficiency virus Env and Nef. Nat. Med. 1999. 5: 1270-1276. |
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