107. Development of Novel Simian Immunodeficiency Virus (SIVagm)-Derived Lentiviral Vectors Pseudotyped with Envelope Proteins from Paramyxovirus and Orthomyxovirus

ABSTRACT AIDS vaccination has a pressing need for more potent vaccination vectors capable of eliciting strong, diversified, and long-lasting cellular immune responses against human immunodeficiency virus (HIV). Lentiviral vectors have demonstrated efficiency not only as gene delivery vehicles for gene therapy applications but also as vaccination tools. This is likely due to their ability to transduce nondividing cells, including dendritic cells, enabling sustained endogenous antigen presentation and thus the induction of high proportions of specific cytotoxic T cells and long-lasting memory T cells. We show in a first proof-of-concept pilot study that a prime/boost vaccination strategy using lentiviral vectors pseudotyped with a glycoprotein G from two non-cross-reactive vesicular stomatitis virus serotypes elicited robust and broad cellular immune responses against the vector-encoded antigen, simian immunodeficiency virus (SIV) GAG, in cynomolgus macaques. Vaccination conferred strong protection against a massive intrarectal challenge with SIVmac251, as evidenced both by the reduction of viremia at the peak of acute infection (a mean of over 2 log10 fold reduction) and by the full preservation of the CD28+ CD95+ memory CD4+ T cells during the acute phase, a strong correlate of protection against pathogenesis. Although vaccinees continued to display lower viremia than control macaques during the early chronic phase, these differences were not statistically significant by day 50 postchallenge. A not-optimized SIV GAG antigen was chosen to show the strong potential of the lentiviral vector system for vaccination. Given that a stronger protection can be anticipated from a modern HIV-1 antigen design, gene transfer vectors derived from HIV-1 appear as promising candidates for vaccination against HIV-1 infection.

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Identification of four antibody-binding sites in the envelope proteins of simian immunodeficiency virus, SIVsm

AIDS ◽

10.1097/00002030-199302000-00002 ◽

1993 ◽

Vol 7 (2) ◽

pp. 159-166 ◽

Cited By ~ 4

Author(s):

Astrid Samuelsson ◽

Ewa Björling ◽

Per Putkonen ◽

Göran Utter ◽

Francesca Chiodi ◽

...

Keyword(s):

Simian Immunodeficiency Virus ◽

Binding Sites ◽

Envelope Proteins ◽

Antibody Binding ◽

Immunodeficiency Virus

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Kinetic Rates of Antibody Binding Correlate with Neutralization Sensitivity of Variant Simian Immunodeficiency Virus Strains

Journal of Virology ◽

10.1128/jvi.79.19.12311-12320.2005 ◽

2005 ◽

Vol 79 (19) ◽

pp. 12311-12320 ◽

Cited By ~ 34

Author(s):

Jonathan D. Steckbeck ◽

Irina Orlov ◽

Andrew Chow ◽

Heather Grieser ◽

Kenneth Miller ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Simian Immunodeficiency Virus ◽

Neutralizing Antibody ◽

Envelope Proteins ◽

Antibody Binding ◽

Immunodeficiency Virus ◽

Kinetic Rates ◽

Aids Vaccines ◽

Virus Strains

ABSTRACT Increasing evidence suggests that an effective AIDS vaccine will need to elicit both broadly reactive humoral and cellular immune responses. Potent and cross-reactive neutralization of simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) by polyclonal and monoclonal antibodies is well documented. However, the mechanisms of antibody-mediated neutralization have not been defined. The current study was designed to determine whether the specificity and quantitative properties of antibody binding to SIV envelope proteins correlate with neutralization. Using a panel of rhesus monoclonal antibodies previously characterized for their ability to bind and neutralize variant SIVs, we compared the kinetic rates and affinity of antibody binding to soluble envelope trimers by using surface plasmon resonance. We identified significant differences in the kinetic rates but not the affinity of monoclonal antibody binding to the neutralization-sensitive SIV/17E-CL and neutralization-resistant SIVmac239 envelope proteins that correlated with the neutralization sensitivities of the corresponding virus strains. These results suggest for the first time that neutralization resistance may be related to quantitative differences in the rates but not the affinity of the antibody-envelope interaction and may provide one mechanism for the inherent resistance of SIVmac239 to neutralization in vitro. Further, we provide evidence that factors in addition to antibody binding, such as epitope specificity, contribute to the mechanisms of neutralization of SIV/17E-CL in vitro. This study will impact the method by which HIV/SIV vaccines are evaluated and will influence the design of candidate AIDS vaccines capable of eliciting effective neutralizing antibody responses.

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Effect of the Cytoplasmic Domain of the Simian Immunodeficiency Virus Envelope Protein on Incorporation of Heterologous Envelope Proteins and Sensitivity to Neutralization

Journal of Virology ◽

10.1128/jvi.74.18.8219-8225.2000 ◽

2000 ◽

Vol 74 (18) ◽

pp. 8219-8225 ◽

Cited By ~ 25

Author(s):

A. N. Vzorov ◽

R. W. Compans

Keyword(s):

Influenza Virus ◽

Host Cell ◽

Simian Immunodeficiency Virus ◽

Neutralizing Antibodies ◽

Cytoplasmic Domain ◽

Envelope Proteins ◽

Viral Envelope ◽

Full Length ◽

Viral Glycoprotein ◽

Immunodeficiency Virus

ABSTRACT In addition to the viral envelope (Env) proteins, host cell-derived proteins have been reported to be present in human immunodeficiency virus and simian immunodeficiency virus (SIV) envelopes, and it has been postulated that they may play a role in infection. We investigated whether the incorporation of host cell proteins is affected by the structure and level of incorporation of viral Env proteins. To compare the cellular components incorporated into SIV particles and how this is influenced by the structure of the cytoplasmic domain, we compared SIV virions with full-length and truncated Env proteins. The levels of HLA-I and HLA-II molecules were found to be significantly (15- to 25-fold) higher in virions with full-length Env than in those with a truncated Env. Virions with a truncated Env were also found to be less susceptible to neutralization by specific antibodies against HLA-I or HLA-II proteins. We also compared the level of incorporation into SIV virions of a coexpressed heterologous viral glycoprotein, the influenza virus hemagglutinin (HA) protein. We found that SIV infection of cells expressing influenza virus HA resulted in the production of phenotypically mixed SIV virions containing influenza virus HA as well as SIV envelope proteins. The HA proteins were more effectively incorporated into virions with full-length Env than in virions with truncated Env. The phenotypically mixed particles with full-length Env, containing higher levels of HA, were sensitive to neutralization with anti-HA antibody, whereas virions with truncated Env proteins and containing lower levels of HA were more resistant to neutralization by anti-HA antibody. In contrast, SIV virions with truncated Env proteins were found to be highly sensitive to neutralization by antisera to SIV, whereas virions with full-length Env proteins were relatively resistant to neutralization. These results indicate that the cytoplasmic domain of SIV Env affects the incorporation of cellular as well as heterologous viral membrane proteins into the SIV envelope and may be an important determinant of the sensitivity of the virus to neutralizing antibodies.

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