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Rasmussen, Robert

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Rasmussen

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Rasmussen, Robert

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Author's Publications: search.filters.isAuthorOfPublication.818d3bfa-ccec-4f17-b62c-5ce729f27cfb

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    Passive immunization with polyclonal anti-SHIV IgG: partial protection or increased acquisition of heterologous tier 2 SHIV – depending on IgG dose
    (BioMed Central, 2012) Sholukh, Anton M.; Siddappa, NB; Shanmuganathan, V; Lakhashe, Samir; Rasmussen, Robert; Watkins, Jennifer D.; Vyas, Hemant Kumar; Mukhtar, Muhammad Mahmood; Hemashettar, G; Thorat, Swati; Yoon, JK; Villinger, F; Novembre, FJ; Landucci, G; Forthal, DN; Ratcliffe, S; Robert-Guroff, M; Polonis, V; Montefiori, DC; Ertl, HC; Ruprecht, Ruth Margrit
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    R5 Clade C SHIV Strains with Tier 1 or 2 Neutralization Sensitivity: Tools to Dissect Env Evolution and to Develop AIDS Vaccines in Primate Models
    (Public Library of Science, 2010) Wassermann, Klemens J.; Song, Ruijiang; Wang, Wendy; Kramer, Victor G.; Novembre, Francis J.; Villinger, François; Else, James G.; Montefiori, David C.; Watkins, Jennifer D.; Siddappa, Nagadenahalli B.; Lakhashe, Samir; Santosuosso, Michael Robert; Poznansky, Mark; Rasmussen, Robert; Ruprecht, Ruth Margrit
    Background: HIV-1 clade C (HIV-C) predominates worldwide, and anti-HIV-C vaccines are urgently needed. Neutralizing antibody (nAb) responses are considered important but have proved difficult to elicit. Although some current immunogens elicit antibodies that neutralize highly neutralization-sensitive (tier 1) HIV strains, most circulating HIVs exhibiting a less sensitive (tier 2) phenotype are not neutralized. Thus, both tier 1 and 2 viruses are needed for vaccine discovery in nonhuman primate models. Methodology/Principal Findings: We constructed a tier 1 simian-human immunodeficiency virus, SHIV-1157ipEL, by inserting an “early,” recently transmitted HIV-C env into the SHIV-1157ipd3N4 backbone [1] encoding a “late” form of the same env, which had evolved in a SHIV-infected rhesus monkey (RM) with AIDS. SHIV-1157ipEL was rapidly passaged to yield SHIV-1157ipEL-p, which remained exclusively R5-tropic and had a tier 1 phenotype, in contrast to “late” SHIV-1157ipd3N4 (tier 2). After 5 weekly low-dose intrarectal exposures, SHIV-1157ipEL-p systemically infected 16 out of 17 RM with high peak viral RNA loads and depleted gut CD4\(^+\) T cells. SHIV-1157ipEL-p and SHIV-1157ipd3N4 env genes diverge mostly in V1/V2. Molecular modeling revealed a possible mechanism for the increased neutralization resistance of SHIV-1157ipd3N4 Env: V2 loops hindering access to the CD4 binding site, shown experimentally with nAb b12. Similar mutations have been linked to decreased neutralization sensitivity in HIV-C strains isolated from humans over time, indicating parallel HIV-C Env evolution in humans and RM. Conclusions/Significance: SHIV-1157ipEL-p, the first tier 1 R5 clade C SHIV, and SHIV-1157ipd3N4, its tier 2 counterpart, represent biologically relevant tools for anti-HIV-C vaccine development in primates.
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    Inducing Cross-Clade Neutralizing Antibodies against HIV-1 by Immunofocusing
    (Public Library of Science, 2008) Humbert, Michael; Rasmussen, Robert; Ong, Helena; Kaiser, Fabian M. P.; Hu, Shiu-Lok; Ruprecht, Ruth Margrit
    Background: Although vaccines are important in preventing viral infections by inducing neutralizing antibodies (nAbs), HIV-1 has proven to be a difficult target and escapes humoral immunity through various mechanisms. We sought to test whether HIV-1 Env mimics may serve as immunogens. Methodology/Principal Findings: Using random peptide phage display libraries, we identified the epitopes recognized by polyclonal antibodies of a rhesus monkey that had developed high-titer, broadly reactive nAbs after infection with a simian-human immunodeficiency virus (SHIV) encoding env of a recently transmitted HIV-1 clade C (HIV-C). Phage peptide inserts were analyzed for conformational and linear homology using computational analysis; some peptides mimicked various domains of the original HIV-C Env, such as conformational V3 loop epitopes and the conserved linear region of the gp120 C-terminus. Next, we devised a novel prime/boost strategy to test the immunogenicity of such phage-displayed peptides and primed mice only once with HIV-C gp160 DNA followed by boosting with mixtures of recombinant phages. Conclusions/Significance: This strategy, which was designed to focus the immune system on a few Env epitopes (immunofocusing), not only induced HIV-C gp160 binding antibodies and cross-clade nAbs, but also linked a conserved HIV Env region for the first time to the induction of nAbs: the C-terminus of gp120. The identification of conserved antigen mimics may lead to novel immunogens capable of inducing broadly reactive nAbs.
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    SHIV-1157i and Passaged Progeny Viruses Encoding R5 HIV-1 Clade C Env Cause AIDS in Rhesus Monkeys
    (BioMed Central, 2008) Song, Ruijiang; Ong, Helena; Sharma, Prachi; Chenine, Agnès L; Kramer, Victor G; Xu, Weidong; Else, James G; Novembre, Francis J; Strobert, Elizabeth; O'Neil, Shawn P; Humbert, Michael; Rasmussen, Robert; Siddappa, Nagadenahalli B.; Ruprecht, Ruth Margrit
    Background: Infection of nonhuman primates with simian immunodeficiency virus (SIV) or chimeric simian-human immunodeficiency virus (SHIV) strains is widely used to study lentiviral pathogenesis, antiviral immunity and the efficacy of AIDS vaccine candidates. SHIV challenges allow assessment of anti-HIV-1 envelope responses in primates. As such, SHIVs should mimic natural HIV-1 infection in humans and, to address the pandemic, encode HIV-1 Env components representing major viral subtypes worldwide. Results: We have developed a panel of clade C R5-tropic SHIVs based upon env of a Zambian pediatric isolate of HIV-1 clade C, the world's most prevalent HIV-1 subtype. The parental infectious proviral clone, SHIV-1157i, was rapidly passaged through five rhesus monkeys. After AIDS developed in the first animal at week 123 post-inoculation, infected blood was infused into a sixth monkey. Virus reisolated at this late stage was still exclusively R5 tropic and mucosally transmissible. Here we describe the long-term follow-up of this initial cohort of six monkeys. Two have remained non-progressors, whereas the other four gradually progressed to AIDS within 123–270 weeks post-exposure. Two progressors succumbed to opportunistic infections, including a case of SV40 encephalitis. Conclusion: These data document the disease progression induced by the first mucosally transmissible, pathogenic R5 non-clade B SHIV and suggest that SHIV-1157i-derived viruses, including the late-stage, highly replication-competent SHIV-1157ipd3N4 previously described (Song et al., 2006), display biological characteristics that mirror those of HIV-1 clade C and support their expanded use for AIDS vaccine studies in nonhuman primates.