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- Title
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.
- Authors
Siddappa, Nagadenahalli B.; Watkins, Jennifer D.; Wassermann, Klemens J.; Ruijiang Song; Wendy Wang; Kramer, Victor G.; Lakhashe, Samir; Santosuosso, Michael; Poznansky, Mark C.; Novembre, Francis J.; Villinger, François; Else, James G.; Montefiori, David C.; Rasmussen, Robert A.; Ruprecht, Ruth M.
- Abstract
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.
- Subjects
ZAMBIA; IMMUNOGLOBULINS; AIDS vaccines; IMMUNOGENETICS; PHENOTYPES; T cells; PRIMATES as laboratory animals; RHESUS monkeys; RNA; DISEASES
- Publication
PLoS ONE, 2010, Vol 5, Issue 7, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0011689