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

Nagadenahalli B. Siddappa, Jennifer D. Watkins, Klemens J. Wassermann, Ruijiang Song, Wendy Wang, Victor G. Kramer, Samir Lakhashe, Michael Santosuosso, Mark C. Poznansky, Francis J. Novembre, Francois Villinger, James G. Else, David C. Montefiori, Robert A. Rasmussen, Ruth M. Ruprecht

Research output: Contribution to journalArticle

38 Scopus citations

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.

Original languageEnglish (US)
Article numbere11689
JournalPloS one
Volume5
Issue number7
DOIs
StatePublished - Aug 17 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Siddappa, N. B., Watkins, J. D., Wassermann, K. J., Song, R., Wang, W., Kramer, V. G., Lakhashe, S., Santosuosso, M., Poznansky, M. C., Novembre, F. J., Villinger, F., Else, J. G., Montefiori, D. C., Rasmussen, R. A., & Ruprecht, R. M. (2010). 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. PloS one, 5(7), [e11689]. https://doi.org/10.1371/journal.pone.0011689