Abstract
BackgroundHIV-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 FindingsWe 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/SignificanceSHIV-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.
Highlights
Recent developments in AIDS vaccine research focused attention on the need for developing vaccine strategies that can generate both cellular and humoral immunity [2]
We suggest that development of vaccines designed to induce anti-HIV Neutralizing antibody (nAb) should proceed in a stepwise approach: preclinical vaccine efficacy studies in primates should first attempt to induce protection against simian-human immunodeficiency viruses (SHIVs) encoding primary HIV envelopes that are relatively easy to neutralize
We describe the development and characterization of the R5 SHIV-1157ipEL-p that encodes an early env from an African pediatric HIV-1 clade C (HIV-C) isolate
Summary
Recent developments in AIDS vaccine research focused attention on the need for developing vaccine strategies that can generate both cellular and humoral immunity [2]. Tcell as well as nAb-based responses are believed to be necessary for eliciting an effective response against HIV-1 (reviewed in [3]). The availability of a primate model that reflects the salient biologic features of HIV-1 transmission among humans will enhance our understanding of lentiviral pathogenesis and facilitate the development of an effective vaccine. 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. Both tier 1 and 2 viruses are needed for vaccine discovery in nonhuman primate models
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