SHIV-1157i and passaged progeny viruses encoding R5 HIV-1 clade C env cause AIDS in rhesus monkeys

Michael Humbert,Prachi Sharma,Helena Ong,Elizabeth Strobert,Robert A Rasmussen,Nagadenahalli B Siddappa,Ruth M Ruprecht,Francis J Novembre,Agnès L Chenine,Victor G Kramer,James G Else,Weidong Xu,Ruijiang Song,Shawn P O'Neil

doi:10.1186/1742-4690-5-94

Abstract

BackgroundInfection 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.ResultsWe 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.ConclusionThese 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.

Highlights

Infection of nonhuman primates with simian immunodeficiency virus (SIV) or chimeric simianhuman immunodeficiency virus (SHIV) strains is widely used to study lentiviral pathogenesis, antiviral immunity and the efficacy of AIDS vaccine candidates
The first recipient was inoculated i.v. with 6 ml cell-free supernatant from 293T cells transfected with the infectious molecular clone, SHIV-1157i
Plasma viral loads in monkeys infected with SHIV-1157i or passaged virus The details of the molecular cloning and biological characterization of SHIV-1157i have been previously published [8]

Summary

Introduction

Infection of nonhuman primates with simian immunodeficiency virus (SIV) or chimeric simianhuman immunodeficiency virus (SHIV) strains is widely used to study lentiviral pathogenesis, antiviral immunity and the efficacy of AIDS vaccine candidates. In the case of HIV, macaque models are used to mimic HIV transmission and disease progression in humans, using either simian immunodeficiency virus (SIV) or chimeric simian-human immunodeficiency virus (SHIV) strains that can be tracked prospectively by markers such as plasma viremia levels and loss of peripheral blood CD4+ T cells. We show that infection of macaques with either SHIV-1157i or with passaged virus leads to depletion of both memory and total CD4+ T cells, resulting in AIDS and multiple opportunistic infections in some monkeys. These hallmarks of primate immunodeficiency virus virulence arose gradually, reflecting the disease progression rate seen in HIV-infected humans

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