title: Generation of lineage-related, mucosally transmissible subtype C R5 simian-human immunodeficiency viruses capable of AIDS development, induction of neurological disease, and coreceptor switching in rhesus macaques.
abstract: Most human immunodeficiency virus (HIV) transmissions are initiated with CCR5 (R5)-using viruses across mucosal surfaces, with the majority in regions where HIV type 1 (HIV-1) clade C predominates. Mucosally transmissible, highly replication competent, pathogenic R5 simian-human immunodeficiency viruses (SHIVs) encoding biologically relevant clade C envelopes are therefore needed as challenge viruses in vaccine efficacy studies with nonhuman primates. Here we describe the generation of three lineage-related subtype C SHIVs through four successive rapid transfers in rhesus macaques of SHIVC109F.PB4, a molecular clone expressing the soluble-CD4 (sCD4)-sensitive CCR5-tropic clade C envelope of a recently infected subject in Zambia. The viruses differed in their monkey passage histories and neutralization sensitivities but remained R5 tropic. SHIVC109P3 and SHIVC109P3N were recovered from a passage-3 rapid-progressor animal during chronic infection (24 weeks postinfection [wpi]) and at end-stage disease (34 wpi), respectively, and are classified as tier 1B strains, whereas SHIVC109P4 was recovered from a passage-4 normal-progressor macaque at 22 wpi and is a tier 2 virus, more difficult to neutralize. All three viruses were transmitted efficiently via intrarectal inoculation, reaching peak viral loads of 10(7) to 10(9) RNA copies/ml plasma and establishing viremia at various set points. Notably, one of seven (GC98) and two of six (CL31, FI08) SHIVC109P3- and SHIVC109P3N-infected macaques, respectively, progressed to AIDS, with neuropathologies observed in GC98 and FI08, as well as coreceptor switching in the latter. These findings support the use of these new SHIVC109F.PB4-derived viruses to study the immunopathology of HIV-1 clade C infection and to evaluate envelope-based AIDS vaccines in nonhuman primates.
authors.affiliation: Aaron Diamond AIDS Research Center, New York, New York, USA.
authors.forename: Wuze
authors.initials: W
authors.lastname: Ren
authors.forename: Alexandra
authors.initials: A
authors.lastname: Mumbauer
authors.forename: Agegnehu
authors.initials: A
authors.lastname: Gettie
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Kasi
authors.initials: K
authors.lastname: Russell-Lodrigue
authors.forename: James
authors.initials: J
authors.lastname: Blanchard
authors.forename: Susan
authors.initials: S
authors.lastname: Westmoreland
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cheng-Mayer
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism / Q000473:pathology / Q000635:transmission / Q000821:virology*; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D016097:Simian Acquired Immunodeficiency Syndrome; D015302:Simian Immunodeficiency Virus / Q000145:classification / Q000235:genetics / Q000502:physiology*
chemical_list: D019713:Receptors, CCR5; D015728:Receptors, HIV