title: A rapid progressor-specific variant clone of simian immunodeficiency virus replicates efficiently in vivo only in the absence of immune responses.
abstract: A subset of simian immunodeficiency virus (SIV)-infected macaques progresses rapidly to disease with transient SIV-specific immune responses and high viral loads. Unique SIV variants with convergent Env mutations evolve in these rapid progressor (RP) macaques. To address the pathogenic significance of RP-specific variants, we generated infectious molecular clones from the terminal-phase plasma of an RP macaque. Inoculation of macaques with a representative clone, SIVsmH635FC, resulted in a persistent viremia, comparable to that produced by pathogenic SIVsmE543-3, and a chronic disease with progressive loss of CD4(+) T cells. However, SIVsmH635FC did not reproduce the rapid-disease phenomenon. Molecular analyses of viruses from these macaques revealed rapid reversion to the wild-type SIVsmE543-3 sequence at two RP-specific sites and slower reversion at another three sites. SIVsmH635FC infection was not sufficient to cause rapid progression even following coinoculation with SIVsmE543-3, despite acute depletion of memory CD4(+) T cells. SIVsmH635FC competed efficiently during primary infection in the coinoculated macaques, but SIVsmE543-3 predominated after the development of SIV-specific immune responses. These data suggest that the replication fitness of the RP variant was similar to that of SIVsmE543-3 in a naïve host; however, SIVsmH635FC was at a disadvantage following the development of SIV-specific immune responses. Consistent with these findings, neutralization assays revealed that SIVsmH635FC was highly sensitive to neutralization but that the parental SIVsmE543-3 strain was highly resistant. This study suggests that the evolution of RP-specific variants is the result of replication in a severely immunocompromised host, rather than the direct cause of rapid progression.
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kuwata
authors.forename: Russell
authors.initials: R
authors.lastname: Byrum
authors.forename: Sonya
authors.initials: S
authors.lastname: Whitted
authors.forename: Robert
authors.initials: R
authors.lastname: Goeken
authors.forename: Alicia
authors.initials: A
authors.lastname: Buckler-White
authors.forename: Ronald
authors.initials: R
authors.lastname: Plishka
authors.forename: Ranjini
authors.initials: R
authors.lastname: Iyengar
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hirsch
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D018791:CD4 Lymphocyte Count; D004195:Disease Models, Animal; D018450:Disease Progression; D019143:Evolution, Molecular; D015686:Gene Products, env / Q000737:chemistry / Q000235:genetics; D016867:Immunocompromised Host; D008251:Macaca; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009500:Neutralization Tests; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D019562:Viral Load; D014766:Viremia; D014779:Virus Replication / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D015686:Gene Products, env; C087575:SIV envelope glycoprotein gp160