The previous posting on Nancy Wilson’s SIV vaccine study
referenced that the dose of challenge virus was titrated to try and mirror
human mucosal exposure to HIV. The research that allowed this new approach to
be developed has been published online today in the Journal of Experimental
Medicine.
The background to this work is a suite of recent studies,
primarily from the research group of George Shaw, showing that most
heterosexual HIV infections appear to be established by a single founder virus.
Less frequently, infection can be traced back to 2-5 viruses, and the
preliminary evidence suggests that transmission of multiple variants may be
more common among men who have sex with men and intravenous drug users.
The purpose of the SIV study was to establish whether the
same technique – called single genome amplification (SGA) – could shed light on
the number of viral variants transmitted after a challenge with SIVmac251 or
SIVsmE660. Mucosal and intravenous routes were both studied, along with
different doses of challenge viruses.
Results showed that the number of transmitted variants
could be inferred by analyzing the genetics of multiple viral env sequences
taken after infection, and that the founder viruses establishing infection could
be traced back to the SIV challenge stocks. Lower challenge doses were less
efficient at establishing infection, and more likely to lead to infection with
fewer variants. However, the researchers note that this relationship between
dose and number of transmitted variants is not straightforward, as some animals
challenged with the highest doses also showed evidence of infection with a
single variant and most of the animals infected with multiple variants received
intermediate challenge doses. Intravenous challenge was shown exceed the
efficiency of rectal transmission by 2,000-20,000-fold. The paper concludes
that intrarectal SIV infection of rhesus macaques “recapitulates at a
biological and molecular level many of the features of human HIV-1 mucosal
transmission.”
ARTICLE
Brandon F. Keele1, Hui Li1, Gerald H. Learn1, Peter Hraber2,
Elena E. Giorgi2,3, Truman Grayson1, Chuanxi Sun1, Yalu Chen1, Wendy W. Yeh4,
Norman L. Letvin4,5, John R. Mascola5, Gary J. Nabel5, Barton F. Haynes6,
Tanmoy Bhattacharya2,7, Alan S. Perelson2, Bette T. Korber2,7, Beatrice H.
Hahn1, and George M. Shaw1
1 University of Alabama at Birmingham, Birmingham, AL 35223
2 Los Alamos National Laboratory, Los Alamos, NM 87545
3 University of Massachusetts, Amherst, MA 01002
4 Division of Viral Pathogenesis, Department of Medicine,
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115
5 Vaccine Research Center, National Institute of Allergy and
Infectious Disease, National Institutes of Heath, Bethesda, MD 20892
6 Duke University Medical Center, Durham, NC 27710
7 Santa Fe Institute, Santa Fe, NM 87501
We recently developed a novel strategy to identify
transmitted HIV-1 genomes in acutely infected humans using single-genome
amplification and a model of random virus evolution. Here, we used this
approach to determine the molecular features of simian immunodeficiency virus
(SIV) transmission in 18 experimentally infected Indian rhesus macaques.
Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with
stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of
early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48
per animal) were determined from plasma virion RNA 1–5 wk after infection. i.r.
inoculation was followed by productive infection by one or a few viruses
(median 1; range 1–5) that diversified randomly with near starlike phylogeny
and a Poisson distribution of mutations. Consensus viral sequences from ramp-up
and peak viremia were identical to viruses found in the inocula or differed
from them by only one or a few nucleotides, providing direct evidence that
early plasma viral sequences coalesce to transmitted/founder viruses. i.v.
infection was >2,000-fold more efficient than i.r. infection, and viruses
transmitted by either route represented the full genetic spectra of the inocula.
These findings identify key similarities in mucosal transmission and early
diversification between SIV and HIV-1, and thus validate the SIV–macaque
mucosal infection model for HIV-1 vaccine and microbicide research.
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