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Type of publication: Master Thesis
Type of document:

Year: 2010

Authors: Landskron, Lisa

Title: Understanding the relationship between viral monkey infectious doses and intra-host viral diversity.

Source: Master Thesis, Vet. Med. Univ. Wien, pp. 125.


Varela Mariana
Klein Dieter

Saalm├╝ller Armin

Vetmed Research Units:
Institute of Virology

Graduation date: 31.08.10

HIV-1 pre-clinical vaccine studies are usually performed by immunizing macaques with candidate antigens and later challenging them with a defined virus stock of interest. To ensure infection of all animals at a single round of challenge, high doses ranging from 10 to 25 times the infectious dose at which 50% of the animals get infected, are used. Since approximately 80% of HIV-1 infected individuals have evidence of infection by one single virus variant (KEELE et al., 2008), concerns have been raised if these high-dose studies can mimic HIV-1 infections in humans adequately. Moreover, low-dose infections with simian immunodeficiency virus (SIV) restricted the number of transmitted virus variants similar to observations for HIV-1 in humans, whereas high doses led to multi-variant infections (LIU et al., 2010). Here we investigated this relationship in a better and more robust pre-clinical vaccine model that uses chimeric SIV virions bearing the HIV-1 envelope (SHIV) as a challenge stock, since no data is available for this model up to date. To this end, samples from week 2 and 12 post-challenge from a SHIV clade B titration study in rhesus macaques were investigated by amplifying proviral fulllength envelope genes by single genome amplification and direct sequencing. Eight animals divided into 4 groups of 2 monkeys were challenged with descending inoculum doses. Using phylogenetic reconstruction we could identify multiple founder variants for animals challenged with a high dose and single-variant infections for animals receiving a low dose. The data clearly showed that high challenge doses were associated with higher diversity in the envelope gene, a less profound bottleneck and a higher number of founder viruses in the SHIV/macaque model. No distinct variant of the challenge stock preferentially infected the animals, but mostly minor variants established infection. Moreover, we investigated the selective pressures acting upon the envelope gene and found negatively as well as positively selected sites in the envelope. We detected no drastic change in the glycan shield, although we showed that neutralizing antibodies against the founder population evolve rapidly in the SHIV model unlike for HIV and SIV infections. In summary, the here presented results will increase our understanding of the underlying evolutionary forces acting upon the envelope in the SHIV model used for pre-clinical evaluation of HIV-1 vaccines.

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