"Restriction factors" is probably the hottest area of research investigation in the HIV/SIV/AIDS arena at the present time. It turns out that all mammals, monkeys and humans included, have evolved individual genes whose sole function in life appears to be to block infection by viruses of the retrovirus family of viruses. The protein products of these genes are called restriction factors. Quite clearly, retroviruses have played a major role in limiting the expansion and even survival of individual species. Three restriction factors have been defined so far that can inhibit, or even totally block, infection by HIV or SIV: APOBEC3, Tetherin, and TRIM5. It is generally believed that it is these restriction factors that limit the ability of SIV to jump species, why species such as baboons remain naturally uninfected by SIV despite routinely eating other monkey species that do carry their own SIV, and why humans have remained uninfected with HIV/SIV until recently in evolutionary history. When such viruses do take hold in a species, the virus in general has evolved a resistance to the effects of these three restriction factors.

AIDS vaccine studies performed in monkeys have a variety of different SIV strains from which to choose. This is a good thing; the field wants to make sure not to be misled by use of only one or two strains that for whatever reason may be unusual, or not representative, in their properties. Many vaccine studies use SIVmac239 and SIVmac251, challenge stocks developed here at NEPRC. Others use strains SIVsmE543 and SIVsmE660, originally obtained from sooty mangabey monkeys with little or no passage in rhesus macaques.

The Welkin Johnson laboratory has previously documented a collection of genetic polymorphisms present at the TRIM5 locus in rhesus monkeys. In the recent publication by Kirmaier et al, Andrea Kirmaier, Welkin Johnson, Ruchi Newman, Jen Morgan, Mareike Meythaler, and Amitinder Kaur from NEPRC teamed up with Vanessa Hirsch and her colleagues at NIH and with others to examine the influence of Trim5 genotype on take of SIVsmE543 and SIVsmE660 in rhesus monkeys. What they found was remarkable. Rhesus monkeys that were Q/Q homozygous at the TRIM5 locus had viral load set points that were more than 100-fold higher than those in monkeys that were TFP/TFP homozygous at the TRIM5 locus. Such differences are not seen with the macaque viruses SIVmac239 and SIVmac251 because these strains are already extensively adapted for rhesus monkeys and have already "learned" to circumvent restriction by rhesus Trim5.

These findings are incredibly important for vaccine studies as the field moves forward. If one is designing a vaccine study in rhesus monkeys that uses SIVsmE543 or SIVsmE660 for challenge, it is important that the distribution of TRIM5 genotypes be taken into consideration such that the results are not biased by unequal distribution of genotypes. Keith Mansfield and I have our own first-hand experience on the impact of these findings. We were trying to estimate the infectious titer of an SIVsmE543 stock to be used in a vaccine study but we were getting wildly varying results one rhesus monkey to another that we could not explain. Then, when the Kirmaier et al findings became known, we checked. Sure enough, our results were entirely explained by the TRIM5 genotypes of the monkeys that we were using. Monkeys that had the Q genotype were yielding high titers and monkeys that had the TFP genotype were yielding much lower titers. We are now in a position to design the study accordingly.

Discovery research helping the field to move forward.

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