This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The pigtail macaque (PTM) is well recognized as being highly susceptible to SIV-induced disease, with SIVmac239 reproducibly and rapidly causing AIDS. We have shown that when SIVmac239 contains a mutation that ablates a GYxx? trafficking signal in the Env TM cytoplasmic tail, the resulting virus (?GY) replicates to a high acute RNA peak (1.8-9.3x10^6 copies/ml) comparable to SIVmac239 in PTMs (p=0.90) and to ?GY in rhesus macaques (RhM) (p=0.93). In RhMs (n=4) ?GY acute infection is followed by a 2-3 log reduction in viral set point (VSP) with minimal acute loss of CD4 cells in the lamina propria, but with a gradual decline in CD4 cells over 1 year. However, in PTMs (n=4) with the onset of host immune responses ?GY is suppressed to extremely low to undetectable levels (15, 15, 15, and 210 copies/ml by 19 weeks post infection), much lower than SIVmac239 (p=0.003) and ?GY (p=0.007) in RhM. Strikingly, the sustained, severe depletion of lamina propria CD4 T-cells that occurs with SIVmac239 infection did not occur with ?GY in PTM;from preinfection levels (median 43.9 %;range 25.4 ?54.3%) only a modest reduction occurred during acute infection (median 18.4 %;range 8.4 ?20.7%) with evidence of recovery by 22 weeks (median 27 %;range 18.3 - 46%). Moreover, monocyte turnover, determined by BrdU labeling, which we have shown increases with pathogenic SIV infection, was only minimally and transiently increased in ?GY-infected PTMs compared to SIVmac239-infected RhMs (p=0.03), possibly reflecting a lower level of microbial translocation and/or macrophage infection. ?GY control is clearly not the result of poor replicative ability, given its high acute viral peak in both PTM and RhM. How the ?GY mutation alters the pathogenic potential of SIVmac239 and why PTMs, a more susceptible species for pathogenic SIVmac infection, exhibit better control of ?GY than RhM will be of great interest in determining viral and host interactions that are relevant to virologic control and disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000164-50
Application #
8358143
Study Section
Special Emphasis Panel (ZRR1-CM-8 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
50
Fiscal Year
2011
Total Cost
$57,750
Indirect Cost
Name
Tulane University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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