Dr. Chung Presents Her Work on Viral Latency at 30th Annual Symposium on NHP Models for AIDS
The 30th Annual Symposium for NHP Models for AIDS was held in San Antonio, TX from October 24 to October 27, 2012.
SHIV-Infected Macaques as a Model of Viral Latency and Activation
H.K. Chung, P. Firpo, R. Pal, S-L. Hu, and S.H. Pincus
NHP models of retroviral latency and reactivation will be of great utility for defining protocols to eradicate HIV and understanding in vivo mechanisms of virus activation. Here we demonstrate that macaques infected with Env-SHIV represent such a model. We have studied 40 pigtail and rhesus macaques with undetectable plasma virus loads for at least 6 months, some as long as 3 years. We measured plasma viremia, proviral DNA, and cellular viral mRNA. Methods to activate latent virus included CD8 depletion, interleukins, and drugs found to activate HIV in vitro.
We found 10-1000 provirus/106 PBMC, which remained stable in each animal, but varied among animals. Levels in most lymphoid organs were similar, but in many animals there were single compartments with 10-100X higher levels, and this site varied among animal to animal. Provirus levels in the gut were consistent with other lymphoid organs, regardless of route of infection. Provirus was also found in brain, epididymis, and other non-lymphoid organs, but generally at lower levels. Provirus was found primarily in memory CD4+ T-cells. The tissue distribution of provirus was remarkably similar to that reported for latency induced by ART in macaques.
CD8 depletion resulted in high titered plasma viremia, up to 108 copies/ml, beginning at 4-5 days and resolving 3-4 weeks later, often before reappearance of CD8+ cells. Multiple cytokines were elevated, some within days, most 1-2 weeks later. We detected 11-1790 transcripts per provirus during the activation phase. ART treatment prevented the development of plasma viremia.
These studies demonstrate that aviremic SHIV-infected macaques have a functional reservoir of latently infected cells. The mechanism whereby SHIV is driven into latency is not understood, but is surely different than ART-induced latency in humans. Nevertheless, the anatomic localization of provirus and kinetics of activation are very similar to that observed in other macaque models.
