A new paper in PLoS One by Collin Diedrich and colleagues reports progress in developing an animal model of HIV/TB coinfection. Cynomolgus macaques with latent TB were infected with the pathogenic SIVmac251 and studied to assess the factors associated with reactivation of TB. The authors report that there was a significant correlation between the depletion of peripheral blood CD4 T cells (measured 2–8 weeks after SIV infection) and time to TB reactivation (p=0.011, R2 = 0.755). An association with CD4 T cell depletion from the airways was also observed. The data are consistent with a paper from 2008 by Christof Geldmacher that reported an early loss of TB-specific CD4 T cell responses after acute HIV infection. Taken together, these studies offer insight into why TB is frequently the earliest opportunistic disease in people co-infected with both pathogens. Dierdrich et al plan to use their model to explore the pathogenesis of HIV/TB coinfection in greater detail.
PLoS ONE 5(3): e9611. doi:10.1371/journal.pone.0009611
Collin R. Diedrich1#, Joshua T. Mattila1#, Edwin Klein2, Chris Janssen2, Jiayao Phuah1, Timothy J. Sturgeon3, Ronald C. Montelaro3, Philana Ling Lin4, JoAnne L. Flynn1*
1 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America, 2 Division of Laboratory Animal Resources, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America, 3 Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America, 4 Department of Pediatrics, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
HIV-infected individuals with latent Mycobacterium tuberculosis (Mtb) infection are at significantly greater risk of reactivation tuberculosis (TB) than HIV-negative individuals with latent TB, even while CD4 T cell numbers are well preserved. Factors underlying high rates of reactivation are poorly understood and investigative tools are limited. We used cynomolgus macaques with latent TB co-infected with SIVmac251 to develop the first animal model of reactivated TB in HIV-infected humans to better explore these factors. All latent animals developed reactivated TB following SIV infection, with a variable time to reactivation (up to 11 months post-SIV). Reactivation was independent of virus load but correlated with depletion of peripheral T cells during acute SIV infection. Animals experiencing reactivation early after SIV infection (<17 weeks) had fewer CD4 T cells in the periphery and airways than animals reactivating in later phases of SIV infection. Co-infected animals had fewer T cells in involved lungs than SIV-negative animals with active TB despite similar T cell numbers in draining lymph nodes. Granulomas from these animals demonstrated histopathologic characteristics consistent with a chronically active disease process. These results suggest initial T cell depletion may strongly influence outcomes of HIV-Mtb co-infection.