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.
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