Abstract
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.
Highlights
90% of human Mycobacterium tuberculosis (Mtb) infections are clinically latent and likely represent an immune response that successfully limits bacterial growth, resulting in persistence within multi-cellular structures called granulomas [1]
Peak virus loads in peripheral blood mononuclear cells (PBMC) and plasma occurred at 2–3 weeks post simian immunodeficiency virus (SIV) infection and declined to low levels for the duration of the study
While most opportunistic infections commonly occur when CD4 T cell numbers have significantly declined, TB occurs throughout the entire spectrum of human immunodeficiency virus (HIV) disease, including when CD4 T cells numbers are well preserved and stable [4,5,6]
Summary
90% of human Mycobacterium tuberculosis (Mtb) infections are clinically latent and likely represent an immune response that successfully limits bacterial growth, resulting in persistence within multi-cellular structures called granulomas [1]. While granulomas are composed of many different cell types, macrophages and T cells are important components that collaborate to limit bacterial replication and prevent dissemination. The immune response of immunocompetent individuals can prevent active tuberculosis for years or decades, and latently infected individuals have only a 5–10% lifetime risk of developing reactivated tuberculosis (TB) [2]. Immunosuppressed individuals have a significantly greater chance of developing active disease, and TB is the leading killer of individuals infected with human immunodeficiency virus (HIV) [3]. While factors explaining the high rates of reactivated TB in coinfected humans remain unclear, depletion of CD4 T cells [7] and increased virus loads [8] within granulomatous tissue may be contributors
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