CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection.
The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4(+) T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4(+) T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8(+) memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.
Tulane National Primate Research Center, Covington, LA 70471; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112;
Taylor W
TW
Foreman
Tulane National Primate Research Center, Covington, LA 70471; Center for Biomedical Research Excellence, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803; Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA 70803;
Smriti
S
Mehra
Tulane National Primate Research Center, Covington, LA 70471;
Denae N
DN
LoBato
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
Adel
A
Malek
Tulane National Primate Research Center, Covington, LA 70471;
Xavier
X
Alvarez
Tulane National Primate Research Center, Covington, LA 70471;
Nadia A
NA
Golden
Tulane National Primate Research Center, Covington, LA 70471; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112;
Allison N
AN
Bucşan
Tulane National Primate Research Center, Covington, LA 70471;
Peter J
PJ
Didier
Tulane National Primate Research Center, Covington, LA 70471;
Lara A
LA
Doyle-Meyers
Tulane National Primate Research Center, Covington, LA 70471;
Kasi E
KE
Russell-Lodrigue
Tulane National Primate Research Center, Covington, LA 70471;
Chad J
CJ
Roy
Tulane National Primate Research Center, Covington, LA 70471;
James
J
Blanchard
Tulane National Primate Research Center, Covington, LA 70471;
Marcelo J
MJ
Kuroda
Tulane National Primate Research Center, Covington, LA 70471; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112;
Andrew A
AA
Lackner
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
John
J
Chan
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110;
Shabaana A
SA
Khader
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY 10461 jacobsw@hhmi.org dkaushal@tulane.edu.
William R
WR
Jacobs
Tulane National Primate Research Center, Covington, LA 70471; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112; jacobsw@hhmi.org dkaushal@tulane.edu.
Deepak
D
Kaushal
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000821:virology; D049109:Cell Proliferation / Q000235:genetics; D060085:Coinfection / Q000821:virology; D006678:HIV / Q000276:immunology / Q000472:pathogenicity; D015658:HIV Infections / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D055985:Latent Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology / Q000821:virology; D008213:Lymphocyte Activation / Q000276:immunology; D008253:Macaca mulatta / Q000276:immunology / Q000382:microbiology / Q000821:virology; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity*; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000472:pathogenicity*
B cells; CD4 T cells; CD8 T cells; Nonhuman primate; tuberculosis