Although infection with Mycobacterium tuberculosis (MTb) is the largest cause of pulmonary disease and death in HIV patients globally, little is known about how TB co-infection impacts long-term antiretroviral (ART)- mediated immune reconstitution. The Cambodian Early vs. Late Introduction of Antiretrovirals (CAMELIA) randomized clinical trial showed that early initiation of ART at 2 weeks after TB therapy initiation versus late initiation of ART at 8 weeks in severely immunocompromised TB+/HIV+ patients (median CD4=24/mm3), resulted in a significant (34%) decrease in mortality?a survival benefit that persisted for at least 3 years after the timing intervention. In a scientific sub-study nested within the CAMELIA trial, we have discovered that active TB disease in these highly immunosuppressed TB+/HIV+ patients led to significantly greater pre-ART levels of several pro-inflammatory cytokines and greater pre-ART frequencies of activated CD4+ and CD8+ T cells, and significantly lower pre-ART frequencies of CD28+CD8+ and ICOS+CD4+ T cells, as compared to TB-/HIV+ patients. Moreover, these differences in T cell subset frequencies persisted for at least 8 months after treatment initiation and 2 months after TB cure. Furthermore, we have demonstrated that TB-associated immune reconstitution syndrome (TB-IRIS), which occurred 2.6-fold more frequently in the early CAMELIA treatment arm, results in profound changes in the T cell compartment. For example, TB-IRIS patients exhibited a significant post-ART expansion of (CD62L-CD45RA-) effector memory CD4+T cells and a decrease in (CD62L+CD45RA-) central memory CD4+T cells as compared to non-TB-IRIS patients. We have also found that a Th1-like CD4+ T cell subset that is CXCR3+CCR6+ and thought to mediate a large portion of anti-TB responses was present at significantly elevated frequencies pre-ART in TB-IRIS patients, and the frequency of these cells remained elevated for at least 8 months after treatment onset. Based on our preliminary data, we hypothesize that TB co-infection exacerbates HIV-induced premature aging of the immune system, leading to long-term consequences and poor recall responses.
In Aim 1 we will investigate immunosenescent and methylomic signatures in pre-treatment archived samples from TB+/HIV+ CAMELIA and TB-/HIV+ and TB+ /HIV- patients, and in freshly isolated samples from the same patients >5 years after TB treatment and ART initiation. We further hypothesize that within the TB+/HIV+ group the subset of patients who experienced TB- IRIS possessed superior anti-MTb immunity, which was amplified once ART was initiated.
In Aim 2 we will compare CXCR3+CCR6+CD4+ T cells in TB-IRIS versus non-TB-IRIS patients to determine their anti-MTb function. Findings from these experiments will provide critical insights into how TB co-infection in HIV+ patients affects phenotypic and epigenetic features of the immune system prior to and following ART-mediated immune reconstitution, and they will elucidate the long-term consequences of TB-IRIS on functional MTb-specific T cell responses that were associated with successful ART-mediated immune reconstitution and TB cure.

Public Health Relevance

Analysis of HIV+ patients who survived tuberculosis (TB) when they were extremely immunosuppressed, especially those who had the TB-associated vigorous immune reconstitution syndrome (TB-IRIS) during co- therapy, should lead to insights about necessary T cell responses to control TB and new therapeutic approaches. Such information is crucial since, TB continues to be the largest cause of death in AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI127169-01
Application #
9205082
Study Section
Special Emphasis Panel (ZRG1-AARR-M (57)R)
Program Officer
Boggiano, Cesar Augusto
Project Start
2016-06-24
Project End
2018-05-31
Budget Start
2016-06-24
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$269,748
Indirect Cost
$117,348
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115