1. Chronic immune activation in HIV associated Non Hodgkin lymphoma and the effect of antiretroviral therapy
Brian Flepisi
University of the Western Cape
Department of Medical Biosciences
New Life Science Building

2. Non-Hodgkin Lymphoma (NHL)
Heterogeneous group of malignancies of lymphoid origin arising from
B lymphocytes (85-90%)
T lymphocytes or natural killer (NK) lymphocytes (10%)
Exact cause is not yet known
Previously associated with the presence of EBV
Develops from the lymph nodes, but can occur in almost any tissue
Comprises many types, each with distinct epidemiology, aetiology and features

3. HIV+NHL Also develops in immunodeficiency states such as:
Congenital immunodeficiency disorder
State of pharmacologic immunosuppression
Immunodeficient state associated with HIV disease
Associated with HIV-1 infections since the beginning of the HIV epidemic
Most common subtype is diffuse large B-cell lymphoma (DLBCL)
Accounts for 30-40% of all adult NHL
Characterized by diffuse nodal architectural effacement or
Extranodal infiltration by sheets of large B-cell phenotype

4. Chronic immune activation
Prolonged HIV infection causes immune dysfunction including chronic immune suppression and B cell hyperactivation
Systemic chronic immune activation has been shown to be the primary driving force in HIV pathogenesis
Altered immune mechanisms play a critical role in the pathogenesis of NHL
Previous studies indicate that those patients with the most marked B cell activation are at increased risk of developing NHL

5. AIMS Primary aim: Secondary aims:
To determine whether selected biomarkers of B-, T-cell activation are associated with the presence of NHL in HIV-1 infected patients
Secondary aims:
To determine whether biomarkers of B- and T-cell activation are elevated in HIV+NHL patients
To determine whether cART use has an effect on these biomarker profiles

6. OBJECTIVES Primary objective: Secondary objectives:
To determine the serum concentrations of biomarkers of B-cell activation, and the levels of expression of biomarkers of T-cell activation and regulation in HIV positive NHL patients
Secondary objectives:
To determine the levels of expression of selected biomarkers of T-cell activation and regulation
To determine the serum concentrations of circulating biomarkers of B-cell activation

8. Participant Characteristics

9. T-cell activation and regulation
Chronic immune activation may lead to development of HIV+ NHL
Increased expression of CD8+CD38 was previously associated with immune activation, progression of HIV disease, and death
T-reg suppresses T-cell activation, proliferation and cytokine production
Dysregulated T-reg (FoxP3) cell expression has been associated with a number of pathological conditions including cancer
T-cell activation and regulation in HIV+NHL patients were investigated
Sherman et al., 2002; Epeldegui et al., 2010; Card et al., 2009; Presicce et al., 2011

10. Specific Aims To determine Conducted by Flow cytometry
Expression of CD38 on CD8+ T-cells in HIV+NHL patients
Expression of FoxP3 in HIV+NHL patients
Whether cART increases FoxP3 expression and down-regulates T-cell activation
Conducted by Flow cytometry

11. Results
CD8+CD38
FoxP3

12. Discussion T-cell activation is increased in NHL
Influence of HIV-1 infection on T-cell activation in HIV+NHL was not clearly defined
Chronic T-cell activation in HIV-1 infected patients may have been caused by a decreased regulatory T-cell expression
cART decreases T-cell activation while increasing its regulation
Recommend that early cART initiation could be beneficial

13. B-cell activation
HIV-1 infection causes chronic immune suppression and B-cell hyper-activation
B-cell activation has been suggested to play a role in the development of HIV+NHL
Patients with B-cell hyper-activation are at risk of developing NHL
B-cell activation is characterized by
Lymphocyte proliferation
Class switch recombination
Somatic hypermutation
Serum concentrations of circulating sCD20, sCD23, sCD27, sCD30 and sCD44 were studied
De Roos et al., 2012; Hussain et al., 2013

14. Specific Aims To determine Determined by ELISA
Serum concentrations of circulating B-cell activation markers (sCD20, sCD23, sCD27, sCD30, sCD44) in HIV+NHL patients
Whether cART has an impact on their serum concentrations
Determined by ELISA

15. Results

16. CORRELATIONS

17. Discussion B-cell activation is increased in HIV+NHL
Associated with increased T-cell activation
sCD20, sCD23 and sCD44 were independently associated with HIV+NHL
B-cell activation is increased in naive HIV+ and in NHL patients
Increased immune activation may have been caused by persistent HIV-1 infection, as well as suppressed immune regulation
cART may decrease B-cell activation
Evidenced by increased serum concentrations of circulating B-cell activation markers

18. OVERALL CONCLUSION
B-cell activation is increased in HIV+NHL as evidenced by increased B-cell activation markers
Associated with suppressed T-cell regulation and increased T-cell activation
Increased T-cell activation may have been caused by
HIV-1 infection
Reduced immune regulation
Presence of EBV
Anti-tumor immune response against malignant lymphoma cells
cART may decrease immune activation
These markers should be monitored in HIV+ patients

19. THANK YOU