ACKNOWLEDGEMENTS

We thank the patients who participated in this study and the clinical study stafffor their assistance. This study was supported by NIH P01 AI074415 (M.A.), theBill & Melinda Gates Foundation, and Doris Duke Grant 208682. S.A.V issupported by NIH T32 AI07387-23 and P30 AI060354-10. This study was alsosupported by the Philip T. and Susan Ragon Foundation.

1Ragon Institute of MGH, MIT, and Harvard, Cambridge, USA, 2Division of Infectious Diseases, Massachusetts General Hospital, Boston, USA, 3Department of Biostatistics, Harvard School of Public Health, Boston USA, 4Department of Viral Immunology, Heinrich-Pette-Institut, Hamburg, Germany

a

Days to CD4<500

IL-6

CRPR=0.02

nsD-dimer

IL-1bR=-0.06

ns

IFNg

TNFa

CRP

IL-1b

VL CD4p=0.0001*

Days to ART

IL-6

D-dimer

IFNg

TNFa

CRP

IL-1b

VL CD4

% R

each

ing

End

po

int

b

% R

each

ing

End

po

int

Low GroupHigh GroupFigure 2

p=0.001*

p=0.95 p=0.73

p=0.17 p=0.91

p=0.006* p=0.71

p<0.0001* p<0.0001*

p=0.16 p=0.003*

p=0.21 p=0.37

p=0.049* p=0.44

TNFα in Viral Control and Early Disease Progression in Patients with HIV-1 Infection

Sagar A. Vaidya1,2, Christian Körner1, Michael N. Sirignano1, Molly Amero1, Sue Bazner2, Jenna Rychert2, Todd M. Allen1, Eric S. Rosenberg2, Ronald J. Bosch3, and Marcus Altfeld1,4

ABSTRACTInflammation in early HIV-1 disease progression isnot well-characterized. Patients with untreatedprimary HIV-1 infection (N=90) were studied todetermine associations of inflammatory proteinswith early disease progression. High plasma TNFαlevels (≥8.5 pg/mL) were significantly associatedwith increased viral load set point (VLSP), andshorter time to CD4+ T-cell count <500 cells/mm3

and initiation of antiretroviral therapy (ART).Increased risk of reaching CD4+ T-cell count <500cells/mm3 in the high TNFα group was driven byviral load but independent of concurrent CD4+ T-cell count. Thus, TNFα appears to be an importantmediator of inflammation in patients with poorviral control and early HIV-1 disease progression.

Author Contact Information:

Sagar A. Vaidya MD PhD

Email: svaidya@mgh.harvard.edu

BACKGROUND• Inflammation is a hallmark of HIV-1 disease in acute andchronic infection

• Inflammatory proteins (such as IL-6, D-dimer, and others) areassociated with increased cardiovascular risk and all-causemortality in chronic HIV-1 infection

• Role of inflammation in early HIV-1 disease progression ispoorly understood

METHODS

• Analysis of a cohort of 90 subjects with untreated early HIV-1infection

• VLSP determined for all study subjects during the first yearpost-infection

• Plasma was tested for TNFa, IL-6, CRP, D-dimer, IL-1b, and IFNg

levels

• Primary endpoints: VLSP and days to CD4+ T cell count <500cells/mm3

• Secondary endpoints: days to CD4+ T cell count <350cells/mm3, ART start

CONCLUSIONS

• High levels of TNFa in early HIV-1 infection were associated with poorer viral control, as well as decreased time to reach CD4+ T cell count <500 cells/mm3 and initiation of ART

• Association of TNFa and early HIV-1 disease progression was driven by HIV-1 viral load but was independent of concurrent CD4+ T cell count by Cox multivariate analysis

• Further study required to understand impact of high TNFa levels on long-term inflammation and immune dysregulation by HIV-1.

TABLE 1. Patient Characteristics of Acute and Early HIV-1

Cohort. Study subjects who did not receive ART in first 2 monthsafter enrollment and had least 6 months of follow up, CD4/VLtesting, and sufficient HIV-1 viral load data available to calculateVLSP were tested for plasma levels of inflammatory proteins todetermine associations with clinical measures of early HIV-1disease progression.

a bcTNFa

R=0.48p<0.0001* IL-6

R=0.22p=0.08

CRPR=0.02p=0.74 D-dimer

R=0.18p=0.10

IL-1b R=-0.06p=0.43

IFNg R=0.18p=0.12

TNFaR=-0.26p=0.08 IL-6

R=0.00p=0.84

CRPR=0.13p=0.26 D-dimer

R=0.10p=0.39

IL-1b R=0.04p=0.81

IFNg R=-0.06p=0.33

dCD4 R=-0.42

p<0.0001*

VLR=0.97

p<0.0001*

VLSPVLSP CD4

Figure 1

eVLSP

c

> 500< 500

TNFa

CD4 =

p=0.046*

FIGURE 1. Association of Inflammatory Proteins with Viral Load

Set Point (VLSP) and CD4+ T-cell count in Early HIV-1 Infection.Inflammatory proteins were tested in study subjects and compared to(a) VLSP and (b) CD4+ T-cell count at the time of testing usingSpearman-rank analysis. (c) TNFa was significantly higher in subjectswith CD4+ T-cell count <500 cells/mm3 (Mann-Whitney test). (d) VLSPwas significantly correlated with CD4+ T-cell count. Nominalunadjusted two-sided p-values are presented.

FIGURE 2. Association of Inflammatory Proteins with Early

HIV-1 Disease Progression. Subjects were categorized into high orlow groups based on mean values (median used for VL). Log rankanalysis used to examine differences in time-to-endpoint for (a)days to CD4+ T cell count <500 cell/mm3 and (b) days to ART start.

TABLE 2. Log Rank Analysis of Inflammatory Proteins in Early HIV-

1 Disease Progression. Additional results from log rank analysisshown in Figure 2 defining the high and low groups for cutoff levels,N, and median time to endpoint.

Significant values with p<0.05 shown in bold, n/a not applicable+subjects who reached endpoint at or prior to biomarker testing were excluded from analysis++median cutoff used for viral load due to logarithmic distribution

TABLE 3. Cox Proportional Hazard Analysis for Inflammatory

Proteins in Early HIV-1 Infection. Cox hazard ratios shown for highvs. low groups using univariate (UV) and multivariate models (MV)adjusted for 1 log10 HIV-1 VL or 100 cell increments in CD4 count.

Significant values with p<0.05 shown in bold*MV analysis not done due to lack of significance in UV model+subjects who reached endpoint at or prior to biomarker testing were excluded

p=0.02*