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Impact of HAART Initiation on Immune Regulation (activation/senescence) in Aging HIV-infected Women -Women's Interagency HIV Study
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Reported by Jules Levin
CROI 2012 March 5-8 Seattle, WA
1Robert C. Kaplan, PhD, 1Christina M. Parrinello, MPH, 2Howard N. Hodis, MD, 3Stephen J. Gange, PhD, 4Mary Young, MD, 1Kathryn Anastos, MD, 5,6Phyllis C. Tien, MD, 7Jason Lazar, MD, MPH, 8Alan L. Landay, PhD, 8Seema Desai, PhD*
1Albert Einstein College of Medicine, Bronx, NY, US, 2University of Southern California, Los Angeles, CA, US, 3Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, US, 4Georgetown University Medical Center, Washington, DC, US,
5University of California, San Francisco, San Francisco, CA, US, 6San Francisco Veteran Affairs Medical Center, San Francisco, CA, US, 7State University of New York, Downstate Medical Center, Brooklyn, NY, US, 8Rush University Medical Center, Chicago, IL, US
SUMMARY OF RESULTS
All women were observed for three visits prior to HAART (average = 15.2 months) and
three visits after first use of HAART (average = 15.6 months follow-up after first use of
HAART).
A significant decrease in immune activation was observed in both CD4 and CD8 T cell
subsets post-HAART (mean difference = -2.13%, P = 0.0012 and -17.1%, P < 0.0001,
respectively) .
A significant decrease in pro-apoptotic Caspase-3 was observed in both CD4 and CD8 T
cells (mean difference = -0.42%, P = 0.02 and -2.77%, P = 0.0002, respectively).
A significant decrease was observed in the level of immune exhaustion post-HAART in
CD8 T cells (mean difference = -15.93%, P < 0.0001) with an increase in IL-2 responses
(mean difference = 3.81%, P = 0.02).
Following HAART initiation, CD8 T cell senescence decreased significantly (mean
difference = -5.02%, P = 0.03) though at a slower rate per year compared to the decrease
in activation and exhaustion. The rate of change in CD8 T cell senescence was -5.48% per
year (P = 0.0007) vs. CD8 T cell activation: -13.40% per year, P < 0.0001, and CD8 T cell
exhaustion: -11.40% per year, P < 0.0001.
CONCLUSIONS
Highly active antiretroviral therapy significantly reduces the degree of immune activation,
exhaustion and apoptosis in aging HIV-infected women
Immune senescence levels were reduced to a lesser extent compared to immune activation
or immune exhaustion post-HAART
Therapies to reverse immune senescence adjunct to HAART may be warranted
METHODS
STUDY POPULATION: 16 HIV-infected women who responded to HAART optimally (all women had
undetectable HIV RNA at 2 or more post-HAART visits)
LABORATORY METHODS: PBMC from all study groups were treated with anti human antibodies for surface
markers, cells were washed and fixed in 1% Para Formaldehyde until acquisition on LSRII (Beckton Dickinson
CA). For intracellular markers, cells were permeabilized following fixation and treated with antihuman
antibodies. Data were analyzed using Flow Jo software (Tree Star Inc)
Marker of immune activation/apoptosis immune-exhaustion and senescence: Immune activation markers
(cells co-expressing HLADR and CD38), marker of apoptosis Caspase-3, marker of immune exhaustion PD-1,
and immune senescence measured as loss of CD28 and CD57 expression (CD28-CD57+) were evaluated on
CD4 and CD8 T- cells by 10 color flow
Cytokine responses: Intracellular interferon (IFN)-g, IL-2 & IL-17, IL-10, TNF-alpha responses were evaluated
in CD4 and CD8 T cells following 6 hours of PMA+Ionomycin stimulation
STATISTICAL ANALYSES
¥ Paired t-tests to test the significance of pre-HAART to post-HAART mean differences in immune responses
¥ Linear mixed-effects models to determine the post-HAART rate of change per year in immune response
measures
ABSTRACT
Background: Initiation of HAART has improved life expectancy, nonetheless immune activation and inflammation persist despite effective HAART. In this longitudinal study, we examine the impact of HAART initiation on immune activation, exhaustion and senescence in HIV-infected women. We hypothesize that HAART improves immune regulation in HIV-infected women.
Methods: Immune response patterns were evaluated in 16 HIV-infected women considered HAART responders, over 6 sequential visits (3 pre-and 3 post-HAART). We evaluated markers of T cell activation (CD38+HLADR+), immune exhaustion (PD-1+), immune senescence (CD28-CD57+) and apoptosis (Caspase-3) as well as cytokine responses (interferon-g, IL-2, IL-17 & TNF-alpha) to PMA+Ionomycin in CD4 and CD8 T cells using 10 color flow cytometry. Expression of immune markers pre and post-HAART
were averaged per subject and mean difference pre-HAART to post-HAART was assessed using paired ttest. Linear mixed effects models with random intercept and random slope terms were used to assess
post-HAART rate of change in immunemarker per year.
Results: The mean age of women in the study was 41.2 years at entry. The mean CD4 count was 351 and 505 cells/mm3 pre- and post-HAART and the mean log HIV RNA was 4.4 and 2.1copies/mL pre- and post-HAART, respectively. We observed significant decreases in CD4 and CD8 T cell activation post-HAART (mean difference = -2.13%, P = 0.0012 and -17.1%, P < 0.0001, respectively) as well as proapoptotic Caspase-3 in both CD4 and CD8 T cells (mean difference = -0.42%, P = 0.02 and -2.77%, P =
0.0002 respectively). Immune exhaustion in CD8 T cells decreased significantly post-HAART (mean difference = -15.93%, P < 0.0001) with increase in IL-2 responses (mean difference = 3.81%, P = 0.02).
Following HAART initiation, CD8 T cell senescence decreased significantly (mean difference = -5.02%, P= 0.03) though at a slower rate per year compared to the decrease in activation and exhaustion. The rate of change in CD8 T cell senescence was -5.48% per year (P = 0.0007) vs. CD8 T cell activation: -13.40%per year, P < 0.0001, and CD8 T cell exhaustion: -11.40%per year, P < 0.0001.
Conclusion: After initiation of HAART, immune activation, exhaustion, senescence, and apoptosis in CD8 T cells are reduced significantly. Levels of immune senescence appear to decrease at a slower rate per year than levels of immune activation and exhaustion. Therapies to reverse senescence as adjunct to HAART may be warranted.
INTRODUCTION/RATIONALE
Advances in antiretroviral (ARV) therapy have resulted in increased life expectancy of HIV-infected individuals, nonetheless survival among HIV-infected patients is less than among HIVuninfected
individuals1. It is expected that by 2015 over 50% of HIV positive patients will be over 50 years old2
Chronic immune activation and inflammation persist despite viral control and are known to be associated with co-morbidities such as atherosclerosis3, liver disease4, neurocognitive decline5,
cancers6 and frailty7 - a constellation of conditions that mimics aging
A declining immune system is a hallmark of aging. Chronic immune activation and persistent infections in HIV-1 infected individuals provide a milieu for accelerated replicative senescence of T cells that progressively accumulate as in the normal course of aging8
HAART improves immune regulation although the impact of HAART on immune senescence is not known. We report the impact of HAART initiation on markers of immune activation, exhaustion and senescence in HIV-infected women studied longitudinally pre- and post-HAART.
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