Early and Delayed Antiretroviral Therapy Results in Comparable Reductions in CD8+T Cell Exhaustion Marker Expression.
In untreated HIV infection, CD8+T cell exhaustion (i.e., decreased proliferative and effector capacity) is associated with high levels of expression of coinhibitory receptors, including PD-1, T cell immunoreceptor with Ig and ITIM domains (TIGIT), CD160, and 2B4. This is evident for both HIV-specific and non-HIV-specific CD8+T cells. Antiretroviral therapy (ART) initiated during chronic infection decreases but may not completely normalize the expression of such "exhaustion markers." Compared to initiation of ART later in the course of disease, initiation soon after infection reduces some parameters of chronic inflammation and adaptive immune dysfunction. However, it is not known if Early ART (e.g., initiated within the first 6 months after HIV infection) versus Delayed ART (e.g., initiated during chronic infection) preferentially reduces expression of exhaustion markers. We evaluated exhaustion marker expression on subsets of circulating effector and memory CD8+T cells at longitudinal pre- and post-ART (2 and 5 years on ART) time points from n = 19 (Early ART) and n = 23 (Delayed ART) individuals. Before ART, TIGIT and CD160 were expressed on a statistically significantly higher proportion of effector and transitional memory cells from individuals in the Delayed ART group: the timing of ART initiation, however, did not consistently affect the expression of the exhaustion markers once viral suppression was achieved. Understanding which factors do and do not regulate aspects of CD8+T cell exhaustion, including the expression of exhaustion markers, is critical to inform the rational design of CD8+T cell-based therapies to treat HIV, for which CD8+T cell exhaustion remains an important barrier to efficacy.
1 Department of Medicine, University of California , San Francisco, San Francisco, California.
Rachel Lena
RL
Rutishauser
2 Department of Epidemiology and Biostatistics, University of California , San Francisco, San Francisco, California.
Wendy
W
Hartogensis
1 Department of Medicine, University of California , San Francisco, San Francisco, California.|3 Department of Biochemistry, University of the Philippines , Manila, Philippines .
Christian Deo
CD
Deguit
2 Department of Epidemiology and Biostatistics, University of California , San Francisco, San Francisco, California.
Melissa
M
Krone
1 Department of Medicine, University of California , San Francisco, San Francisco, California.
Rebecca
R
Hoh
1 Department of Medicine, University of California , San Francisco, San Francisco, California.
Frederick M
FM
Hecht
1 Department of Medicine, University of California , San Francisco, San Francisco, California.
Christopher D
CD
Pilcher
2 Department of Epidemiology and Biostatistics, University of California , San Francisco, San Francisco, California.
Peter
P
Bacchetti
1 Department of Medicine, University of California , San Francisco, San Francisco, California.
Steven G
SG
Deeks
1 Department of Medicine, University of California , San Francisco, San Francisco, California.
Peter W
PW
Hunt
1 Department of Medicine, University of California , San Francisco, San Francisco, California.
Joseph M
JM
McCune
D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D055502:Secondary Prevention; D055815:Young Adult
D044966:Anti-Retroviral Agents
CD8+ T cell; Early ART; HIV; exhaustion