During Stably Suppressive Antiretroviral Therapy Integrated HIV-1 DNA Load in Peripheral Blood is Associated with the Frequency of CD8 Cells Expressing HLA-DR/DP/DQ.
BACKGROUND
Characterising the correlates of HIV persistence improves understanding of disease pathogenesis and guides the design of curative strategies. This study investigated factors associated with integrated HIV-1 DNA load during consistently suppressive first-line antiretroviral therapy (ART).


METHODS
Total, integrated, and 2-long terminal repeats (LTR) circular HIV-1 DNA, residual plasma HIV-1 RNA, T-cell activation markers, and soluble CD14 (sCD14) were measured in peripheral blood of 50 patients that had received 1-14 years of efavirenz-based or nevirapine-based therapy.


RESULTS
Integrated HIV-1 DNA load (per 10(6) peripheral blood mononuclear cells) was median 1.9 log10 copies (interquartile range 1.7-2.2) and showed a mean difference of 0.2 log10 copies per 10 years of suppressive ART (95% confidence interval - 0.2, 0.6; p = 0.28). It was positively correlated with total HIV-1 DNA load and frequency of CD8(+)HLA-DR/DP/DQ(+) cells, and was also higher in subjects with higher sCD14 levels, but showed no correlation with levels of 2-LTR circular HIV-1 DNA and residual plasma HIV-1 RNA, or the frequency of CD4(+)CD38(+) and CD8(+)CD38(+) cells. Adjusting for pre-ART viral load, duration of suppressive ART, CD4 cell counts, residual plasma HIV-1 RNA levels, and sCD14 levels, integrated HIV-1 DNA load was mean 0.5 log10 copies higher for each 50% higher frequency of CD8(+)HLA-DR/DP/DQ(+) cells (95% confidence interval 0.2, 0.9; p = 0.01).


CONCLUSIONS
The observed positive association between integrated HIV-1 DNA load and frequency of CD8(+)DR/DP/DQ(+) cells indicates that a close correlation between HIV persistence and immune activation continues during consistently suppressive therapy. The inducers of the distinct activation profile warrant further investigation.
Department of Clinical Infection, Microbiology and Immunology (CIMI), Institute of Infection and Global Health (IGH), University of Liverpool, 8 West Derby Street, Liverpool L697BE, United Kingdom.
Alessandra
A
Ruggiero
HIV Translational Research Unit, Department of Internal Medicine, Ghent University and University Hospital Ghent, De Pintelaan 1859000, Ghent, Belgium.
Ward
W
De Spiegelaere
Department of Infection and Population Health, University College London, Royal Free Campus, Rowland Hill Street, London, NW32PF, United Kingdom.
Alessandro
A
Cozzi-Lepri
HIV Translational Research Unit, Department of Internal Medicine, Ghent University and University Hospital Ghent, De Pintelaan 1859000, Ghent, Belgium.
Maja
M
Kiselinova
Department of Clinical Infection, Microbiology and Immunology (CIMI), Institute of Infection and Global Health (IGH), University of Liverpool, 8 West Derby Street, Liverpool L697BE, United Kingdom.
Georgios
G
Pollakis
Department of Clinical Infection, Microbiology and Immunology (CIMI), Institute of Infection and Global Health (IGH), University of Liverpool, 8 West Derby Street, Liverpool L697BE, United Kingdom.
Apostolos
A
Beloukas
HIV Translational Research Unit, Department of Internal Medicine, Ghent University and University Hospital Ghent, De Pintelaan 1859000, Ghent, Belgium.
Linos
L
Vandekerckhove
VA San Diego Healthcare System and Center for AIDS Research, University of California San Diego, La Jolla, CA 92093, United States.
Matthew
M
Strain
VA San Diego Healthcare System and Center for AIDS Research, University of California San Diego, La Jolla, CA 92093, United States.
Douglas
D
Richman
Department of Infection and Population Health, University College London, Royal Free Campus, Rowland Hill Street, London, NW32PF, United Kingdom.
Andrew
A
Phillips
Department of Clinical Infection, Microbiology and Immunology (CIMI), Institute of Infection and Global Health (IGH), University of Liverpool, 8 West Derby Street, Liverpool L697BE, United Kingdom.
Anna Maria
AM
Geretti
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004279:DNA, Viral / Q000097:blood*; D005260:Female; D015497:HIV-1 / Q000276:immunology*; D006682:HLA-DP Antigens / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D019562:Viral Load / Q000276:immunology*
D004279:DNA, Viral; D006682:HLA-DP Antigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens
2-LTR, 2-long terminal repeats; ART, Anti-retroviral therapy; Activation; CMV, cytomegalovirus virus; CRN, Clinical Research Network; EBV, Epstein-Bar virus; ELISA, enzyme-linked immune-enzymatic assay; HIC, HIV-1 controllers; HIV-1 VL, HIV-1 viral load; HIV-1, Human Immunodeficiency Virus type 1; HLA, Human Leukocyte Antigen; Integration; LPS, lipopolysaccharide; NIHR, National Institute for Health Research; NNRTI, Non-nucleoside reverse-transcriptase inhibitors; NRTI, nucleoside/nucleotide reverse transcriptase inhibitors; PBMCs, Peripheral blood mononuclear cells; PCR, Polymerase chain reaction; PFA, paraformaldehyde; Persistence; Reservoir; Suppression; VLS, Viral Load Suppression; WHO, World Health Organisation; sCD14, soluble CD14