Polymorphisms in the CD14 and TLR4 genes independently predict CD4+ T-cell recovery in HIV-infected individuals on antiretroviral therapy.
Chronic HIV infection leads to marked depletion of CD4 T cells in the gastrointestinal tract and increased microbial translocation measured by an increase in circulating lipopolysaccharide (LPS) levels. Here, we hypothesized that single-nucleotide polymorphisms (SNPs) in genes encoding the Toll-like receptor 4 (TLR4) and CD14, the principal receptors for LPS, were associated with CD4 T-cell recovery postantiretroviral therapy (ART).



Prospective study of predominantly white HIV-infected participants receiving suppressive ART for at least 12 months. We analysed the CD14 SNPs C-260T and the TLR4 SNPs A+896G, C+1196T. We also determined the levels of LPS and soluble CD14 in plasma samples collected pre-ART and post-ART initiation. CD4 T-cell recovery was assessed by linear mixed models.



Following ART, individuals with a TT genotype compared with a CT or CC genotype for CD14 C-260T SNP showed higher levels of soluble CD14 (P = 0.008 and 0.003, respectively). The CC genotype for the CD14 C-260T SNP, compared with CT or TT, and the TLR4 SNP (AC/GT), compared with the homozygous genotype (AA/CC), were both independently associated with enhanced long-term CD4 T-cell recovery (>3 months; P < 0.001).



Polymorphisms in CD14 and TLR4 are independently associated with long-term CD4 T-cell recovery in HIV-infected individuals post-ART.
aCentre of Excellence for Research in AIDS (CERiA) bTropical Infectious Diseases Research and Education Centre (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia cThe Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital dCentre of Population Health, Burnet Institute eSchool of Public Health and Preventive Medicine, Monash University fMelbourne Sexual Health Centre, Alfred Hospital gCentral Clinical School, Monash University hDepartment of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia iInfectious Disease Unit, University Malaya Medical Centre, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia jCentre for Biomedical Research, Burnet Institute, Melbourne, Australia.
Yean K
YK
Yong
Esaki M
EM
Shankar
Ajantha
A
Solomon
Tim
T
Spelman
Christopher K
CK
Fairley
Julian H
JH
Elliott
Jennifer
J
Hoy
Paul U
PU
Cameron
Adeeba
A
Kamarulzaman
Sharon R
SR
Lewin
D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D000074243:Immune Reconstitution; D018950:Lipopolysaccharide Receptors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051197:Toll-Like Receptor 4 / Q000235:genetics*
D044966:Anti-Retroviral Agents; D018950:Lipopolysaccharide Receptors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4