Biological determinants of immune reconstitution in HIV-infected patients receiving antiretroviral therapy: the role of interleukin 7 and interleukin 7 receptor α and microbial translocation.
BACKGROUND
Multiple host factors may influence CD4(+) T cell reconstitution in human immunodeficiency virus (HIV)-infected patients after suppressive antiretroviral therapy (ART). We hypothesized that residual immune activation and polymorphisms in the interleukin 7 (IL-7) receptor α (IL-7Rα) gene were important for immune recovery.


METHODS
We examined HIV-infected patients receiving suppressive ART (n = 96) for their IL-7Rα haplotypes and measured levels of lipopolysaccharide (LPS), soluble CD14, and IL-7 in plasma samples collected before and after ART initiation. Levels of soluble IL-7Rα were measured in HIV-infected patients with IL-7Rα haplotype 2 (n = 11) and those without IL-7Rα haplotype 2 (n = 22). Multivariate analysis was used to identify variables associated with faster recovery to CD4(+) T cell counts of >500 and >200 cells/μL.


RESULTS
Both LPS and soluble CD14 levels were significantly decreased with ART (P < .001, respectively) but remained elevated compared with uninfected controls. In a multivariate analysis, faster recovery to a CD4(+) T cell count of >500 cells/μL was significantly associated with higher baseline CD4(+) T cell count, younger age, lower pre-ART LPS level, higher pre-ART soluble CD14 level, lower pre-ART IL-7 level, and IL-7Rα haplotype 2 (hazard ratio, 1.50; 95% confidence interval, 1.03-2.19; P = .034). HIV-infected patients with haplotype 2 had significantly lower soluble IL-7Rα levels compared with those of patients without haplotype 2 (P < .001).


CONCLUSIONS
Both the extent of immune depletion prior to ART and IL-7Rα haplotype 2 are important determinants of time to CD4(+) T cell recovery to counts of >500 cells/μL.
Rajasuriar
Reena
R
Department of Medicine, Monash University, Burnet Institute, University of Melbourne, Melbourne, Australia.
Booth
David
D
Solomon
Ajantha
A
Chua
Kyra
K
Spelman
Tim
T
Gouillou
Maelenn
M
Schlub
Timothy E
TE
Davenport
Miles
M
Crowe
Suzanne
S
Elliott
Julian
J
Hoy
Jennifer
J
Fairley
Christopher
C
Stewart
Graeme
G
Cameron
Paul
P
Lewin
Sharon R
SR
D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015851:Interleukin-7 / Q000097:blood / Q000276:immunology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000097:blood / Q000235:genetics / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000097:blood; D008070:Lipopolysaccharides / Q000097:blood; D008297:Male; D008875:Middle Aged; D013997:Time Factors
D044966:Anti-Retroviral Agents; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides