326-W. A Novel Genetic Variant of CD28 Gene Is Associated with Susceptibility to HIV Infection

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Session 51 Poster Session
Impact of Host Genetics on Viral Transmission and Disease Progression
Session Time: 4:30-6:30 pm
Room 4E-F

326-W.

A Novel Genetic Variant of CD28 Gene Is Associated with Susceptibility to HIV Infection
A. Soriano¹, C. Martinez¹, F. García¹, M. Plana*¹, E. Palou¹, J. Aróstegui¹, M. Leujeune¹, J. Joseph¹, J. Miró¹, J. del Romero², C. Rodriguez², A. Barrasa², J. I. Lorenzo³, F. Lozano¹, J. M. Gatell¹, and T. Gallart¹
¹Hosp. Clínic-IDIBAPS, Univ. of Barcelona; ²Ctr. Med., Sandoval, Madrid; and ³Hosp. La Fe, Valencia, Spain

Background: CD28 plays an essential role in the effectiveness of T-cell immune responses. In addition, CD28 co-stimulation of CD4+ T-cells confers resistance to in vitro infection by R5-tropic HIV-1 strains by down-regulating CCR5, while it increases CXCR4 expression. We analyzed the presence of polymorphisms in the 5’Untranslated region (5’UTR) of CD28 gene and its relationship with resistance/susceptibility to HIV-1 infection and its progression to AIDS.
Methods: This was a cross-sectional study with HIV+ individuals (175), including long-term non-progressors (LTNP) (n=82), and progressors (n=93) at different stages of HIV disease; highly-exposed but uninfected individuals (EU) (n=57); healthy controls (HC) (n=77). Cold single-strand conformation polymorphism (SSCP) in 4-20% gradient polyacrilamide gel electrophoresis at 15º C of the PCR amplified product encompassing the first known 559 bp of the CD28 5’ UTR. DNA sequencing and cloning.
Results: 2 main SSCP patterns (a and b) were observed. Sequencing and cloning demonstrated that pattern a corresponded to the homozygous state of the wild type allele, while pattern b was a heterozygous combination of the wild type allele and a new allele resulting from the deletion of a 5-bp repeat (CTTTT) of the 4 CTTTT repeats found in the wild type allele, located 28 bp upstream of the Alu family sequence present in the CD28 5’UTR. There were no significant differences in the frequency of this CD28 5’UTRdelta5 heterozygote genotype between HC (31%), whole HIV+ group (28.7%) , LTNP (24.0%), and progressors (28.5%), although there was a trend for an increased frequency in the most advanced patients (40.0%). In contrast, the frequency of CD28 5’UTRdelta5 heterozygotes among EU (10.5%) showed a highly significant decrease compared with HC and HIV+ individuals (p=0.009).
Conclusions: Not previously reported is the genetic variant of CD28 gene (CD28 5’UTRdelta5), which is significantly under-represented in highly exposed but uninfected individuals, indicating its association with susceptibility to HIV infection.