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143 A Novel Polymorphism in the 5-Untranslated Region (5UTR) of CD28 Gene Is Associated with Susceptibility to HIV-1 Infection
A. Soriano*1, C. Martinez1, M. Plana1, F. García1, J. I. Aróstegui1, E. Palou1, F. Lozano1, M. Leujeune1, J. M. Miró1, J. del Romero2, C. Rodriguez2, A. Barrasa2, J. I. Lorenzo3, J. M. Gatell1, and T. Gallart1
1Hosp. Clin., Barcelona, Spain; 2Centro Médico Sandoval, Madrid, Spain; and 3Hosp. La Fe, Valencia, Spain
Background: CD28 plays a critical role in determining the effectiveness of T-cell immune responses and is also involved in down-regulating the expression of CCR5, the main coreceptor of HIV-1 NSI (R5) strains, which transmit the infection. We hypothesised therefore that genetic variants of CD28 might exist, which could be related to resistance/susceptibility to HIV infection and/or its progression to AIDS. Methods: A PCR product encompassing the first 559 bp of the 5UTR of CD28, was analysed by single-strand conformation polymorphism (SSCP) as a screening method in 294 individuals: 77 healthy controls (HC), 57 uninfected but highly exposed to HIV-1 (EU), and 160 HIV-1+ patients; 82 long-term non progressors (LTNP) and 78 typical progressors (TP). Sequencing and cloning were also performed. Results: Several SSCP patterns were identified, the most common being those designated a and b. Pattern a corresponds to a homozygous state of the wild-type (wt) allele, whereas pattern b is a heterozygous combination of the wt allele with a new allele resulting from a 5-bp repeat (CTTTT) deletion. There were no significant differences in the frequency of heterozygotes among HC (31%), HIV1+ individuals (28.75%), LTNP (24%), and TP (28.5%). In contrast, the frequency of heterozygotes in EU (10.5%) was significantly decreased as compared with HC (p = 0.008) and HIV-1+ group (p = 0.009).
Conclusions: Data demonstrate the existence of a previously unreported genetic variant of CD28 consisting of a 5-bp repeat deletion at the 5 end of 5UTR. It is significantly underrepresented in EU, indicating its association with susceptibility to HIV-1 infection. The functional consequences of this deletion and its role for favouring HIV-1 infection remain to be determined.
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