Background:  CD8⁺ T-cell activation level is established early in HIV-1 infection, and has been identified as a powerful predictor of disease progression among HIV-1-infected adults. The genetic basis for variation in CD8^+.activation levels observed in recently infected individuals is not known. Rare HLA class I B allele frequency has been associated with delayed rates of disease progression, and lowered HIV-1 RNA levels. We assessed whether HLA class I B allele frequency associated with CD8⁺ T-cell activation independent of HIV-1 RNA levels.

Methods:  CD8⁺ T-cell activation was measured as the mean fluorescence intensity of CD38 (CD8CD38) expression upon CD3⁺CD8⁺ T cells. Molecular typing of the HLA B locus was performed using a non-radioactive PCR-based sequence specific oligonucleotide probe reverse line-blot assay. We employed tree-structured methods, and mixed effects modeling to assess the relationship between HLA B allele frequency and CD8⁺ activation.

Results:  We observed 129 treatment naïve subjects, who at study entry had been infected with HIV-1 for < 1 year. At study entry, among 129 persons, those carrying at least 1 rare class I B allele (< 10% population frequency) had significantly lower activation (104-point lower mean fluorescence intensity, p = 0.03) than those carrying 2 common alleles (> 10% population frequency), in a model adjusted for HIV-1 RNA levels (105-point higher mean fluorescence intensity per log₁₀ HIV-1 RNA, p < 0.0001). We followed 37 subjects over time, for a median 162 days (IQR 36, 364). In a model adjusted for study entry HIV-1 RNA levels, we found that persons carrying at least 1 rare class I B allele had significantly lower CD8⁺ T-cell activation levels (235-point lower CD8CD38 mean fluorescence intensity on average over time, p < 0.01) than those who had at 2 common class I B alleles. This effect was independent of HIV-1 RNA levels, which was marginally associated with CD8CD38 (34-point higher mean fluorescence intensity over time per log₁₀ HIV-1 RNA, p < 0.06).

Conclusions:  Among recently infected adults, carrying at least 1 rare class I B allele was associated with lower T-cell activation independent of HIV-1 RNA levels. Common class I alleles have likely forced progressive epitope escape in the pool of circulating viruses over the course of the epidemic. To exploit what little CD8⁺ effector function is available, patients carrying 2 common class I B alleles may develop compensatory and ultimately aberrant levels of activation.

Keywords: Activation; HLA; HIV-1 RNA