AEGiS-13IAC: Genetic Predictors of Virologic and Immunologic Responses to Combination Therapy in Early HIV-1 Infection.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

Genetic Predictors of Virologic and Immunologic Responses to Combination Therapy in Early HIV-1 Infection.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. TuOrA284)

Malhotra U, Dutta S, Holte S, Berrey MM, Corey L, McElrath MJ
U. Malhotra, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., D3-100, Seattle, WA 98109, United States, Tel.: +1 206 667 6738, Fax: +1 206 667 4411, E-mail: uma@u.washington.edu

BACKGROUND: Most patients receiving combination therapy early in infection respond favorably, but not all maintain viral suppression. To address this, we prospectively evaluated 21 patients with early HIV-1 infection to assess potential genetic inheritance patterns that may be associated with virologic and immunologic responses to combination therapy. Methods. Plasma HIV-1 RNA (RT-PCR), Gag-specific lymphoproliferation (LP) and IFN-gamma secretion (ELISA) were monitored in 21 patients receiving ZDV, 3TC, and IDV. The CCR5 32-base pair (bp) gene deletion, the CCR5 59029 A/G promoter polymorphism, and HLA class II alleles were identified by PCR. Epitope mapping and HLA restriction analyses for Gag-specific CD4+ T cell clones were performed.

RESULTS: All subjects achieved viral suppression (>50 copies/ml) following treatment. All 7 subjects with the HLA DRB1*13-DQB1*06 haplotype compared to 3/14 (21%) without the haplotype maintained virus suppression (>50 copies/ml) at all follow-up time points (p = 0.003). The mean log p24 LP response and IFN-gamma secretion post-therapy were greater among those with than those without the haplotype (1.077 and 0.663, p = 0.01; 43.4 versus 1.5 fold, p>0.001, respectively). The likelihood of maintaining virus suppression, the mean log p24 LP response and IFN-gamma secretion were similar among those with and without the CCR5 32-bp deletion or the 59029 G/G polymorphism (60% and 36%, p = 0.102; 0.885 and 0.718, p = 0.272; 14.2 versus 2.6-fold, p = 0.114, respectively). Duration of infection at treatment initiation was not predictive of virus suppression or Th1 response. HLA DRB1*13 restricted Gag-specific clones mapped to aa 129-149 (TNNPPIPVGEIYKRWIILGL) and 159-179 (EPFRDYVDRFYKTLRAEQAS).

CONCLUSIONS: Early-treated patients with the HLA DRB1*13-DQB1*06 haplotype, but not CCR5 32-bp deletion and 59029 G/G promoter mutations, have a more durable virus suppression and stronger Th1 responses, suggesting a better long-term outcome and perhaps suitability for withdrawal of therapy. DRB1*13 restricted Th1 epitopes may be suitable targets for vaccine design.

Keywords: AEGIS, HIV-1, Zidovudine, Lamivudine, HLA-DR Antigens, T-Lymphocytes, Epitopes, HLA-DRB1, Human, virology, immunology
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