The Major Histocompatibility Complex Class II Alleles Mamu - DRB1 * 1003 and -DRB1 * 0306 Are Enriched in a Cohort of Simian Immunodeficiency Virus-Infected Rhesus Macaque Elite Controllers (cid:1)

The role of CD4 (cid:1) T cells in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication is not well understood. Even though strong HIV- and SIV-specific CD4 (cid:1) T-cell responses have been detected in individuals that control viral replication, major histocompatibility complex class II (MHC-II) molecules have not been definitively linked with slow disease progression. In a cohort of 196 SIVmac239-infected Indian rhesus macaques, a group of macaques controlled viral replication to less than 1,000 viral RNA copies/ml. These elite controllers (ECs) mounted a broad SIV-specific CD4 (cid:1) T-cell response. Here, we describe five macaque MHC-II alleles ( Mamu - DRB * w606 , -DRB * w2104 , - DRB1 * 0306 , -DRB1 * 1003 , and - DPB1 * 06 ) that restricted six SIV-specific CD4 (cid:1) T-cell epitopes in ECs and report the first association between specific MHC-II alleles and elite control. Interestingly, the macaque MHC-II alleles, Mamu - DRB1 * 1003 and - DRB1 * 0306 , were enriched in this EC group ( P values of 0.02 and 0.05, respectively). Additionally, Mamu - B * 17 -positive SIV-infected rhesus macaques that also expressed these two MHC-II alleles had significantly lower viral loads than Mamu - B * 17 -positive animals that did not express Mamu - DRB1 * 1003 and - DRB1 * 0306 ( P value of <0.0001). The study of MHC-II alleles in macaques that control viral replication could improve our understanding of the role of CD4 (cid:1) T cells in suppressing HIV/SIV replication and further our understanding of HIV vaccine design. ELISPOT An enzyme-linked immunospot (ELISPOT) assay was used to quantify IFN- (cid:5) -positive responses in PBMCs depleted in vitro of CD8 (cid:1) cells, map CD4 (cid:1) T-cell responses, and define the macaque MHC-II restricting alleles by using RM3 cell transferents. When fresh PBMCs were used, we performed the assay as previously described Fresh CD8-depleted PBMCs were isolated to map SIV-specific CD4 (cid:1) T-cell responses using several pools of 10 peptides of 15 amino acids in length, overlapping by 11 amino acids. These pools comprised most of the viral proteome. Fresh CD8-depleted PBMCs

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