Due to constitutive expression in cells targeted by human immunodeficiency virus (HIV), and immediate mode of viral restriction upon HIV entry into the host cell, APOBEC3G (A3G) and APOBEC3F (A3F) have been considered primarily as agents of innate immunity. Recent bioinformatic and mouse model studies hint at the possibility that mutation of the HIV genome by these enzymes may also affect adaptive immunity but whether this occurs in HIV-infected individuals has not been examined. We evaluated whether APOBEC-mediated mutations within common HIV CD8+ T cell epitopes can potentially enhance or diminish activation of HIV-specific CD8+ T cells from infected individuals. We compared ex vivo activation of CD8+ T lymphocytes from HIV-infected individuals by wild type HIV peptide epitopes and synthetic variants bearing simulated A3G/F-induced mutations by measuring interferon-γ (IFN-γ) production. We found that A3G/F-induced mutations consistently diminished HIV-specific CD8+ T cell responses against the common epitopes we tested. If this reflects a significant trend in vivo, then adaptation by HIV to enrich sequences that are favored for mutation by A3G/F (A3G/F hotspots) in portions of its genome that encode immunogenic CD8+ T cell epitopes would favor CTL escape. Indeed, we found the most frequently mutated A3G motif (CCC) is enriched up to 6-fold within viral genomic sequences encoding immunodominant CD8+ T cell epitopes in Gag, Pol and Nef. Within each gene, A3G/F hotspots are more abundant in sequences encoding epitopes that are commonly recognized due to their HLA restriction. Thus, in our system, mutations of the HIV genome, mimicking A3G/F activity, appeared to abrogate or severely reduce CTL recognition. We suggest that the physiological significance of this potential effect in facilitating CTL escape is echoed in the adaptation of the HIV genome to enrich A3G/F hotspots in sequences encoding CTL epitopes that are more immunogenic at the population level.

Activating receptor-mediated recognition of stress-induced ligands or IgG antibody bridging of tumor or pathogen-associated antigens to the FcγRIII CD16 triggers NK cells to kill transformed and infected cells with reduced HLA-I expression. According to the licensing hypothesis, NK cells become competent for activating receptor-mediated triggering after a formative encounter between a NK inhibitory receptor and its ligand. This general hypothesis is supported by murine and human studies, but to date, evidence of a role for such licensing in human ADCC is ambiguous. Inhibitory receptor interactions with HLA-C promote NK cell ADCC licensing, but interactions between KIR3DL1 and its HLA-Bw4 ligand may be insufficient. We investigated the impact of KIR3DL1 and HLA-Bw4 coexpression on NK cell ADCC using a robust, genuine target system of antibody-bearing EBV-transformed B lymphocytes. Although numbers of KIR3DL1(+) NK cells were similar in HLA-Bw4(+) and HLA-Bw4(-) individuals, general levels of ADCC mediated against target cells were significantly higher in a group of HLA-Bw4(+)KIR3DL1(+) individuals than in a comparable HLA-Bw4(-) group. Flow cytometry demonstrated directly that a significantly higher fraction of KIR3DL1(+) NK cells derived from HLA-Bw4(+) compared with HLA-Bw4(-) individuals produced IFN-γ following stimulation with ADCC targets. Murine FcR-bearing P815 target cells also triggered higher levels of CD16-mediated cytotoxicity by NK cells from HLA-Bw4(+)KIR3DL1(+) individuals. These results indicate a prominent role for KIR3DL1/HLA-Bw4 interactions in licensing NK cells for CD16-mediated effector function.

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Certain human class I histocompatibility-linked leukocyte antigen (HLA)/killer cell immunoglobulin-like receptor (KIR) genotypic combinations confer more favourable prognoses upon exposure to human immunodeficiency virus (HIV). These combinations influence natural killer (NK) cell function, thereby implicating NK cells in protection from HIV infection or disease progression. Since CD8+ T cells restrict HIV replication, depend upon HLA class I antigen presentation and can also express KIR molecules, we investigated how these HLA/KIR combinations relate to the phenotype and function of CD8+ T cells from uninfected controls and individuals with chronic HIV infection. CD8+ T cells from KIR3DL1 and KIR3DS1 homozygous individuals, and expressing the corresponding KIR, were enumerated and phenotyped for CD127, CD57 and CD45RA expression. Ex vivo and in vitro responsiveness to antigen-specific and polyclonal stimulation was compared between KIR-expressing and non-expressing CD8+ T cells by interferon-γ production. There were higher numbers and fractions of KIR3DL1-expressing CD8+ T cells in HIV-infected individuals independent of HLA-Bw4 co-expression, whereas expansion of KIR3DS1-expressing CD8+ T cells reflected HLA-Bw4*80I co-expression. KIR3DL1+ and S1+ CD8+ T cells were predominantly CD127−CD57+CD45RA+. KIR3DL1-expressing CD8+ T cells were insensitive to ex vivo stimulation with peptides from HIV or common viruses, but responded to anti-CD3 and recovered responsiveness to common viruses in vitro. Ex vivo non-responsiveness of KIR3DL1-expressing CD8+ T cells was also independent of HLA-Bw4. KIR3DS1-expressing T cells responded normally to ex vivo antigenic stimulation, illustrating functional superiority over KIR3DL1+ CD8+ T cells.