Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.

Functional defects in cytotoxic CD8؉ T cell responses arise in chronic human viral infections, but the mechanisms involved are not well understood. In mice, CD4 cell-mediated interleukin-21 (IL-21) production is necessary for the maintenance of CD8 ؉ T cell function and control of persistent viral infections. To investigate the potential role of IL-21 in a chronic human viral infection, we studied the rare subset of HIV-1 controllers, who are able to spontaneously control HIV-1 replication without treatment. HIV-specific triggering of IL-21 by CD4؉ T cells was significantly enriched in these persons (P ‫؍‬ 0.0007), while isolated loss of IL-21-secreting CD4 ؉ T cells was characteristic for subjects with persistent viremia and progressive disease. IL-21 responses were mediated by recognition of discrete epitopes largely in the Gag protein, and expansion of IL-21 cells in acute infection resulted in lower viral set points (P ‫؍‬ 0.002). Moreover, IL-21 production by CD4؉ T cells of HIV controllers enhanced perforin production by HIV-1-specific CD8 ؉ T cells from chronic progressors even in late stages of disease, and HIV-1-specific effector CD8؉ T cells showed an enhanced ability to efficiently inhibit viral replication in vitro after IL-21 binding. These data suggest that HIV-1-specific IL-21؉ CD4 ؉ T cell responses might contribute to the control of viral replication in humans and are likely to be of great importance for vaccine design. CD4ϩ T cell help is essential to generate long-lived antiviral CD8 ϩ T cell memory (17, 18). Although antigen-specific CD8 ϩ T cells can be primed in the absence of CD4 ϩ T cell help, secondary expansion upon antigen reencounter is inefficient under such circumstances (7,11,18,22). Progressive loss of CD4 ϩ T cells in human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections has been associated with dysfunction of virus-specific CD8 ϩ T cells and ineffective containment of these chronic viral infections. Moreover, under repetitive antigenic stimulation, virus-specific cytotoxic CD8 ϩ T cells (CTL) become increasingly impaired, exhibiting decreased effector functions and upregulation of negative immunoregulatory molecules (2, 19). This dysfunction is likewise more severe in the absence of CD4 ϩ T cell help (21). The nature of CD4 help required to control chronic human infections remains unclear. In mice, recent studies indicate that CD4 ϩ T cell production of interleukin-21 (IL-21), a common ␥-chain cytokine, is required for maintenance of CD8 ϩ T cell function in persistent but not resolving viral infections (3,4,23). During lymphocytic choriomeningitis virus (LCMV) infection, expansion of CD4 ϩ T helper cells producing IL-21 is required for sustained CD8 ϩ T cell proliferation and control of viremia. In contrast, mice lacking either IL-21 or the IL-21 receptor are more susceptible to uncontrolled chronic LCMV infection, providing evidence that this cytokine is a key regulator of viral control in a murine model of chronic viral infection.

HIV elite controllers are able to control HIV-1 infection spontaneously to undetectable levels in the absence of antiretroviral therapy, but the mechanisms leading to this phenotype are poorly understood. Although, low frequencies of HIV infected peripheral CD4+ T-cells have been reported in this group, it remains unclear to what extent this is due to viral attenuation, active immune containment, or intracellular host factors that restrict virus replication. Here we assessed proviral DNA levels, autologous viral growth from and infectability of in-vitro activated, CD8+ T-cell depleted CD4+ T cells from HIV elite controllers (mean VL<50cp/ml), viremic controllers (mean VL<2000cp/ml), chronic progressors and HAART treated individuals. Although we successfully detected autologous virus production in ex-vivo activated CD4+ T-cells from all chronic progressors and most of the viremic controllers we were only able to measure robust autologous viral replication in only 2 of 14 elite controllers subjected to the same protocol. In vitro activated autologous CD4+ T-cells from elite controllers, however, supported infection with both X4 and R5 tropic HIV strains at comparable levels to CD4+ T-cells from HIV negative subjects. Proviral DNA levels were the lowest in elite controllers, suggesting that extremely low frequencies of infected cells contributes to difficulty in isolation of virus. These data indicate that elite control is not due to inability of activated CD4+ T-cells to support HIV infection, but the relative contribution of host and viral factors that account for maintenance of low level infection remain to be determined.

Highlights d CXCR2 controls neutrophil recruitment into the brain in HSV-1 encephalitis d Cxcr2 À/À mice have decreased BBB permeability and improved outcome in HSV-1 infection d CXCL1 is produced by both astrocytes and neurons in response to IL-1a d CXCL1-CXCR2 is required for neutrophil transendothelial migration into the brain