The timing of type I interferon signalling determines the disease course of SIV infection. Type I interferon (IFN-I) is shown here to have dual effects in rhesus macaques exposed to simian immunodeficiency virus (SIV): it is beneficial at the onset of infection but as infection progresses it becomes detrimental. IFN signaling was manipulated in two ways. IFN-I receptor blockade results in increased plasma viraemia, accelerated CD4 T cell loss and progression to AIDS. In contrast, IFN-α2a administration prior to high-dose intrarectal SIV challenge increases resistance to systemic infection. However, continued IFN-α2a treatment induces IFN-I desensitization and facilitates SIV infection. Overall, the benefits of early antiviral activity appear to outweigh the detrimental effects of immune activation during acute SIV infection. Inflammation in HIV infection is predictive of non-AIDS morbidity and death1, higher set point plasma virus load2 and virus acquisition3; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection4,5,6,7,8,9,10, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression6,7,11,12,13,14,15,16,17,18,19. Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-α2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-α2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution.

Thwarting HIV: Multiple genome-wide association studies have revealed that human leukocyte antigen (HLA) genes of the major histocompatibility complex locus have the strongest impact on HIV. In particular, a single-nucleotide polymorphism 35 base pairs upstream of HLA-C shows significant association with viral load and protection against HIV. How HLA-C mediates these effects is unknown. Apps et al. (p. 87 ) now demonstrate that increasing surface expression of HLA-C is associated with reduced viral load and reduced rate of progression to low CD4 ⁺ T cell counts in African and European Americans. High HLA-C expression likely promoted improved HIV control through a more effective cytotoxic CD8 ⁺ T cell response. In contrast to HIV infection, high HLA-C expression was associated with a higher risk of the inflammatory bowel disease, Crohn's disease.

A primary obstacle to an HIV-1 cure is long-lived viral reservoirs, which must be eliminated or greatly reduced. Cure strategies have largely focused on monitoring changes in T cell reservoirs in peripheral blood (PB), even though the lymphoid tissues (LT) are primary sites for viral persistence. To track and discriminate viral reservoirs within tissue compartments we developed a specific and sensitive next-generation in situ hybridization approach to detect vRNA, including vRNA+ cells and viral particles (“RNAscope”), vDNA+ cells (“DNAscope”) and combined vRNA and vDNA with immunohistochemistry to detect and phenotype active and latently infected cells in the same tissue section. RNAscope is highly sensitive with greater speed of analysis compared to traditional in situ hybridization. Highly sensitive and specific DNAscope detected SIV/HIV vDNA+ cells, including duplexed detection of vDNA and vRNA or immunophenotypic markers in the same section. Analysis of LT samples from macaques prior to and during combination antiretroviral therapy demonstrated that B cell follicles are an important anatomical compartment for both latent and active viral persistence during treatment. These new tools should allow new insights into viral reservoir biology and evaluation of cure strategies.

The expression level of HLA class-I proteins is known to influence pathological outcomes: pathogens downregulate HLA to evade host immune responses, host inflammatory reactions upregulate HLA, and differences among people with regard to the steady-state expression levels of HLA associate with disease susceptibility. Yet precise quantification of relative expression levels of the various HLA loci is difficult because of the tremendous polymorphism of HLA. We report relative expression levels of HLA-A, HLA-B, HLA-C, and HLA-E proteins for the specific haplotype A*02:01, B*44:02, C*05:01, which were characterized using two independent methods based on flow cytometry and mass spectrometry. PBLs from normal donors showed that HLA-A and HLA-B proteins are expressed at similar levels, which are 13–18 times higher than HLA-C by flow cytometry and 4–5 times higher than HLA-C by mass spectrometry; these differences may reflect variation in the conformation or location of proteins detected. HLA-E was detected at a level 25 times lower than that of HLA-C by mass spectrometry. Primary CD4⁺ T cells infected with HIV in vitro were also studied because HIV downregulates selective HLA types. HLA-A and HLA-B were reduced on HIV-infected cells by a magnitude that varied between cells in an infected culture. Averaging all infected cells from an individual showed HLA-A to be 1–3 times higher and HLA-B to be 2–5 times higher than HLA-C by flow cytometry. These results quantify substantial differences in expression levels of the proteins from different HLA loci, which are very likely physiologically significant on both uninfected and HIV-infected cells.

Inhibiting natural killer cells in AIDS: The human leukocyte antigen (HLA) gene complex varies enormously among individuals and helps explain individual variation in immunity to infectious diseases. Ramsuran et al. examined data from almost 10,000 HIV infections. Expression of the HLA-A and - B alleles was associated with higher viral load, reduced CD4 ⁺ T cell counts, and accelerated progression to AIDS. Higher levels of HLA-A expression increased expression of HLA-E , which blocks a specific receptor (NKG2A) on the immune cells that normally eliminate virus-infected cells. Thus, targeting NKG2A might provide a therapeutic avenue for HIV treatment. Science , this issue p. 86