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HIV-1 replication depends on the state of cell activation and division. It is established that SAMHD1 restricts HIV-1 infection of resting CD4T cells. The modulation of SAMHD1 expression during T-cell activation and proliferation, however, remains unclear, as well as a role for SAMHD1 during HIV-1 pathogenesis.

Reduced CD73 on T cells in HIV correlates with disease progression, as well as functional CD8+ T cell defects, and is partially reversible by ART. Recent studies indicate that murine Tregs highly express the ENTDP1, as well as the 5′‐NT and thereby, suppress Teff function by extracellular adenosine production. Furthermore, CD73 seems to play a role as costimulatory molecule for T cell differentiation. In this study, we analyzed the expression of CD73 on peripheral and lymph nodal Teffs and Tregs in a cohort of 95 HIV patients at different stages of disease, including LTNP and ECs. In contrast to murine Tregs, CD73 was only expressed on a small minority (∼10%) of peripheral Tregs. In contrast, we see high expression of CD73 on peripheral CD8+T cells. In HIV infection, CD73 is markedly reduced on all Teffs and Tregs, regardless of the memory subtype. On CD8+T cells, a positive correlation between CD73 expression and CD4 counts (P=0.0003) was detected. CD73 expression on CD8+T cells negatively correlated with HLA‐DR (<0.0001) and PD1 (P=0.0457) expression. The lower CD73 expression on CD8+T cells was partially reversible after initiation of ART (P=0.0016). Functionally, we observed that CD8+CD73+T cells produce more IL‐2 upon HIV‐specific and unspecific stimulation than their CD73−counterparts and show a higher proliferative capacity. These data indicate that down‐regulation of CD73 on CD8+T cells correlates with immune activation and leads to functional deficits in HIV infection.

CD8+T-cell responses are an essential antiviral host defense in persistent viral infections, and their sustained effectiveness is thought to be critically dependent on CD4+T-helper cells. To determine the relationship between HIV-1–induced CD4+T-cell depletion and hepatitis C virus (HCV)–specific CD8+T-cell responses during viral persistence, we studied 103 persons positive for HCV, 74 coinfected with HIV-1. CD8+T-cell responses to the entire HCV polyprotein were determined by using an interferon-γ enzyme-linked immunospot (ELISpot) assay. Although HIV-1 infection by itself was not associated with a diminished HCV-specific response, HIV-1–associated CD4+depletion was associated with significantly lower HCV-specific CD8+T cells (R = 0.48, P< .0001). In contrast, declining CD4+counts over the same range were not associated with diminished Epstein-Barr virus (EBV)– (R = 0.19, P= .31) or HIV-1–specific (R = –0.13, P= .60) CD8+T-cell responses in persons infected with all viruses. These data indicate that frequencies of circulating HCV-specific CD8+T-cell responses are sensitive to absolute CD4+T-cell counts and provide a possible explanation for the accelerated HCV disease course in persons coinfected with HIV-1 and HCV.

CD8+ T-cell responses are an essential antiviral host defense in persistent viral infections, and their sustained effectiveness is thought to be critically dependent on CD4+ T-helper cells. To determine the relationship between HIV-1–induced CD4+ T-cell depletion and hepatitis C virus (HCV)–specific CD8+ T-cell responses during viral persistence, we studied 103 persons positive for HCV, 74 coinfected with HIV-1. CD8+ T-cell responses to the entire HCV polyprotein were determined by using an interferon-γ enzyme-linked immunospot (ELISpot) assay. Although HIV-1 infection by itself was not associated with a diminished HCV-specific response, HIV-1–associated CD4+ depletion was associated with significantly lower HCV-specific CD8+ T cells (R = 0.48, P < .0001). In contrast, declining CD4+ counts over the same range were not associated with diminished Epstein-Barr virus (EBV)– (R = 0.19, P = .31) or HIV-1–specific (R = –0.13, P = .60) CD8+ T-cell responses in persons infected with all viruses. These data indicate that frequencies of circulating HCV-specific CD8+ T-cell responses are sensitive to absolute CD4+ T-cell counts and provide a possible explanation for the accelerated HCV disease course in persons coinfected with HIV-1 and HCV.

In the setting of acute hepatitis C virus (HCV) infection, robust HCV-specific CD8+ cytotoxic T lymphocyte (CTL) responses are associated with initial control of viremia. Despite these responses, 70–80% of individuals develop persistent infection. Although viral escape from CD8 responses has been illustrated in the chimpanzee model of HCV infection, the effect of CD8 selection pressure on viral evolution and containment in acute HCV infection in humans remains unclear. Here, we examined viral evolution in an immunodominant human histocompatibility leukocyte antigen (HLA)-B8–restricted NS3 epitope in subjects with acute HCV infection. Development of mutations within the epitope coincided with loss of strong ex vivo tetramer and interferon γ enzyme-linked immunospot responses, and endogenous expression of variant NS3 sequences suggested that the selected mutations altered processing and presentation of the variant epitope. Analysis of NS3 sequences from 30 additional chronic HCV-infected subjects revealed a strong association between sequence variation within this region and expression of HLA-B8, supporting reproducible allele-specific selection pressures at the population level. Interestingly, transmission of an HLA-B8–associated escape mutation to an HLA-B8 negative subject resulted in rapid reversion of the mutation. Together, these data indicate that viral escape from CD8+ T cell responses occurs during human HCV infection and that acute immune selection pressure is of sufficient magnitude to influence HCV evolution.

The nonstructural protein 3 (NS3) of hepatitis C virus (HCV) inhibits the nuclear transport and the enzymatic activity of the catalytic subunit of protein kinase A. This inhibition is mediated by an arginine-rich domain localized between amino acids 1487–1500 of the HCV polyprotein. The data presented here indicate that the arginine-rich domain, when embedded in recombinant fragments of NS3, interacts with the catalytic site of protein kinase C (PKC) and inhibits the phosphorylation mediated by this enzyme in vitroand in vivo. Furthermore, a direct binding of PKC to the NS3 fragments leads to an inhibition of the free shuttling of the kinase between the cytoplasm and the particulate fraction. In contrast, a peptide corresponding to the arginine-rich domain (HCV (1487–1500)), despite also being a PKC inhibitor, did not influence the PKC shuttling process and was transported to the particulate fraction by the translocating kinase upon activation with tetradecanoylphorbol-13-acetate. Using the tetradecanoylphorbol-13-acetate -stimulated respiratory burst of NS3-introduced neutrophils as a model system, we could demonstrate that NS3 is able to block PKC-mediated functions within intact cells. Our data support the possibility that NS3 disrupts the PKC-mediated signal transduction.