Effects of HIV-1 Tat on Expression of HLA Class I Molecules

Self Cite

CD8ϩ cytotoxic T lymphocytes (CTLs) recognize virus-derived peptides in association with major histocompatibility complex class I molecules on the surface of antigen-presenting cells and kill the virus-infected target cells. There are a number of evidences showing that CTLs play a central role in the clearance of pathogenic viruses (67). In case of hepatitis C virus (HCV) infection, vigorous HCV-specific CTL responses existed in the persons resolving acute HCV infection (27). In the experimental model, chimpanzees who cleared HCV generated strong CTL but poor antibody responses, whereas other chimpanzees developing chronic hepatitis generated much weaker CTL response (12). Thus, spontaneous resolution of HCV is likely to be associated with HCV-specific CTLs rather than neutralizing antibodies (12,18,27,58). However, Ͼ60% of HCV-infected individuals turn out to have chronic hepatitis (1). Chronic HCV hepatitis eventually progresses to cirrhosis and hepatocellular carcinoma (53). In the chronic stage, HCVspecific CTLs are detectable in both peripheral blood and liver, but the precursor frequency of HCV-specific CTLs is extremely low (27,50,51). Therefore, enhancement of HCVspecific CTL induction in HCV-infected individuals should be considered to be a strategy to clear the virus. DNA vaccination has been proven to be a useful strategy for inducing both humoral and cellular immune responses (19). DNA vaccine safely mimics the effect of live, attenuated virusbased vaccine to generate a long-lasting CTL response. However, the efficiency of DNA vaccine is sometimes quite low and, therefore, several modifications have been attempted in recent years (19). Thus far, the most successful protocol of DNA immunization for CTL induction is likely to be a consecutive immunization involving priming with plasmid DNA and boosting with recombinant virus (2,24,35,43,54). The rationale behind this strategy is that DNA priming elicits low-level but persistent immunity, followed by strong boosting with virus encoding the same recombinant antigen as the DNA encodes. This regimen of the consecutive immunization has been proven to be efficient for CTL induction by many groups (2,24,35,37,43,54). Recently, McConkey et al. (37) have shown that the prime-boost immunization induced high frequencies of antigen-specific T-cell responses to malaria antigen and displayed partial protection in humans.Interleukin-12 (IL-12) is a heterodimeric proinflammatory cytokine formed by a 35-kDa light chain (p35) and a 40-kDa heavy chain (p40) (57). This cytokine is a dominant factor in the differentiation of T helper type 1 (Th1) cells and plays an essential role in a link between innate and adaptive immunities (60). Recently, two novel polypeptides, p19 (42) and p28 (48), have been identified by searching the databases with a computationally derived profile of IL-6. These factors do not show

Section: Methodsmentioning

confidence: 99%

Adjuvant Activities of Novel Cytokines, Interleukin-23 (IL-23) and IL-27, for Induction of Hepatitis C Virus-Specific Cytotoxic T Lymphocytes in HLA-A*0201 Transgenic Mice

Matsui

Moriya

Belladonna

et al. 2004

Self Cite

“…We used a physiological model where primary CD4 ϩ T cells were infected with primary HIV-1 isolates. One advantage of this approach is that it accounts for HLA downregulation mediated by viral proteins such as Tat (24), as well as Nef. Similar amounts of MHC-I downregulation were seen for cells infected with replication-competent isolates cultured from ES and progressors.…”

Section: Activated Cd4mentioning

confidence: 99%

Effective Downregulation of HLA-A2 and HLA-B57 by Primary Human Immunodeficiency Virus Type 1 Isolates Cultured from Elite Suppressors

Nou

Zhou

Nou

et al. 2009

Elite controllers or suppressors (ES) are human immunodeficiency virus type 1 (HIV-1)-infected patients who control viral replication to <50 copies/ml without antiretroviral therapy. Downregulation of HLA class I molecules is an important mechanism used by HIV-1 to evade the immune system. In this study, we showed that primary isolates from ES are as effective as isolates obtained from patients with progressive HIV-1 disease at downregulating HLA-A*2 and HLA-B*57 molecules on primary CD4+ T cells. Thus, a diminished ability of viral isolates from ES to evade HIV-specific immune responses probably does not contribute to the control of viral replication in these patients.

“…Several HIV-1 accessory genes are involved in this down-regulation, such as nef, vpu, and tat, with Nef protein having the strongest effect (20,28,39). Nef protein down-regulates HLA-A and HLA-B molecules but not HLA-C or HLA-E molecules (10,24).…”

Section: Human Immunodeficiency Virus Type 1 (Hiv-1)-specific Cd8mentioning

confidence: 99%

Different Effects of Nef-Mediated HLA Class I Down-Regulation on Human Immunodeficiency Virus Type 1-Specific CD8⁺T-Cell Cytolytic Activity and Cytokine Production

Tomiyama

Akari

Adachi

et al. 2002

105

A previous study using a Nef-defective human immunodeficiency virus type 1 (HIV-1) mutant suggested that Nef-mediated down-regulation of HLA class I on the infected cell surface affects the cytolytic activity of HIV-1-specific cytotoxic T-lymphocyte (CTL) clones for HIV-1-infected primary CD4 ؉ T cells. We confirmed this effect by using a nef-mutant HIV-1 strain (NL-M20A) that expresses a Nef protein which does not induce down-regulation of HLA class I molecules but is otherwise functional. HIV-1-specific CTL clones were not able to kill primary CD4 ؉ T cells infected with a Nef-positive HIV-1 strain (NL-432) but efficiently lysed CD4 ؉ T cells infected with NL-M20A. Interestingly, CTL clones stimulated with NL-432-infected CD4 ؉ T cells were able to produce cytokines, albeit at a lower level than when stimulated with NL-M20A-infected CD4 ؉ T cells. This indicates that Nef-mediated HLA class I down-regulation affects CTL cytokine production to a lesser extent than cytolytic activity. Replication of NL-432 was partially suppressed in a coculture of HIV-1-infected CD4 ؉ T cells and HIV-1-specific CTL clones, while replication of NL-M20A was completely suppressed. These results suggest that HIV-1-specific CD8 ؉ T cells are able to partially suppress the replication of HIV-1 through production of soluble HIV-1-suppressive factors such as chemokines and gamma interferon. These findings may account for the mechanism whereby HIV-1-specific CD8 ؉ T cells are able to partially but not completely control HIV-1 replication in vivo.