CD8<sup>+</sup>-Cell Antiviral Factor Activity Is Not Restricted to Human Immunodeficiency Virus (HIV)-Specific T Cells and Can Block HIV Replication after Initiation of Reverse Transcription

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) mediate immunologic selection pressure by both cytolytic and noncytolytic mechanisms. Non cytolytic mechanisms include the release of ␤-chemokines blocking entry of R5 HIV-1 strains. In addition, CD8؉ cells inhibit X4 virus isolates via release of as yet poorly characterized soluble factors. To further characterize these factors, we performed detailed analysis of CTL as well as bulk CD8؉ T lymphocytes from six HIV-1-infected individuals and from six HIV-1-seronegative individuals. Kinetic studies revealed that secreted suppressive activities of HIV-1-specific CTL and bulk CD8؉ T lymphocytes from all HIV-1-infected persons are significantly higher than that of supernatants from seronegative controls. The suppressive activity could be blocked by monensin and brefeldin A, was heat labile, and appeared in a pattern different from that of secretion of chemokines (MDC, I-309, MIP-1␣, MIP-1␤, and RANTES), cytokines (gamma interferon, tumor necrosis factor alpha, and granulocytemacrophage colony-stimulating factor), and interleukins (interleukin-13 and interleukin-16). This suppression activity was characterized by molecular size exclusion centrifugation and involves a suppressive activity of >50 kDa which could be bound to heparin and a nonbinding inhibitory activity of <50 kDa. Our data provide a functional link between CD8؉ cells and CTL in the noncytolytic inhibition of HIV-1 and suggest that suppression of X4 virus is mediated through proteins. The sizes of the proteins, their affinity for heparin, and the pattern of release indicate that these molecules are not chemokines.

Section: Discussionmentioning

confidence: 68%

Noncytolytic Inhibition of X4 Virus by Bulk CD8⁺Cells from Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Persons and HIV-1-Specific Cytotoxic T Lymphocytes Is Not Mediated by β-Chemokines

Geiben-Lynn

Kursar

Brown

et al. 2001

“…A major hallmark of noncytotoxic HIV-1 suppression by CD8 ϩ T cells is the inhibition of both CCR5-and CXCR4-tropic virus replication (5,16,24). We assayed exosome-mediated antiviral activity against a panel of CCR5-and CXCR4-tropic isolates in infected primary CD4 ϩ T cells.…”

Section: Characterization Of Cd8mentioning

confidence: 99%

“…A lack of major histocompatibility complex (MHC) restriction (24,27,31,35) and suppression of HIV-1 replication in heterologous CD4 ϩ cell targets (16,17,45) distinguish this antiviral mechanism from the classical cytotoxic activity of CD8 ϩ T cells. The noncytotoxic mechanism has been shown to suppress the in vitro replication of a broad range of primary clinical and laboratory-adapted isolates and different HIV-1 clades varying widely in genotype as well as HIV-2 and simian immunodeficiency virus (2,21,47).…”

mentioning

confidence: 99%

Noncytotoxic Suppression of Human Immunodeficiency Virus Type 1 Transcription by Exosomes Secreted from CD8⁺T Cells

Tumne¹,

Prasad²,

Chen³

et al. 2009

CD8؉ T cells display a noncytotoxic activity that suppresses transcription of human immunodeficiency virus type 1 (HIV-1) in an antigen-independent and major histocompatibility complex-unrestricted manner. To date, the precise cellular and molecular factors mediating this CD8 ؉ T-cell effector function remain unsolved. Despite evidence indicating the dependence of the activity on cell-cell contact, the possibility of a membranemediated activity that represses transcription from the viral promoter remains unexplored. We therefore investigated whether this inhibition of HIV-1 transcription might be elicited by a membrane-bound determinant. Using a CD8؉ T-cell line displaying potent noncytotoxic HIV-1 suppression activity, we have identified a membrane-localized HIV-1-suppressing activity that is concomitantly secreted as 30-to 100-nm endosomederived tetraspanin-rich vesicles known as exosomes. Purified exosomes from CD8 ؉ T-cell culture supernatant noncytotoxically suppressed CCR5-tropic (R5) and CXCR4-tropic (X4) replication of HIV-1 in vitro through a protein moiety. Similar antiviral activity was also found in exosomes isolated from two HIV-1-infected subjects. The antiviral exosomes specifically inhibited HIV-1 transcription in both acute and chronic models of infection. Our results, for the first time, indicate the existence of an antiviral membrane-bound factor consistent with the hallmarks defining noncytotoxic CD8 ؉ T-cell suppression of HIV-1.

“…␤-Chemokines such as macrophage inflammatory protein 1␣ (MIP-1␣) and RANTES suppress HIV-1 infection through competition for CCR5 (2,8), while IFN-␥ directly suppresses HIV-1 replication by inducing cellular antiviral proteins (30). In addition, several unknown factors produced by CD8 ϩ T cells inhibit the transcription of HIV-1 (5,26). However, although HIV-1-infected individuals exhibit a strong HIV-1-specific cytolytic response, these individuals usually develop AIDS if they are not treated with antiretrovirus therapy (22,29).…”

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.