The CD8⁺T Cell Noncytotoxic Antiviral Responses

Abstract

SUMMARY The CD8+ T cell noncytotoxic antiviral response (CNAR) was discovered during studies of asymptomatic HIV-infected subjects more than 30 years ago. In contrast to CD8+ T cell cytotoxic lymphocyte (CTL) activity, CNAR suppresses HIV replication without target cell killing. This activity has characteristics of innate immunity: it acts on all retroviruses and thus is neither epitope specific nor HLA restricted. The HIV-associated CNAR does not affect other virus families. It is mediated, at least in part, by a CD8+ T cell antiviral factor (CAF) that blocks HIV transcription. A variety of assays used to measure CNAR/CAF and the effects on other retrovirus infections are described. Notably, CD8+ T cell noncytotoxic antiviral responses have now been observed with other virus families but are mediated by different cytokines. Characterizing the protein structure of CAF has been challenging despite many biologic, immunologic, and molecular studies. It represents a low-abundance protein that may be identified by future next-generation sequencing approaches. Since CNAR/CAF is a natural noncytotoxic activity, it could provide promising strategies for HIV/AIDS therapy, cure, and prevention.

CCL5-Secreting Virtual Memory CD8+ T Cells Inversely Associate With Viral Reservoir Size in HIV‐1−Infected Individuals on Antiretroviral Therapy

“…Alternatively, CD8+ T cells can exert anti-HIV-1 effects via a bystander mechanism (18,20,47,48). The incapability of antigen-specific CD8+ T cells might be due to the escape mutation of HIV-1 epitopes (49), whereas viral killing mediated by bystander CD8+ T cells did not need MHC matching (18,19). Our recent findings supported this notion.…”

“…Given that the determinant roles of antigen-specific CD8+ T cells in controlling primary HIV-1 infection have been established, accumulating evidence suggested that the capability of HIV-1-specific CD8+ T cells is limited in eliminating latent cells carrying provirus, and shaping the viral epitope landscape in individuals undergoing ART (21)(22)(23). Alternatively, CD8+ T cells can exert anti-HIV-1 effects via a bystander mechanism (18,20,47,48). The incapability of antigen-specific CD8+ T cells might be due to the escape mutation of HIV-1 epitopes (49), whereas viral killing mediated by bystander CD8+ T cells did not need MHC matching (18,19).…”

“…Such innate-like, bystander effect was also observed in HIV-1 infection. For instance, it was reported that major histocompatibility complex (MHC) matching is not necessary for CD8+ T cells to kill HIV-1-infected cells during primary infection (18,19). Furthermore, bystander CD8+ T cells play an important role in maintaining the suppression of viremia in individuals undergoing ART (18,(20)(21)(22)(23)(24)(25).…”

“…For instance, it was reported that major histocompatibility complex (MHC) matching is not necessary for CD8+ T cells to kill HIV-1-infected cells during primary infection (18,19). Furthermore, bystander CD8+ T cells play an important role in maintaining the suppression of viremia in individuals undergoing ART (18,(20)(21)(22)(23)(24)(25). Of which, we previously showed that a virtual memory T (T VM ) cells subset, defined by CD44 hi CD122 hi CD49d lo in mice and CD45RA+ killer Ig-like receptors (KIR)+ and/or CD94 natural killer group 2 member A (NKG2A)+ in humans (17,26,27), senses and inhibits the reactivation of HIV-1 reservoir through KIR (28).…”

Vaccination against the Koala Retrovirus (KoRV): Problems and Strategies

“…Antiviral factors may have been induced by immunization with the adjuvant, which may act in the neutralization assay. Such antiviral factors produced by CD8 + T cells have been described in the case of HIV infections [ 52 ]. In addition, intracellular restriction factors may have been activated in the process of immunization [ 53 ].…”