Abstract
MHC-I-restricted, virus-specific cytotoxic CD8+ T cells (CTLs) may control human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication via the recognition and killing of productively infected CD4+ T cells. Several studies in SIV-infected macaques suggest that CD8+ T cells may also decrease virus production by suppressing viral transcription. Here, we show that non-HIV-specific, TCR-activated non-cytolytic CD8+ T cells suppress HIV transcription via a virus- and MHC-independent immunoregulatory mechanism that modulates CD4+ T cell proliferation and activation. We also demonstrate that this CD8+ T cell-mediated effect promotes the survival of infected CD4+ T cells harboring integrated, inducible virus. Finally, we used RNA sequencing and secretome analyses to identify candidate cellular pathways that are involved in the virus-silencing mediated by these CD8+ T cells. This study characterizes a previously undescribed mechanism of immune-mediated HIV silencing that may be involved in the establishment and maintenance of the reservoir under antiretroviral therapy and therefore represent a major obstacle to HIV eradication.
Highlights
Several lines of experimental evidence suggest that CD8+ T cells play a significant role in the control of virus replication during the acute and chronic phases of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection
Correlative evidence includes the temporal association between the development of HIV/SIV-specific CTL responses and post-peak decline of viremia[2, 3], the emergence of virus CTL escape mutants[4, 5], the association between certain MHC class I haplotypes and disease progression[6, 7], and the presence of vigorous CTL responses in the so-called “elite controllers” (EC), persons living with HIV (PLWH) that show very low levels of viremia in absence of antiretroviral therapy (ART)[8]
Given that HIV-1-specific CTL responses have not been detected in CD8+ T cells isolated from HIV-negative subjects by either staining or ELISpot [31,32,33], in the current study we examined the distinct contribution of those CD8+ T cells to the suppression of viral transcription (we will further refer to these non-HIV-specific CD8+ T cells isolated from healthy HIV-negative subjects as CD8+ T cells, as opposed to the HIV-specific CD8+ T cells (CTLs) that are found in PLWH)
Summary
Several lines of experimental evidence suggest that CD8+ T cells play a significant role in the control of virus replication during the acute and chronic phases of HIV and SIV infection (reviewed in[1]). The most direct evidence in favor of a major role of CD8+ T cells in controlling virus replication derives from studies in which the depletion of CD8+ T lymphocytes in SIV-infected macaques was consistently followed by increased virus replication[9,10,11,12]. Intriguing evidence in support of the role of non-cytolytic mechanisms of virus suppression was first provided by two independent studies showing that CD8+ T lymphocyte depletion resulted in increased viremia in SIV-infected rhesus macaques (RMs) without prolonging the average in vivo lifespan of productively infected cells[16, 17]. The conclusion that non-cytolytic mechanisms of virus suppression are involved in controlling HIV/SIV replication is further supported by two additional independent studies
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call