INTRODUCTION
The CD8 T-cells act against HIV strains in two principal ways during primary infection by: 1. killing HIV- infected cells and 2. secreting soluble factors, such as chemokines and other unknown factors, which suppress viral replication.
HIV-specific CD8 T-cells have the ability to recognize specific HIV sequences, which is copied and primes the CD8+ T cells to save the host against future encounters with similar strains. Although soluble non-cytolytic activity mediated by soluble factors is potent in inhibiting HIV without MHC restriction, it also described that this function can be carried out by the CTLs as well, which upon CD3 stimulation can produce soluble factors that impinge on viral replication in MHC-mismatched target infected cells. The cell supernatant from activated CTLs is also highly effective in viral suppression in vitro. In general the inhibition with active supernatant is less efficient than the cell-to-cell-contact between CTL and the target cell. Thus, overall it appears that the release of soluble factor is incumbent upon cellular activation. Even though the soluble factor release by CTLs is highly antigen-specific and MHC-restricted, the soluble factors can achieve this without MHC-restriction.The significance of CD8+ T cells and the antiviral and/or soluble factors secreted by HIV-specific CD8+ T cells in HIV immunobiology is indisputable. HIV-infected individuals mount a powerful cytotoxic T-cell- mediated immune response against specific HIV epitopes, which confers protection to the host against disease progression. As the CD4+ T cells are the target cells for HIV, greater attention has been paid to the role of CD4+ T lymphocytes in HIV pathogenesis. Even though HIV is capable of infecting diverse blood leukocytes, yet the importance of CD8+ T cells, particularly in relation to HIV infection remains underestimated.
Their sheer numbers and high level of activation during HIV infection provides the strongest support in favor of their key role in progressive and non-progressive HIV disease, reviewed in [1].The CD8+ T lymphocytes from HlV-I-Seropositive individuals are also known to inhibit HIV-1 replication in CD4+ T lymphocytes in vitro. These CD8+ T lymphocytes from HIV+ individuals are 'primed' against HIV-1 antigens, conferring partial HIV-specific resistance during infection through the secretion of HIV-specific soluble factors. Previously, in support of this [2, 3] it has been shown that the stripping of CD8+ lymphocytes derived from the whole PBMC fraction obtained from HIV-1-seronegative individuals can also result in a significant increase of HIV-1 replication in the remaining fraction, supporting their significant and definitive role in the immunologic defense against HIV. The CD8+ lymphocytes control viral replication either by direct antigen-specific cytolysis or through the secretion of soluble antiviral factors, which are highly HIV-specific or in other cases specific to the infectious agent. Thus, the cytotoxic and non-cytotoxic arms of the CD8+ T cells play a significant role in controlling HIV. Although the CD8 antiviral activity has been very well characterized and remains an intense subject of study in the field of innate and adaptive immunity, yet the biochemical components of this potent antiviral activity remain undefined, to date. As a consequence, the identity of CAF has remained elusive. The antiviral or non-cytolytic activity of CD8+T cells has been referred to with different terminologies, such as CNAR (CD8+ cell non-cytotoxic anti-HIV response) or CASA (CD8+ anti-HIV suppressor activity) (CASA is synonymous to CNAR), with CAF (CD8+ antiviral Factor) being the most commonly used terminology for this unidentified group of anti-HIV soluble factor(s). CAF secreted by CD8+ T cells in culture supernatants confers a potent anti-HIV activity against primary CD4+ T cells infected with a variety of beta chemokine insensitive HIV-1 strains in vitro.
In contrast, the antigen-specific cytotoxic T-lymphocytes (CTL) mediate direct killing of virus-infected cells through a cytolytic mechanism.
This review, in the subsequent sections, makes an attempt to discuss several mechanisms and hypotheses in regards to CD8 antiviral factors at various stages of HIV disease, and provide comprehensive discussion highlighting the relevance of interactions between CD8+T cells and in innate and adaptive immunity.