Received 6/18/97, Accepted 7/22/97

Rapid viral replication during the course of HIV-1 infections is now considered to be an important factor in the in vivo pathogenesis of this human retroviral disease (29-31). Quantitation of viral burden in plasma, peripheral blood mononuclear cells (PBMC) and lymphoid organs have been closely correlated with HIV-1 stage, clinical status and CD4-positive T-lymphocyte counts (29-36). It appears that, from the time of HIV-1-infection until the development of the AIDS, the major sites of viral replication are the secondary lymphoid organs (35-36). CAF from HIV-1 individuals, SIV-infected monkeys, Feline immunodeficiency virus (FIV) infected cats, or from uninfected healthy individuals can suppress corresponding retroviral replications (17-24, 37). This observed suppressive activity is non restricted by MHC, does not require cell-to-cell contact between effector and target cells and can be mediated through soluble factors (17-24). Therefore, this CD8+ cell- mediated HIV-1 resistance is unique and does not fit into the known concepts of humoral or cell-mediated immune response, which requires cell-to-cell contacts between targets (T) and the effector (E) cells, requires certain E- to-T ratio to be effective and is MHC restricted. Therefore, we believe that CD8+ cell-mediated anti-retroviral immunity belongs to a unique form of natural immunity, distinct from CMI and HI. We wish to present existing data to support this hypothesis.

Based upon the observations presented below, we postulate that there may be a third form of immunity (besides humoral and cell-mediated immunities) at work with retroviruses, which we call "molecular immunity". We hypothesize this molecular response is akin to both humoral and cell-mediated responses, but it involves a particular virus-specific messenger molecule that delivers to individual cells crucial genetic information about the pathogen in question. Furthermore, the critical messenger molecule seems to be associated with a specific CD8+ subset of T-cell lymphocytes, and various stimuli, cytokines/chemokines, and other "cofactors" that modulate the response of these CD8+ T-cells also modulate the course of retroviral infection, particularly during the initial stages of the infection (see below). Most importantly, the host can be primed with genetically-related non-pathogenic strains, such that the host can develop a persistent genetic "molecular immunity" that specifies a particular retrovirus. The body, then, manifests protective "molecular immunity" against this particular retrovirus and genetically-closely-related strains of virus, with or without the concomitant presence of classical humoral or cell-mediated responses (38-43: see below).

Many others have recently published on the important role of CD8+ lymphocytes and associated cytokines/chemokines and their receptors in HIV-1 infection, but we believe that these data are manifestations of only part of the picture (4-9, 17-23, 44-47). In the following pages we have examined various aspects of our hypothesis, particularly those linked to what we have termed "molecular immunity" and which appears to be responsible for controlling HIV-1-replication in human and other retroviruses in their animals.