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

The fact is that retroviruses are a wholly unique form of infectious agent and one that has direct access to the genome of the host species. The genetic nature of retroviruses is fundamentally different from all other pathogens known—a characteristic which allows the virus to cause substantial genetic damage to the host, even permanent change to the germline of the host species (in fact, some molecular biologists argue that the action of retroviruses has been a critical factor in vertebrate evolution—it is estimated that about 5 -10% of the mammalian genome has been manipulated and moved around by reverse transcriptase of retroviral origin during evolution). Yet, the two well-characterized forms of immunologic response—humoral immunity (HI) and cell-mediated immunity (CMI)—do not seem to be effective against many retroviruses (reviewed in 25).

It is almost inconceivable that higher organisms have evolved, to the present degree, without developing some special means to control this unusual sort of pathogens, or else retroviruses would long since have caused irreparable genetic damage to a myriad of host species. Furthermore, there is abundance of data, derived both in vitro and in vivo, that shows mammals are indeed quite capable of controlling the actions of retroviruses (see below).

Thus, we propose a new interpretation of previously-derived data which we feel is far better at accommodating these unusual data as well as the observed pathogenesis of HIV-1, Simian immunodeficiency virus (SIV) and other Lentiviral infections. We postulate that there is 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 information about the pathogen in question. This molecule serves as a critical score and cue to a whole orchestra of proteinaceous instruments playing at the molecular level, which must perform in symphony in order to overpower the discordant genes of the infecting retrovirus 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+ cells also modulate the course of retroviral infection, particularly during the initial stages of the infection (see below). Most importantly, the body can be primed with genetically-related non-pathogenic strain, such that the body can develop a persistent genetic "molecular immunity" that specifies a particular retrovirus. The body, then, manifests protective natural defenses against this retrovirus and genetically-closely-related strains of virus, with or without the concomitant presence of classical humoral or cell-mediated responses (see below).

The mechanisms by which CD8+ T-cells inhibit retroviral replication are poorly defined. The problem is that interpreting HIV-1 data through conventional immunologic theory could be compared to sailing a rocky coastline with a map of continental features found on another planet. Meanwhile, the HIV-1 epidemic continues to expand unchecked worldwide, and initially-promising intervention protocols result in ultimate failure in nearly every laboratory where they are tried (26-28). Instead of languishing in this intellectual abyss, let us explore in earnest new realms in our quest for fundamental understanding of infection by retroviruses.