F

rom one of the earliest known descriptions of a viral disease, namely, the report in 1904 of a disease affecting horses called swamp fever, to the sudden appearance of a wasting disease of sheep, which reached epidemic proportions in Iceland in the 1940s, the lentiviruses remained known only among a small group of virologists as a curiously slow infectious agent and were totally unappreciated as a potential source for a global human viral pandemic. Then, in the late 1970s and early 1980s, subtle patterns of a new clinical disease gave way to the parallel epidemics of AIDS in captive primates and humans. Characterized by seemingly unrelated opportunistic infections, the lentiviruses thrust themselves into the scientific, genetic, moral, and cultural fabric of mankind throughout the world.

HIV (human immunodeficiency virus), the cause of AIDS, is a member of the lentiviruses, a subfamily of a larger family called retroviruses. That large family is well known for containing viruses that cause cancer in humans and other animals. Although lentiviruses do not cause cancer, they do present a formidable challenge to the host. First, lentiviruses integrate themselves into their host's genetic blueprint. Second, they contain numerous regulatory genes that allow them to control their rate of replication in both dividing and nondividing cells. Third, and most important, they have evolved, interacted, and survived completely within the cells of the host's immune system-the only viruses described to date that spend their entirety in such cells.

In this article we intend to retrieve from anonymity the lentiviruses associated with animals other than humans and focus attention on their various strategies for survival. We will explain how the AIDS virus and other lentiviruses outsmart the host's immune system and show why traditional ap

proaches to vaccine development will most likely fail against this type of virus. Finally, we will turn to models of host adaptation, in particular, the African green monkey and the chimpanzee, as a probable source of inspiration for understanding and, therefore, developing a successful strategy against AIDS and AIDS-like diseases.

Retroviral Life Cycle and Family History

All viruses are parasitic in nature. They require a host to replicate but unlike parasites, which are living organisms, viruses are functionally nonliving. A virus is best described as an infectious chemical made up of an outer envelope or protein coat that encapsulates the viral genome, the genetic blueprint for constructing more viruses. What they lack are the protein-synthesis and energy-generating capabilities required to manufacture progeny. They infect the host cell by binding to and fusing with the cell's membrane and then depositing the viral genes within the cell where they are free to be read by and interact with the host's manufacturing machinery (Fig. 1).

The "retro"viruses are so-called because at the beginning of their life cycle they reverse the usual flow of genetic information. In all living organisms and in many other viruses, genetic information is stored as deoxyribonucleic acid, or DNA, and later transcribed into ribonucleic acid, or RNA, which serves as a template for protein synthesis. By contrast, retroviruses store their genetic information as RNA and also contain the unique enzyme, reverse transcriptase, which catalyzes the "reverse" transcription of the RNA genome into a DNA copy. The resulting proviral DNA is oftentimes perceived by the host cell as its own and is integrated into its DNA where the provirus can remain dormant or latent for weeks,

STRUCTURE AND LIFE CYCLE OF HIV

Fig. 1. The structure (a) and life cycle (b) of HIV. The cycle starts with the binding of the viral envelope protein gp120 to a CD4 receptor on the surface of the target cell, the fusing of the viral and cellular lipid bilayers, and the entry of the viral core, containing the RNA genome and the enzyme reverse transcriptase, into the cell's interior. The cycle ends with the production of new viral genomes and viral proteins and the assembly of viral cores and budding of new virus particles. Step 4, reverse transcription of the viral genome into proviral DNA, and step 5, integration of proviral DNA into the host cell's genome, are unique to retroviruses. In some cases, after step 4, the DNA will spontaneously close on itself and this circular DNA will remain in the cytoplasm as episomal DNA. Also shown is the possibility that steps 4-6 will be bypassed and the positive strand of genomic RNA will serve directly as a template for protein synthesis, that is, it will be translated directly into viral proteins by ribosomes within the cell.

months, or even years without being expressed. In fact, some retroviruses (for example, those of chickens and mice) have assured their persistent association by integrating into the germ cells of the host. As integrated viruses (so called proviruses), they are transmitted vertically to the next generation without an infectious cycle. There are no known methods of eliminating such retroviruses.

The retrovirus family, evolutionarily speaking, is quite old. It contains three subfamilies: the oncoviruses, the spumaviruses, and the subfamily of most interest to us, the lentiviruses (Table 1). The oncoviruses, or cancercausing viruses, are found to be transmitted both by host-to-host contact and as integrated viruses in germ cells. When integrated into the host's DNA, oncoviruses efficiently "transform" the host cells into cells that have a tumor

Table 1

Subfamilies of the Retroviruses

Visna maedi virus

Caprine arthritis encephalitis virus

Equine infectious anemia virus

Feline T-lymphotropic virus

Bovine immunodeficiency-like virus

ease.

Simian foamy viruses (9 serotypes)
Bovine syncytial virus

Feline syncytial virus
Hamster foamy virus
Human foamy virus.

producing potential. Oncoviruses have been found in either complete or incomplete form within various normal tissues and developing embryos of many species of animals including humans. Their presence in the host through evolutionary spans of time may have been responsible for the shuffling of critical genetic elements between cells during various embryological and differentiative processes, which subsequently led to Darwinian selection.

The lentiviruses and spumaviruses (spuma for foamy) have a somewhat different relationship with the host.

These viruses do not integrate into the host's germ cell lines and do not cause cancer. In vivo both produce lifelong infection of the host cells but may not kill the infected cells. In vitro they infect and kill host cells through massive viral replication and tearing of the cell membranes as they bud from the cell surface. The genomes of spumaviruses and lentiviruses are more closely related to each other than to those of the oncoviruses. However, of the two, only the lentiviruses have been identified as causes of human and animal diseases.

All retroviruses are rapidly changing

because reverse transcription of their RNA genomes often produces mistakes in the DNA copies. In oncoviruses such "mistakes" sometimes create defective viruses, that is, pieces of viral DNA that are incorporated into the host genome but cannot replicate, although their presence may promote the growth of tumors. Under the proper conditions certain other helper viruses “rescue" these defective viral pieces by also incorporating themselves into the host genome and creating new genetic combinations that can replicate. The rescued oncoviruses usually have different physical, biological, and tumor-inducing properties than the original virus. Another type of genetic recombination has also been found in experiments with mice. Genes that specify the envelopes for two different retroviruses or retroviral strains are exchanged. The exchange confers on the viruses the ability to infect new cell types or cells of another species. Recombination of envelope genes can also enable the virus to escape both specific and nonspecific antiviral substances found in the host. Many of these types of genetic recombinations have recently been found to occur in human cells infected by HIV. As we will discuss below, spontaneous mutations, immune selection, and genetic recombination in HIV presents one of the major blocks to developing a traditional vaccine against AIDS.

The Immune System-Host for the Lentiviruses

The central problem in the evolution of multicellular organisms is the recognition of foreign from self. The body, a multicellular organism, may be thought of as an ecosystem containing numerous niches that can be occupied by organisms uniquely adapted to the prevailing environment. One such niche in this ecosystem is the cell, which, like other living members of a natural ecosystem,