The Origins of Viruses

According to this hypothesis, viruses originated through a progressive process. Mobile genetic elements, pieces of genetic material capable of moving within a genome, gained the ability to exit one cell and enter another. To conceptualize this transformation, let's examine the replication of retroviruses, the family of viruses to which HIV belongs.

Retroviruses have a single-stranded RNA genome. When the virus enters a host cell, a viral enzyme, reverse transcriptase, converts that single-stranded RNA into double-stranded DNA. This viral DNA then migrates to the nucleus of the host cell. Another viral enzyme, integrase, inserts the newly formed viral DNA into the host cell's genome. Viral genes can then be transcribed and translated. The host cell's RNA polymerase can produce new copies of the virus's single-stranded RNA genome. Progeny viruses assemble and exit the cell to begin the process again (Figure 2).

This process very closely mirrors the movement of an important, though somewhat unusual, component of most eukaryotic genomes: retrotransposons. These mobile genetic elements make up an astonishing 42% of the human genome (Lander et al. 2001) and can move within the genome via an RNA intermediate. Like retroviruses, certain classes of retrotransposons, the viral-like retrotransposons, encode a reverse transcriptase and, often, an integrase. With these enzymes, these elements can be transcribed into RNA, reverse-transcribed into DNA, and then integrated into a new location within the genome (Figure 3). We can speculate that the acquisition of a few structural proteins could allow the element to exit a cell and enter a new cell, thereby becoming an infectious agent. Indeed, the genetic structures of retroviruses and viral-like retrotransposons show remarkable similarities.

In contrast to the progressive process just described, viruses may have originated via a regressive, or reductive, process. Microbiologists generally agree that certain bacteria that are obligate intracellular parasites, like Chlamydia and Rickettsia species, evolved from free-living ancestors. Indeed, genomic studies indicate that the mitochondria of eukaryotic cells and Rickettsia prowazekii may share a common, free-living ancestor (Andersson et al. 1998). It follows, then, that existing viruses may have evolved from more complex, possibly free-living organisms that lost genetic information over time, as they adopted a parasitic approach to replication.

Viruses of one particular group, the nucleocytoplasmic large DNA viruses (NCLDVs), best illustrate this hypothesis. These viruses, which include smallpox virus and the recently discovered giant of all viruses, Mimivirus, are much bigger than most viruses (La Scola et al. 2003). A typical brick-shaped poxvirus, for instance, may be 200 nm wide and 300 nm long. About twice that size, Mimivirus exhibits a total diameter of roughly 750 nm (Xiao et al. 2005). Conversely, spherically shaped influenza virus particles may be only 80 nm in diameter, and poliovirus particles have a diameter of only 30 nm, roughly 10,000 times smaller than a grain of salt. The NCLDVs also possess large genomes. Again, poxvirus genomes often approach 200,000 base pairs, and Mimivirus has a genome of 1.2 million base pairs; while poliovirus has a genome of only 7,500 nucleotides total. In addition to their large size, the NCLDVs exhibit greater complexity than other viruses have and depend less on their host for replication than do other viruses. Poxvirus particles, for instance, include a large number of viral enzymes and related factors that allow the virus to produce functional messenger RNA within the host cell cytoplasm.

Because of the size and complexity of NCLDVs, some virologists have hypothesized that these viruses may be descendants of more complex ancestors. According to proponents of this hypothesis, autonomous organisms initially developed a symbiotic relationship. Over time, the relationship turned parasitic, as one organism became more and more dependent on the other. As the once free-living parasite became more dependent on the host, it lost previously essential genes. Eventually it was unable to replicate independently, becoming an obligate intracellular parasite, a virus. Analysis of the giant Mimivirus may support this hypothesis. This virus contains a relatively large repertoire of putative genes associated with translation — genes that may be remnants of a previously complete translation system. Interestingly, Mimivirus does not differ appreciably from parasitic bacteria, such as Rickettsia prowazekii (Raoult et al. 2004).

The progressive and regressive hypotheses both assume that cells existed before viruses. What if viruses existed first? Recently, several investigators proposed that viruses may have been the first replicating entities. Koonin and Martin (2005) postulated that viruses existed in a precellular world as self-replicating units. Over time these units, they argue, became more organized and more complex. Eventually, enzymes for the synthesis of membranes and cell walls evolved, resulting in the formation of cells. Viruses, then, may have existed before bacteria, archaea, or eukaryotes (Figure 4; Prangishvili et al. 2006).

Most biologists now agree that the very first replicating molecules consisted of RNA, not DNA. We also know that some RNA molecules, ribozymes, exhibit enzymatic properties; they can catalyze chemical reactions. Perhaps, simple replicating RNA molecules, existing before the first cell formed, developed the ability to infect the first cells. Could today's single-stranded RNA viruses be descendants of these precellular RNA molecules?

Others have argued that precursors of today's NCLDVs led to the emergence of eukaryotic cells. Villarreal and DeFilippis (2000) and Bell (2001) described models explaining this proposal. Perhaps, both groups postulate, the current nucleus in eukaryotic cells arose from an endosymbiotic-like event in which a complex, enveloped DNA virus became a permanent resident of an emerging eukaryotic cell.