laboratory and animal workers has been documented in at least two instances, with no cases of AIDS reported thus far. Taken together, these observations suggest that simian immunodeficiency viruses have the potential to cause disease upon transmission to a new host but that this may actually be a rare occurrence.

The most telling piece of evidence is epidemiological. Only two of the six HIV-2 subtypes described so far have spread epidemically. The four individuals infected with subtypes C to F were all healthy (or, in one case, afflicted with a disease that is not associated with AIDS). Thus, the divergent HIV-2 subtypes C to F may represent viruses poorly adapted to the human hosts. It appears likely, then, that either the epidemic HIV-2 subtypes originated from the transmission of specific variants that happened to be pathogenic for humans or that the emergence of pathogenic HIV requires further adaptation to the human host through unknown mechanisms.

What mechanisms might drive the acquisition of SIV virulence in the human host? Experiments in the macaque models have repeatedly shown that serial intravenous passages increase SIV and HIV virulence in this host. Thus, it is possible to draw a parallel and speculate that serial intravenous passages could have contributed to the propagation and the adaptation of SIVsm and SIVcpz in humans. Epidemiologists and historians have documented multiple instances of reuse of nonsterile needles or even of direct arm–arm vaccination in Africa since the beginning of the 20th century. The main reason why serial intravenous passages can promote SIV adaptation is that they provide the setting for successive viral jumps from primary infection to primary infection. A poorly adapted virus would induce a very low viral load and therefore would be very unlikely to be transmitted during the chronic phase of the infection. The only window of time during which transmission could occur would be the few weeks that precede the establishment of the antiviral immune response—that is, the primary infection.



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