Key Viral Adaptations Preceding the AIDS Pandemic

Abstract

HIV, the causative agent of AIDS, has a complex evolutionary history involving several cross-species transmissions and recombination events as well as changes in the repertoire and function of its accessory genes. Understanding these events and the adaptations to new host species provides key insights into innate defense mechanisms, viral dependencies on cellular factors, and prerequisites for the emergence of the AIDS pandemic. In addition, understanding the factors and adaptations required for the spread of HIV in the human population helps to better assess the risk of future lentiviral zoonoses and provides clues to how improved control of viral replication can be achieved. Here, we summarize our current knowledge on viral features and adaptations preceding the AIDS pandemic. We aim at providing a viral point of view, focusing on known key hurdles of each cross-species transmission and the mechanisms that HIV and its simian precursors evolved to overcome them.

Structural basis for tetherin antagonism as a barrier to zoonotic lentiviral transmission

“…The structural and binding data explain how the absence of this motif in human tetherin renders it resistant to downregulation from the cell surface by SIV Nefs. The inability of SIV to antagonize human tetherin is now considered to be one of the major hurdles to successful simian-human zoonotic transmission (7). Our data thus provide the structural basis for a transmission barrier that helps to protect humans from efficient primate lentiviral transmission.…”

“…Most notably, the lack of an otherwise conserved (G/D)DIWK motif in human tetherin confers resistance to downregulation by the viral protein Nef used by most SIVs to counteract this restriction factor. Thus, antagonism of tetherin is a major barrier to successful simian-human transmission of non-human primate lentiviruses, the origin of HIV (7). Here, we elucidate the structural basis for antagonism of (G/D)DIWK-containing simian tetherin by SIV Nef in near-atomic detail.…”

“…To overcome barriers to cross-species transmission during primate lentiviral evolution, the task of antagonizing tetherin has shifted repeatedly between Nef and Vpu (7). Most SIV including SIVcpz, SIVgor, and SIVsmm, the direct precursors of HIV-1 and HIV-2, respectively, use their Nef protein to target AP-2 at the PM by a mechanism whose details are still unknown (3,6,17,18).…”

“…Here, we report on the Nef of SIVsmm infecting sooty mangabeys. SIVsmm uses Nef and its envelope (Env) glycoprotein as tetherin antagonist in is natural simian host and represents the direct ancestor of HIV-2 and of SIVmac causing simian AIDS in rhesus macaques (7). SIVsmm managed to cross the species barrier from monkeys to humans on at least 9 occasions possibly because its Env protein shows some activity against human tetherin (22).…”

How host genetics dictates successful viral zoonosis

“…SIVcpz was then transmitted to humans, giving rise to HIV-1 group M [47]. Given the enormity of the pandemic that ensued, these events have been intensely scrutinized by the HIV research community, and this topic has been recently reviewed [48].…”