Origins of HIV and the AIDS pandemic

Abstract

Acquired immunodeficiency syndrome (AIDS) of humans is caused by two lentiviruses, human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2). Here, we describe the origins and evolution of these viruses, and the circumstances that led to the AIDS pandemic. Both HIVs are the result of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) naturally infecting African primates. Most of these transfers resulted in viruses that spread in humans to only a limited extent. However, one transmission event, involving SIVcpz from chimpanzees in southeastern Cameroon, gave rise to HIV-1 group M-the principal cause of the AIDS pandemic. We discuss how host restriction factors have shaped the emergence of new SIV zoonoses by imposing adaptive hurdles to cross-species transmission and/or secondary spread. We also show that AIDS has likely afflicted chimpanzees long before the emergence of HIV. Tracing the genetic changes that occurred as SIVs crossed from monkeys to apes and from apes to humans provides a new framework to examine the requirements of successful host switches and to gauge future zoonotic risk.

Figure 1.

Origins of human AIDS viruses. Old World monkeys are naturally infected with more than 40 different lentiviruses, termed simian immunodeficiency viruses (SIVs) with a suffix to denote their primate species of origin (e.g., SIVsmm from sooty mangabeys). Several of these SIVs have crossed the species barrier to great apes and humans, generating new pathogens (see text for details). Known examples of cross-species transmissions, as well as the resulting viruses, are highlighted in red.

Figure 2.

Phylogeny of lentiviruses. The evolutionary relationships among Pol sequences (∼ 770 amino acids) derived from various mammalian lentiviruses; host species are indicated at the right. Exogenous viruses are depicted in black, with HIV-1, HIV-2, and SIVmac highlighted in red; endogenous viruses are shown in purple. The phylogenetic tree was estimated using maximum likelihood methods (Guindon and Gascuel 2003). The scale bar represents 0.10 amino acid replacements per site.

Figure 3.

Geographic distribution of SIVcpz and SIVgor infections in sub-Saharan Africa. Field sites where wild-living (A) chimpanzees and bonobos, and (B) gorillas have been sampled are shown (each site is identified by a two-letter code; because of space limitations, only a subset is depicted). Sites where SIV infections were detected are highlighted in yellow. The upper panel depicts the ranges of the four subspecies of the common chimpanzee (Pan troglodytes verus, gray; P. t. ellioti, magenta; P. t. troglodytes, red; and P. t. schweinfurthii, blue) and of the bonobo (P. paniscus, orange). The lower panel depicts the ranges of western (Gorilla gorilla, green) and eastern (G. beringei, brown) gorillas (map courtesy of Lilian Pintea, The Jane Goodall Institute). Data were compiled from several studies (Santiago et al. 2002, 2003; Worobey et al. 2004; Keele et al. 2006; Van Heuverswyn et al. 2007; Li et al. 2010; Rudicell et al. 2010).

Figure 4.

HIV-1 origins. The phylogenetic relationships of representative SIVcpz, HIV-1, and SIVgor strains are shown for a region of the viral pol gene (HIV-1/HXB2 coordinates 3887–4778). SIVcpz and SIVgor sequences are shown in black and green, respectively. The four groups of HIV-1, each of which represents an independent cross-species transmission, are shown in different colors. Black circles indicate the four branches where cross-species transmission-to-humans has occurred. White circles indicate two possible alternative branches on which chimpanzee-to-gorilla transmission occurred. Brackets at the right denote SIVcpz from P. t. troglodytes (SIVcpzPtt) and P. t. schweinfurthii (SIVcpzPts), respectively. The phylogenetic tree was estimated using maximum likelihood methods (Guindon and Gascuel 2003). The scale bar represents 0.05 nucleotide substitutions per site.

Figure 5.

HIV-2 origins. The phylogenetic relationships of representative SIVsmm and HIV-2 strains are shown for a region of the viral gag gene (SIVmac239 coordinates 1191–1921). SIVsmm and SIVmac are shown in black; the eight groups of HIV-2, each of which represents an independent cross-species transmission, are shown in different colors. The phylogenetic tree was estimated using maximum likelihood methods (Guindon and Gascuel 2003). The scale bar represents 0.05 nucleotide substitutions per site.

Figure 6.

Tetherin function and virus specific antagonism in different primate hosts. (A) Mechanism of restricted virion release by tetherin; two alternative models are shown (for details, see Evans et al. 2010); (B) Viral antagonists of tetherin and their sites of interaction (indicated by arrows). Vpu associates with the trans-membrane domain of tetherin, Nef targets the cytoplasmic domain, and Env interacts either with the extracellular or the cytoplasmic domain (Kirchhoff 2010; Serra-Moreno et al. 2011). (C) Antitetherin function in HIV-1 and HIV-2 and their immediate simian precursors. SIVcpz acquired vpu and nef genes from different sources, the SIVgsn/mus/mon and SIVrcm lineages, respectively. During adaptation in chimpanzees, Nef (and not Vpu) evolved to become an effective tetherin antagonist. SIVgor and SIVsmm also use Nef to counteract tetherin. After transmission to humans, SIVcpz, SIVgor, and SIVsmm Nef were unable to antagonize human tetherin because of a deletion in its cytoplasmic domain. HIV-1 group M adapted by regaining Vpu-mediated antitetherin activity. The Nef and Vpu proteins of HIV-1 groups O and P remained poor tetherin antagonists. The Vpu of HIV-1 group N gained modest antitetherin activity, but lost the ability to degrade CD4. HIV-2 group A adapted by gaining Env-mediated antitetherin activity; whether HIV-2 groups B–H gained antitetherin function has not been tested. Proteins that are active against tetherin are highlighted in red, and those that are inactive are shown in gray (adapted from Kirchhoff [2010] and reprinted, with permission, from Elsevier ©2010).