The HIV-1 pandemic: does the selective sweep in chimpanzees mirror humankind's future?

Abstract

An HIV-1 infection progresses in most human individuals sooner or later into AIDS, a devastating disease that kills more than a million people worldwide on an annual basis. Nonetheless, certain HIV-1-infected persons appear to act as long-term non-progressors, and elite control is associated with the presence of particular MHC class I allotypes such as HLA-B*27 or -B*57. The HIV-1 pandemic in humans arose from the cross-species transmission of SIVcpz originating from chimpanzees. Chimpanzees, however, appear to be relatively resistant to developing AIDS after HIV-1/SIVcpz infection. Mounting evidence illustrates that, in the distant past, chimpanzees experienced a selective sweep resulting in a severe reduction of their MHC class I repertoire. This was most likely caused by an HIV-1/SIV-like retrovirus, suggesting that chimpanzees may have experienced long-lasting host-virus relationships with SIV-like viruses. Hence, if natural selection is allowed to follow its course, prospects for the human population may look grim, thus underscoring the desperate need for an effective vaccine.

Figure 1

Schematic representation of the HIV-1 genome and its gene products. The arrow indicates the transcription initiation site.

Figure 2

Map of the African continent, highlighting habitats of the four different chimpanzee subspecies. Populations that show evidence of contemporary natural infections with SIV_cpz strains are Pan troglodytes troglodytes (light orange) and P.t. schweinfurthii (dark orange). Superimposed is a diagram illustrating the cross-species transmission events that led to the emergence of HIV-1 group M, the initiator of the human pandemic [28]. The lower panel in the figure illustrates the speciation events in the homo-pan lineage. The arrow indicates the putative time span of the MHC repertoire reduction in the pan lineage.

Figure 3

Pie charts showing the presence/absence of MHC class I intron 2 lineages in humans and chimpanzees. A colored section in a pie indicates the presence of a particular intron 2 lineage in that species; red for MHC-A, blue for MHC-B, and orange for MHC-C.

Figure 4

MHC class I intron 2 sequences in humans (HLA) and chimpanzees (Patr). Only the polymorphic nucleotide positions are indicated. Identity to the consensus sequence (depicted at the top) is indicated by dashes. Substitutions and inserts are depicted by the conventional one-letter code; deletions are marked “x”. For instance, “-/A” indicates that differences in a particular sequence have been reported in the literature. The brackets indicate the division of the intron 2 alleles into lineages, and this is based on phylogenetic analysis. (The figure is adapted from De Groot N.G. et al., PNAS 99, 11748-11753, 2002).

Figure 5

Human (HLA) and chimpanzee (Patr) peptide-binding motifs of relevant MHC class I molecules, and the Gag protein regions that are potentially targeted. P2 and PΩ (carboxyl-terminus) represent the anchor-binding positions of the MHC class I molecules; amino acids that are preferred on these positions are indicated by the conventional one-letter code, whereas tolerated amino acids are indicated between brackets. Patr-B*01:01 has a peptide-binding motif that resembles that of HLA-B*57:01, and Patr-B*03:01 has a peptide-binding motif that resembles that of HLA-B*27:05. Parts of the Gag consensus sequences of HIV-1 (HBX2) and SIV_cpz are given (http://www.hiv.lanl.gov). A lower-case letter in the SIV_cpz consensus indicates a variable position. The HLA-B*27 and -B*57 CTL epitopes are indicated by red arrows. For the respective Patr class I molecules, blue arrows indicate the potential Gag epitopes that are tested in peptide-binding studies. Based on IC₅₀ (μM) values determined in peptide-binding competition assays, high (1) or intermediate (2) binding affinities of the peptides to their respective MHC class I molecule are indicated [109].

Figure 6

Conserved regions around the Mamu-B*008 epitopes Vif RL9 and Nef RL10 that can be targeted by HLA and Patr class I molecules. P2 and PΩ (carboxyl-terminus) represent the anchor-binding positions of the MHC class I molecules; amino acids that are preferred on these position are indicated by the conventional one-letter code, whereas amino acids indicated between brackets are tolerated. The epitopes Vif RL9 and Nef RL10 in SIV_mac239 are indicated by a red line [118]. For HIV-1 (HBX2) and SIV_cpz the consensus sequences surrounding these Vif and Nef epitopes are given (http://www.hiv.lanl.gov). A lower-case letter in the SIV_cpz consensus indicates a variable position. A red arrow indicates that the respective MHC class I molecule is predicted to target the SIV_mac239 consensus sequence. A grey arrow indicates prediction of the MHC molecule to target the SIV_cpz/HBX2 consensus sequence. SB stands for solid binding (affinity < 100 nM); WB stands for weak binding (affinity between 100 to 700 nM). Binding affinity of the peptides was predicted using the NetMHCpan algorithm [119], except for Patr-B*03:01 (white dotted arrows), for which binding was assumed based on agreement in the anchor binding positions.