HIV EVOLUTION Santiago Rios Master Proteòmica i Genòmica

History HIV (the virus that causes AIDS) probably transfers to humans in Africa between 1884 and 1924. 1970: African doctors see a rise in opportunistic infections and wasting . Western scientists and doctors remain ignorant of the growing epidemic. 1981: AIDS is detected in California and New York (probably enters around 1970) 1982: AIDS is reported among haemophiliacs and Haitians (probably enters around 1966) and in several European countries. The name AIDS Acquired Immune Deficiency Syndrome is created. 1983: Scientists identify HIV (initially called HTLV-III or LAV) as the cause of AIDS. Western scientists become aware that AIDS is widespread in parts of Africa. 1985: AIDS is found in China, and has therefore been seen in all regions of the world.

HIV (Human Immunodeficiency Viruses) Family Retroviruses gag: Gag polyprotein pol: enzymes reverse transcriptase, integrase, and HIV protease env: precursor to gp120 and gp41 Transactivators: tat, rev, vpr Other regulators: vif, nef, vpu Genome structure - 1. gag (group-specific antigen): codes for the Gag polyprotein, which is processed during maturation to MA (matrix protein, p17); CA (capsid protein, p24); SP1 (spacer peptide 1, p2); NC (nucleocapsid protein, p7); SP2 (spacer peptide 2, p1) and p6. - 2. pol: codes for viral enzymes reverse transcriptase (RNA->DNA), integrase (integrated DNA in host), and HIV protease (sintetize polyproteins). - 3. env (for "envelope"): codes for gp160, the precursor to gp120 and gp41, viral envelope - Transactivators: tat, rev, vpr (overexpression) Other regulators: vif, nef, vpu (manipulate the host's cellular machinery) LTR flanking functional genes. used by viruses to insert their genetic sequences into the host genomes. - Attacks the immune system, replicate slowly. Disease appears late. HIV-1 Groups, M (Major) 90%, O (Outlier) only Cameroon, and N (non-M/non-O), P great similar SIV gorillas. Genus Lentivirus HIV-1 (Groups M “Subtypes: A-K”, O, P and N)and HIV-2

ORIGINS OF HIV Sharp P.M. et al. 2011 Cold Spring Harb Perspect Med HIVs are the result of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) naturally infecting African primates. Known examples of cross-species transmissions, as well as the resulting viruses, are highlighted in red. SIVmacwas not a natural pathogen of macaques. Humans HIV-1 M infected by SIVcpz (chimpanze), SIVs crossed from monkeys to apes and from apes to humans. Sharp P.M. et al. 2011 Cold Spring Harb Perspect Med

Phylogeny of Pol sequences Cross-species transmission. HIV-1, HIV-2, and SIVmac highlighted in red; endogenous viruses are shown in purple SIV sequences suggested that ancestral SIVs existed only a few hundreds of years ago The great majority of lentiviruses are exogenous, meaning that they are transmitted horizontally between individuals  This host specific clustering indicates that the great majority of transmissions occur among members of the same species; however, there are also numerous documented instances when SIVs have crossed between species to the generation of new SIV lineages with substantial secondary spread. In addition, cross-species transmissions have generated mosaic SIV lineages through superinfection and recombination in species that already harbored an SIV The absence of SIVcpz from two of the four subspecies suggested that chimpanzees had acquired this virus more recently, after their divergence into different subspecies.

The phylogenetic relationships of representative SIVcpz, HIV-1, and SIVgor 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 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

Hybrid origin of SIV Clear breakpoint in SIVcpz between Pol and Env Differences. SIVcpz discordance. cross-species transmissions have generated mosaic SIV lineages through superinfection and recombination in species phylogenies of primate lentivirus Pol and Env sequences Species- specific strains of SIV have been identified in more than 20 species of African primates (2), but all, except SIVcpz, infect monkeys. Diversity plots across concatenated Gag, Pol, and Env sequences identified one clear breakpoint in SIVcpz between Pol and Env. Diversity plot comparing SIVcpz to 7 other SIV Phylogenies of primate lentivirus Pol and Env sequences Bailes E. et al, Hybrid Origin of SIV in Chimpanzees, Science 13 June 2003

Infection & Expantion Hypotesis Hunter theory Oral polio vaccine theory use chimpanze kidney cells. (Blancou P. et al, Polio vaccine samples not linked to AIDS, NATURE 2001) The contaminated needle theory for hunter body (Wolfe N.D. et al, Naturally acquired simian retrovirus infections in central African hunters, Lancet. 2004) The colonialism theory The conspiracy theory 4. none of the samples was positive when amplified with primers specific for chimpanzee nuclear DNA . Only macaque sequences were found. Pyhlogenetical diferences. 5. The colonialism theory (colonization camps were set up around the time that HIV was first believed to have passed into humans - the early part of the 20th century.)

Conclusions HIV is host-specific. HIVs are the result of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) naturally infecting African primates. The origin HIV pandemia is not clear. Other HIV types can occur by cross-species transmissions.

Bibliography Sharp P.M. and Hahn B.H., Origins of HIV and the AIDS Pandemic, Cold Spring Harb Perspect Med 2011;1 Hahn B.H. et al, AIDS as a Zoonosis: Scientific and Public Health Implications, Science 287, 607. 2000 Bailes E. et al, Hybrid Origin of SIV in Chimpanzees, Science 13 June 2003: Vol. 300 no. 5626 p. 113 Blancou P. et al, Polio vaccine samples not linked to AIDS, NATURE 26 April 2001: Vol. 410 Wolfe N.D. et al, Naturally acquired simian retrovirus infections in central African hunters, Lancet. March2004: 20;363(9413):932-7.

HIV-Cell Interaction HIV infect T-limfocits cells. Requires the presents of CD4 receptor and co-receptors CCR5 or CXCR4 Gp120 interact with CD4 receptor HIV nucleocapisde fusiona con membrana e inocula RNA strands and enzimes integrasa, protease and reverse transcriptase.

Co-receptors Conversely, populations with lower prevalence of the D32 CCR5 genotype might be expected to have a higher prevalence of HIV infection or a more rapid course of the epidemic. In the United States, a greater risk for HIV infection has been found among African-Americans than among Caucasians, when known risk factors, including social class, were controlled (61). The prevalence of the D32 CCR5 allele is lower in African-Americans than in Caucasians. While increasing HIV prevalence in parts of Asia and Africa may be attributed to social and demographic factors