Lectures for the XXIst Century

The Origins of Human Retroviruses

127 the oriGins of human retroviruses anne-mieke vandamme introduction Retroviruses are RNA viruses which reverse transcribe their genomic RNA into proviral double stranded cDNA. This DNA is then integrated into the host genome. There are only two human retroviruses known (Fig 1), the Human T-Cell Lymphotropic Virus (HTLV) and the Human Immunodeficiency Virus (HIV). Both are associated with fatal diseases. The first to be discovered, HTLV, causes adult T-cell leukaemia (ATL) or HTLV associated myelopathy , also known as tropical spastic paraparesis (HAM/TSP) in a minority of infected individuals. If untreated, HIV causes an acquired immunodeficiency syndrome, AIDS, in all infected people . Fig.1. Taxanomic classification of the Retroviridae based on their evolutionary relationships. Adapted from Van Dooren, 200. A phylogenetic tree was reconstructed from 34 representative retroviral reverse transcriptase sequences, encompassing amino acids 48 to 238 of the HTLV-1 RT, using a maximum likelihood method. The values on the left side of the nodes represent statistical support values. The taxanomic classification in genera is superimposed onto the tree. The taxa in bold are representative of the viruses described in this paper. 128 simian reLatives of htLv and hiv Simian relatives of HTLV have been identified and, phylogenetically , there is no clear separation between simian and human strains. Consequently, this virus is often called primate T-cell lymphotropic virus (PTLV). PTLV-1 has human and simian representatives , with STLV-1 present in all major old world monkey and ape species. HTLV-1 now has 7 clades (HTLV-1a up to -1g), all interspersed between simian clades (Fig 2). Within PTLV-2, there are three HTLV-2 clades (HTLV-2a, -2b, and -2d), while STLV-2 is found only in bonobos (pygmy chimpanzees). Unlike HTLV-1, all HTLV-2 clades cluster neatly together, separate from STLV-2. A third type, PTLV-3, is found in many African monkey species but currently has only 2 known human counterparts, each of them clustering separately among the STLV-3 strains. For the fourth type, HTLV-4, only one human strain is known, although it is anticipated that a simian relative must exist. Fig.2. Phylogenetic relationship between STLV-1 and HTLV-1 strains using a 22 nt consensus fragment in the env region. The human strains are indicated, the simian strains have symbols marked according to the host species. Adapted from Vandamme et al, 1998. Among immunodeficiency viruses, a similar relationship is known between human and simian strains, and the name Primate Immunodeficiency Virus (PIV) is sometimes used. Until recently, 6 clear 129 lineages were identified, but more and more new SIVs are being characterized, such that the PIV tree tends to resemble more a bush than a tree of clades. However, only 2 types of simian viruses are also present in humans: the three clades of HIV-1 (group M, N and O) are each related to different chimpanzee (groups M and N) and gorilla viruses (group O), and all clades of HIV-2 (currently 8) are related to SIVs found in sooty mangabeys (Fig. 3). Fig.3. Phylogenetic relationship between SIV and HIV strains using a partial gag-pol fragment. The simian strains are named according to the host species with an illustration of the host species as inset photographs. Adapted from Lemey, 200. 130 GLoBaL ePidemioLoGy of htLv and hiv Among the HTLV-1 subtypes, HTLV-1a is found worldwide, but has foci of high prevalence (up to 12% in some areas) in the Caribbean basin, Latin America, Africa, the Middle East, Japan, and Taiwan. In Europe, it is mostly found among immigrants from these regions. Five other HTLV-1 subtypes, HTLV-1b, -1d, -1e, 1f , and -1g, are found only in central Africa, while HTLV-1c is restricted to Melanesian-Australian endemic populations. Endemic HTLV-2 is found only among a few remote indigenous populations of African (HTLV-2d) and Amerindian (HTLV-2a and -2b) origin. HTLV-2a and -2b have also been found sporadically in Africa, but have however spread worldwide in the intravenous drug user (IDU) population. Only very recently, two novel human viruses, HTLV-3 and HTLV-4, were discovered in bushmeat hunters of Cameroon. The total HTLV infected population is estimated to be around 20 million people, with few infections in Europe. Fig.4. A global view of HIV infection, 2007. 33 million people (30-36 million) living with HIV. Adapted from UNAIDS 2008 estimate. HIV is widely spread across...