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Chapter 32 : The Human Retroviruses Human Immunodeficiency Virus and Human T-Lymphotropic Virus
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This chapter provides an overview of the currently known exogenous human retroviruses and the diseases associated with them. For handling of clinical specimens, all retroviruses, including human immunodeficiency virus (HIV) and human T-lymphotropic retrovirus (HTLV), are classified as biological agents of moderate risk. The currently used Centers for Disease Control and Prevention (CDC) 1993 classification is based on a combination of clinical and CD4 T-cell count categories that defines nine mutually exclusive stages. Western blot (WB) is preferable to in-house methods of confirmation like radioimmunoprecipitation assay, since the commercial WB kits are better standardized and much easier to run. HTLV-1 is associated with a number of inflammatory disorders in addition to adult T-cell leukemia or lymphoma (ATLL). Virus isolation should not only be evaluated with HTLV-specific tests (antigen assay or immunofluorescence) but, where available, also by assays for particle-associated RT, preferentially product-enhanced RT (PERT) assay. Finally, both allogeneic and autologous bone marrow transplantation are evaluated as possible treatments of ATLL.
HIV replication cycle. (A) Overview. (B) Reverse transcription. The retroviral genome contained in virions consists of RNA. Its characteristic features include terminal repeats (R), U5 (5′ untranslated), U3 (3′ untranslated), 3′ polyadenylation, a binding site for a tRNA which serves as the primer for reverse transcription, and the encapsidation signal Ψ. During reverse transcription, the viral RNA is reverse transcribed into double-stranded DNA, and terminal sequences are partially duplicated in a way that leads to an LTR composed of U3-R-U5. (C) Unintegrated circular DNA is a short-lived by-product of provirus integration; its presence in a cell sample indicates actively replicating virus. (D) Genomic organization of HIV-1 and HIV-2. The hatched boxes denote ORFs for proteins which are contained in particles. Drawing modified from Schüpbach, 2003b.
Origin of HIV-1 and HIV-2. (A) Phylogenetic tree of primate lentiviruses, derived from Pol protein sequences. Numbers 1 to 5 indicate the five major lineages. HIV-1/U455 is a group M, subtype A isolate. ELI is of group M, subtype D, and LAI is of group M, subtype B. ANT70 and MVP5180 represent group O, and YBF30 is group N. ROD and EHO represent different subtypes of HIV-2. SIVcpzGAB1, SIVcpzUS, and SIVcpzANT are chimpanzee (cpz) isolates. mnd, mandrill; agm, African green monkey; syk, Sykes’ monkey; sm, sooty mangabey. The bar at the bottom denotes genomic diversity. (B) Phylogenetic tree showing the relationship of HIV-1 groups M, N, and O to chimpanzee and gorilla (gor) lentiviruses, respectively. Combined and modified from Sharp et al., 1994, Gao et al., 1999, and Van Heuverswyn et al., 2006.
Translational products of HIV-1 and particle composition. (A) Translation. The open boxes in the genome representation at the top denote ORFs of the accessory proteins Tat, Rev, Nef, Vif, Vpr, and Vpu, which are translated into proteins of final size. The hatched boxes denote ORFs translated into precursor proteins. The products of the gag, pol, and env genes are synthesized as polyprotein precursors. The principal Gag precursor, Pr55Gag, is cleaved by the viral protease (PR or p10) into the matrix (MA) protein p17, the capsid (CA) protein p24, and a C-terminal protein p15, which is subsequently cleaved into p7 and the nucleocapsid (NC) protein p9. Cleavage of Pr160Gag-Pol, which is produced by ribosomal frameshifting at the gag-pol junction, yields PR, RT, and IN. All three enzymes remain dimerized after cleavage. RT first forms a homodimer, p66-p66, which is subsequently modified into the heterodimer, p66-p51. The Env precursor gp160 is glycosylated in the Golgi system, oligomerizes into dimers and trimers, and is cleaved by a cellular protease into the SU protein gp120 and the smaller TM protein gp41. The small arrows indicate protease cleavage sites. (B) Localization of viral proteins in mature virions.
Propagation of HIV from the mucosal entry port to the lymphatics and the bloodstream. FDC, follicular DC.
Virologic and immunologic parameters in the typical course of HIV infection.
Kit design and test performance of HIV screening tests. Synopsis of the most frequently used test formats, their principles, the meaning of positive results, and performance in two typical problem situations. Ag, antigen; Ab, antibody; hu, human.
Example of a false-positive HIV-1 WB interpretation according to ASTPHLD-CDC or Consortium for Retrovirus Serology Standardization guidelines. Lanes: a, weakly positive control; b, sample from a healthy individual exhibiting weak reaction with gp160, gp120 (very weak), and p24 (this sample was taken 3.5 months after an initial sample with the same pattern [data not shown]); c, sample from the same individual taken 1 month after the initial sample. p24 antigen with signal amplification-boosted ELISA was negative in all three plasma samples. PCR for viral DNA was negative in PBMC from the samples in lanes b and c, and RNA was negative in the sample in lane b. Culture with PBMC depleted of CD8 T cells from the sample in lane b was negative for p24 antigen and RT by the PERT assay; this test was also negative with the samples in lanes b and c.
Algorithms for diagnosis of HIV infection in adults. The darker shading represents algorithms of U.S. guidelines; the lighter shading illustrates possible alternatives. Reprinted from Schüpbach, 2003b, with permission.
Phylogenetic relationships of PTLV based on polymerase (pol; 662 bp). Sequences isolated from humans in the study by Wolfe et al. (2005) are shown in boxes. Support for the branching order is based on 1,000 bootstrap replicates; only values of 60% or more are shown. Branch lengths are proportional to the evolutionary distance (scale bar) between the taxa. Taxa abbreviations are: Ppn, Pan paniscus (bonobo); Mto, Macaca tonkeana (Celebes macaque); Ppa, Papio papio (Guinea baboon); Cto, Cercocebus torquatus (red-capped mangabey); Tge, Theropitecus gelada (gelada baboon); Pha, Papio hamadryas (sacred baboon). Reprinted from Wolfe et al., 2005, with permission.
HTLV-1 ORFs and transcription map. A scheme of the HTLV-1 genome, alternatively spliced mRNAs, and putative proteins encoded by each mRNA is shown. ORFs are indicated by boxes. Nucleotide numbering starts from the first nucleotide in the mRNA. Reproduced from Nicot et al., 2005, with permission.
Feedback regulation of HTLV-1 gene expression by Tax and Rex. Spontaneous viral expression of Tax from doubly spliced viral transcript. (1) Tax further activates subsequent viral transcription; (2) Rex encoded by the same mRNA as Tax suppresses splicing of viral RNA. (3) Thus, there is accumulation of unspliced mRNAs which express Gag, Pol, and Env proteins on the one side but downregulation of Tax/Rex expression and shutoff of transcription on the other side. Reprinted from Yoshida, 2005, with permission.
Morphology of ATLL cells. Note the typical nuclear indentations (flower cells). Reprinted with permission from Feller and Diebold, 2004.
Natural course from HTLV-1 infection to onset of ATLL. HTLV-1 is transmitted in a cell-to-cell fashion. After infection, HTLV-1 promotes clonal proliferation of infected cells by pleio-tropic actions of Tax and other viral proteins. Proliferation of HTLV-1-infected cells is controlled by cytotoxic T cells in vivo. After a long latent period, ATLL develops in about 5% of asymptomatic carriers. In ATLL, the expression of Tax is inactivated by several mechanisms, suggesting that Tax is no longer necessary in the ATLL stage. Alternatively, alterations and errors in the host genome accumulate progressively during the latent period, finally leading to onset of ATLL. Reprinted from Taylor and Matsuoka, 2005, with permission.
Epidemiologic map of HTLV-1. Countries with a prevalence between 1 and 5% in some populations are shown darkly shaded. Countries with a prevalence of less than 1% in some groups, due mainly to immigration from areas of endemicity, are shown lightly shaded. Note that areas of HTLV-1 endemicity do not correspond exactly to the country boundaries shown in the map. For example, HTLV-1 in Brazil, Japan, and Iran is limited to distinct areas within each country. Modified from Proietti et al., 2005, with permission.