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1 : Discovery, Structure, Heterogeneity, and Origins of HIV
This chapter discusses the discovery of human immunodeficiency virus (HIV) type 1 (HIV-1) and HIV-2, their structural and genetic features, and their classification and proposed origin. Molecular techniques have helped to define the variations in the viral genome associated with HIV heterogeneity. The amplification of parts of a viral genome by PCR followed by DNA sequencing has been very helpful in conducting rapid comparisons of different sequences among HIV-1 and HIV-2 isolates. After examining sequence variations among the three HIV-1 groups and the several HIV-1 subtypes or clades, several investigators have proposed that HIV-1 entered the human population from primates as early as 30 to 100 years ago. The existence of clades can reflect the extensive heterogeneity of HIV-1 and HIV-2 that results from the high mutation rate from the viral error-prone RT, its rapid replicative ability (24 h), and its extensive progeny production (i.e., 1,000 virions/cell). Consideration of lentiviruses from other animal species whose origins remain a mystery also suggests that the simian and human viruses could have evolved independently from a progenitor lentivirus that entered the animal kingdom thousands of years ago. The emergence of HIV has alerted public health officials and governments worldwide to the constant threat of new infectious agents that can be spread rapidly. Research on HIV and approaches for its control should provide insights into future microbial challenges to the wellbeing of human and animal populations.
An HIV virion with the structural and other virion proteins identified. The exact locations of Nef and Vif in association with the core have not been well established. The abbreviated viral protein designations are those recommended (2484).
Processing of viral proteins. Some HIV-1 proteins, which are translated from 10 distinct viral transcripts, are further processed by viral and cellular proteases. From 46 translated open reading frames, which include Tev (not diagrammed), 16 viral proteins are made. They form the virion structure, direct viral enzymatic activities, and serve regulatory and accessory functions. The Gag-Pol precursor of 160 kDa is processed by the viral (aspartyl) protease into seven proteins, which include four Gag proteins (MA, p17; CA, p24; late domain, p7; and NC, p9), protease (P, p10), reverse transcriptase/RNase (RT, p66, p51), and integrase (IN, p32). The Env precursor (gp160) is processed by a cellular protease into the surface glycoprotein (SU, gp120) and the transmembrane glycoprotein (TM, gp41). Viral regulatory and accessory proteins, which include Tat (p14), Tev (p20), Rev (p19), Nef (p27), Vif (p23), Vpr (p15), and Vpu (p16), are not processed. M, myristoylated. Figure provided by M. Peterlin.
Estimated similarities in amino acids for the different HIV-1 gene products. Figure compiled from data analyzing several early HIV-1 isolates worldwide (3185) and provided by C. Kuiken.
Restriction enzyme differences among various HIV isolates. HUT 78 T cells were acutely infected with HIV-1SF2 (formerly ARV-2) (lane 1), SF-4 (lane 3), and SF-19 (lane 4). Lane 2 contains a HUT 78 line chronically infected with HIV-1SF2. High-molecular-weight DNA was prepared from whole cells and treated with restriction enzymes and blotted as described previously (2541). Panel A contains undigested high-molecular-weight cell DNA. The positions of unintegrated forms of HIV-1 DNA are shown. IN, integrated; NC, nicked circles; L, linear (9.7 kb); S, supercoils. Integrated viral DNA in undigested DNA samples is at the exclusion limit of the agarose gel (greater than 20 kDa). Reprinted from reference 2541 with permission.
DNA heteroduplex tracking analysis of HIV envelope gene quasispecies collected over 6.5 years and of derived isolates. The Env V3–V5 region was nested PCR amplified from longitudinally collected PBMC starting at seroconversion (labeled in years starting at year 0) and from two in vitro-amplified cultures (labeled C with year of origin). Time zero PCR product was radiolabeled and reannealed to excess DNA from the same and other samples. Labeled DNA heteroduplexes were separated by nondenaturing polyacrylamide gel electrophoresis and exposed by autoradiography. Analysis shows clearance over time of the earliest time zero variant reflected by the disappearance of the fastest-mobility labeled DNA homoduplex, increasing genetic diversity noted by the large number of DNA heteroduplex bands, and appearance of slow labeled mobility heteroduplexes. The cultured isolates show reduced genetic diversity relative to the uncultured PBMC samples. Provided by E. Delwart.
Two representations, vertical (A) and radial (B), of the same phylogenetic tree. The distances between the HIV-1, M, N, and O groups, and the M group, are illustrated. At the tip of each branch is a modern sequence, and the phylogeny is an attempt to reconstruct their evolutionary relationships—which viruses are most closely related and how far they have evolved. In the radial tree (B) there is no root, but the branching order is identical to the phenogram (A). The branch length reflects the genetic distance, or the number of mutations that could have occurred between two sequences as they diverged from a shared ancestor. Only the horizontal branch lengths are counted in the phenogram, and the sum of the branch lengths between any two sequences is the same in either representation. This tree was made using the program PAUP and is a neighbor-joining tree. Provided by B. Korber and the Los Alamos HIV Database.
Map along the HIV-1 genome showing the patterns of recombination in the two most common circulating recombinant forms, CRF01 and CRF02. Such recombinants are complex and can be important as major epidemic strains. Provided by B. Korber and C. Calef.
HIV-1 is the predominant HIV type distributed throughout the world, but HIV-2, which is less common, has still been found in West Africa and most recently in India at an increasing rate. The distribution of the various subtypes (clades) of the HIV-1 M group is indicated by letters. The HIV-2 groups are not shown separately. Source, UNAIDS, 1996.
Evolutionary relationships of SIVcpz and HIV-1 strains based on maximum-likelihood phylogenetic analyses of full-length envelope protein sequences. SIVcpz strains from P. troglodytes troglodytes and P. troglodytes schweinfurthii are highlighted in red and blue, respectively. Representative strains of HIV-1 groups M, N, and O are included for comparison. Asterisks indicate internal branches with estimated posterior probabilities of 95% or higher. The scale bar denotes 10% replacements per site. Reprinted from reference 4074 with permission.
Relationship between the degree of genetic diversity of a genotype and the duration of the epidemic in a region. Each curve represents the expected distribution of intrasubtype nucleotide substitution frequencies, expressed as a percentage, among all possible pairs of a typical sample of sequences from a country or area. Examples named reflect the most recently reported genetic divergence. The width of each curve represents the approximate range of these frequencies, and the height represents the relative proportion of pairs with that frequency of substitution. Genetic divergence is believed to increase at a rate of approximately 0.5 to 1% per year. Reprinted from reference 4726 with permission.
Unrooted phylogenetic tree showing the relationship of HIV-2 groups and SIVsm representatives inferred from the complete genome alignment by maximum likelihood. The numbers near the nodes indicate the percentage of bootstrap replicates supporting a clade. Bootstrap values greater than 70% are shown. The scale indicates substitutions per site and refers to the branch lengths. Reprinted from reference 964a with permission.
Genomic maps of HIV-1 and HIV-2. Note the unique presence of Vpu in HIV-1 and Vpx in HIV-2. Reprinted from reference 2518 with permission. Copyright © 1989, American Medical Association. All rights reserved.
Immunoblot analyses showing antibody reactions with HIV-1, HIV-2, and SIV proteins. (A) Serum from an African patient with HIV-1 and HIV-2 infections was tested for reactivity against electrophoretically separated cell lysates containing HIV-1 (lane 1) and SIVmac (lane 2). Note the differential detection of the envelope gp160 and gp120 proteins. (B) Proteins from purified HIV-1 (lane 1) and HIV-2 (lane 2) isolates were reacted with serum from an HIV-1- or HIV-2-infected individual. Reprinted with permission from reference 1231. Copyright 1988 AAAS.
(A) Scanning electron micrograph of budding particles, most probably HIV, on the surface of a T lymphocyte. This process can incorporate cell surface proteins onto the surface of the virus and has been considered responsible in part for false-positive reactions in enzyme-linked immunosorbent assay (3941). Antibodies to normal T-cell proteins (e.g., HLA and CD4) could show a positive reaction. Photomicrograph courtesy of H. Gelderblom. (B) Transmission electron micrograph of HIV replicating in a T cell. Photomicrographs provided by R. Munn.
Average CD4+ cell count at diagnosis of an AIDS-defining condition a
Characteristics common to lentiviruses
Comparison of HIV and HTLV a
Features of HIV-2 infection that could explain its less pathogenic nature compared to HIV-1 infection
HIV proteins and their functions
Infection rate of HIV groups and clades a
Sequence similarities between SIV and HIV a