 |
|
|
|
|
Origin and Pathogenesis of HIV
Origin of HIV There are at least five different primate retroviruses belonging to the Lentivirus genus. Two of these infect humans: human immunodeficiency viruses type 1 (HIV-1) and human immunodeficiency virus type 2 (HIV-2). Both appear to have resulted from cross-species transmission from non-human primates: HIV-1 from chimpanzees and HIV-2 from sooty-mangabeys. At least three cross-species transmissions of HIV-1 appear to have occurred leading to HIV-1 group M (Main), group O (Outlier), and group N (non-M, non-O) viruses. The global AIDS pandemic is caused by an HIV-1 group M virus which probably began its spread among humans during the first half of this century (6). HIV-2, which is limited primarily to West Africa, shares about 50% sequence similarity with HIV-1 and causes a form of immunodeficiency that is similar to HIV-1 but which is less rapidly progressive. HIV-2 is limited primarily to West Africa. The remainder of this chapter describes the HIV-1 genome, its replication, and the mechanisms by which it causes disease. Throughout this book the abbreviation HIV is used to refer primarily to HIV-1 because nearly all of what is known about the treatment of these viruses and their complications is based on data from persons infected with HIV-1. [Review Article: Woolhouse MEJ. Where Do Emgerging Pathogens Come from? Microbe 2006;1(11):511-515.]
HIV Genome and Replication HIV is an enveloped virus containing two copies of positive-stranded RNA. It has nine genes: gag, pol, env, tat, rev, nef, vif, vpu, and vpr. gag codes for structural proteins including core, matrix, and nucleoprotein. pol codes for enzymes including protease, reverse transcriptase (RT), and integrase. env codes for the transmembrane (gp41) and extracellular (gp120) envelope glycoproteins. tat, rev, and nef regulate the HIV transcription following its integration into the host genome. vif, vpu, and vpr code for accessory proteins (4). HIV enters CD4+ T lymphocytes through a complex interaction that involves the binding of gp120 first to CD4 and then to a second receptor, either CCR5 or CXCR4. This triggers a process by which gp41 is in position to mediate fusion between HIV and the host cell membrane. Intracellularly, the RT enzyme reverse transcribes the RNA genome to cDNA and then catalyzes the synthesis of a second copy of DNA to create double-stranded DNA. The integrase enzyme then catalyzes the insertion of HIV DNA into the host genome through a series of staged reactions that involve circularizing the virus genome, transporting it to the nucleus, nicking the 3'-ends of the virus and cellular DNA to enable genomic integration (5). To complete its replication, the virus is transcribed into genomic RNA and mRNA coding for each of its proteins. This process depends on the chromosomal location at which HIV is integrated, the state of cellular activation, and the actions of the regulatory genes tat, rev, and nef. Following transcription, HIV is translated into Gag, Gag-Pol, and envelope polyproteins. A host protease cleaves the envelope polyprotein into gp41 and gp120 and then cell budding proceeds by the association of genomic RNA, the immature gag and gag-pol polyproteins, and the envelope proteins. Following budding, HIV protease cleaves the gag polyprotein into the structural proteins of the virus and the gag-pol polyprotein into the structural and enzymatic proteins of the virus. Video: Fusion and Cell Entry and Fusion Inhibition HIV Pathogenesis HIV replication kills productively infected CD4+ T lymphocytes and innocent bystander cells. Three main virus features have interfered with control of infection by the immune system and vaccination. First, the virus infects and destroys the very immune cells that are needed to control infection, possibly initially honing in on those cells that specifically target HIV antigens. Second, the virus mutates at an extraordinary high rate, generating billions of new variants each day (1). Finally, the virus creates a latent proviral DNA reservoir that is resistant to the effects of the immune system but which may reactivate at any time during the course of infection. Viral Dynamics HIV exists extracellularly within virions as in its double-stranded RNA form and intracellularly as either unintegrated double-stranded DNA or as integrated proviral DNA. During acute HIV infection, plasma HIV RNA levels range from 105 to 107 copies/ml and drop about 1- 2 logs after seroconversion as equilibrium develops between virus replication and immunologic containment. In a chronically infected untreated individual, on the order of 103-106 virions/ml are present in plasma; whereas the concentration of virus in lymph nodes is usually two-to-three orders of magnitude higher. This steady-state level is highly variable among patients and is strongly predictive of disease progression (8, 9). HIV develops approximately one mutation during each cycle of virus replication, generating genetically diverse quasispecies in infected individuals (1, 7). The accumulation of latent proviral variants and recombination between virions with different mutations adds to the complexity. The high mutation rate of the virus and its integration into the human genome not only interfere with immune control but also limit the efficacy of antiretroviral therapy and prevent HIV eradication. HIV Diversity The extraordinary degree of genetic diversity of the group M (Main) HIV has been categorized into 9 pure subtypes (A, B, C, D, F, G, H, J, K) and several common recombinant forms (6, 10). Although most isolates in North America and Europe are subtype B, this subtype accounts for only a small proportion of HIV isolates worldwide and non-B isolates are being identified with increasing frequency. Most serologic assays detect all HIV-1 group M subtypes. The three available virus load assays quantify the most commonly occurring non-B subtypes (e.g. subtypes A, C, A/E, and A/G) but whether they are as reliable for these subtypes as for subtype B has not been definitively shown. The currently approved antiretroviral drugs appear to be as active against non-B subtype viruses as they are against subtype B viruses. But there may be subtle differences in the genetic basis of resistance to therapy among the non-B viruses. Targets of Drug Therapy The HIV-1 protease enzyme is an aspartic protease composed of two non-covalently associated, structurally identical monomers 99 amino acids in length. The hydrophobic substrate cleft recognizes and cleaves 9 different peptide sequences to produce the matrix, capsid, nucleocapsid, and p6 proteins from the gag polyprotein and the protease, RT, and integrase proteins from the gag-pol polyprotein. Currently available protease inhibitors are generally peptidomimetic compounds in which the scissile peptide bond has been replaced by a non-cleavable transition-state analog (3). The RT enzyme is responsible for RNA-dependent DNA polymerization, ribonuclease H mediated degradation of the original RNA template, and DNA-dependent DNA polymerization. RT is a heterodimer consisting of p66 and p51 subunits. The p66 subunit contains the DNA-binding groove and the active site; the p51 subunit displays no enzymatic activity and functions as a scaffold for the enzymatically active p66 subunit. The p66 subunit has five subdomains including the "fingers", "palm", and "thumb" subdomains that participate in polymerization, and the "connection" and "RNase H" subdomains (11). Nucleoside RT inhibitors (NRTIs) are nucleoside analogs that compete with natural nucleotide triphosphates for incorporation into the newly synthesized viral DNA chains where they cause chain termination. NRTIs are prodrugs that must be triphosphorylated intracellularly to become active inhibitors. Nucleotide inhibitors (e.g. tenofovir) because they already have one phosphate moiety, require the intracellular addition of only two phosphates. Because they act by a similar mechanism nucleotide inhibitors are also abbreviated as NRTIs. The non-nucleoside RT inhibitors (NNRTIs) are a diverse set of compounds that bind to a hydrophobic pocket in the RT enzyme that is close to, but not contiguous with, the active site. These compounds inhibit HIV-1 replication allosterically by displacing the catalytic residues relative to the viral nucleic acid template and primer. The HIV envelope glycoprotein consists of two noncovalently associated subunits, gp120 and gp41. Portions of gp120 bind to both the CD4 receptor and to one of the chemokine receptors on target cells. After gp120-CD4-coreceptor binding, the gp41 subunit undergoes a conformational change that promotes fusion of viral and cellular membranes (2). The currently available fusion inhibitors are peptides that correspond to predicted regions of gp41 sequences and interfere with the conformational change required for fusion. Video: Targeting HIV Replication HIV Life Cycle and Drug Interaction
REFERENCES 1. Coffin JM. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 1995;267:483-489. [PubMed] 2. Eckert DM, Malashkevich VN, Hong LH, Carr PA, Kim PS. Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket. Cell 1999; 99:103-15. [PubMed] 3. Erickson JW, Gulnik SV, Markowitz M.. Protease inhibitors: resistance, cross-resistance, fitness and the choice of initial and salvage therapies. AIDS 13. 1999; Suppl A:S189-S204. [PubMed] 4. Frankel AD, Young JA. HIV-1: fifteen proteins and an RNA. Annu Rev Biochem 1998;67:1-25. [PubMed] 5. Greene WC, Peterlin BM. Charting HIV's remarkable voyage through the cell: Basic science as a passport to future therapy. Nat Med 2002;8:673-80. [PubMed] 6. Korber B, Muldoon J, Theiler F, Gao R, Gupta A, Lapedes BH, Hahn S, Wolinsky, Bhattacharya T. Timing the ancestor of the HIV-1 pandemic strains. Science 2000;288:1789-1796. [PubMed] 7. Mansky LM. Retrovirus mutation rates and their role in genetic variation. J.Gen.Virol. 1998;79:1337-1345. [PubMed] 8. Mellors JW, Munoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P, Kingsley LA, Todd JA, Saah AJ, Detels R, Phair JP, Rinaldo CR, Jr. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann.Intern.Med. 1997;126:946-954. [PubMed] 9. O'Brien TR, Rosenberg PS, Yellin F, Goedert JJ. Longitudinal HIV-1 RNA levels in a cohort of homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:155-61. [PubMed] 10. Robertson DL, Anderson JL, Bradac JA, Carr JK, Foley B, Funkhouser RK, Gao F, Hahn BH, Kalish ML, Kuiken CL, Learn GH, Jr, Leitner T, McCutchan FE, Osmanov S, Peeters M, Pieniazek D, Salminen MO, Sharp PM, Wolinsky S, Korber B. 2000. HIV-1 nomenclature proposal: A reference guide to HIV-1 classification, p. 492-505. In C. L. Kuiken, B. Foley, B. H. Hahn, P. Marx, F. E. McCutchan, J. Mellors, J. I. Mullins, S. Wolanski, and B. Korber (ed.), Human retroviruses and AIDS: a compilation and analysis of nucleic and amino acid sequences. Los Alamos National Laboratory, Los Alamos, NM. [PubMed] 11. Sarafianos SG, Das K, Ding J, Boyer PL, Hughes SH, Arnold E. 1999. Touching the heart of HIV-1 drug resistance: the fingers close down on the dNTP at the polymerase active site. Chem Biol 1999;6:R137-46. [PubMed]
|
|