THE LANCET

HIV series

HIV as the cause of AIDS

Françoise Barré-Sinoussi

The two known types of HIV are members of a family of primate . HIV, like other , contains a , which consists of the major capsid , the nucleocapsid protein, the diploid single-stranded RNA genome, and the viral protease, , and . HIV isolates show extensive genetic variability, resulting from the relatively low fidelity of reverse transcriptase in conjunction with the extremely high turnover of virions in vivo. These features of may have strong implications for vaccine development. Simian immunodeficiency from naturally infected animals differ from HIV in one fundamental respect: they do not cause disease in their natural hosts. Study of these viruses may therefore lead to information about the interaction between lentiviruses and immune response that could be exploited to combat AIDS.

Since the beginning of the AIDS RNA epidemic researchers have made gp120 great efforts to understand the nature of the disease and of its causal agent, the human immuno- PROT deficiency virus (HIV). The two known types of HIV—HIV-1 and INT HIV-21,2—belong to a family of primate lentiviruses whose other members infect African green RT monkeys (SIVagm), sootey mangabey monkeys (SIVsm), p17 mandrills (SIVmnd), sykes (MA) monkeys (SIVsyk), and p24 (CA) Gag (SIVcpz).3 I shall p7 review the structure and molecular p9 features of HIV and the other (NC) primate lentiviruses and their Figure 1: Schematic diagram of an HIV virion and electronmicrograph phylogenetic relationship and Location of the structural (see text) is indicated. Electronmicrograph by Dr P Gounon, variability, and discuss the Department of Electron Microscopy, Institut Pasteur. hypothesis of a recent simian origin of the AIDS virus. envelope. The matrix protein is involved in the early stages of the cycle and plays a part in the Structure and molecular features of HIV formation and transport of the preintegration DNA 4 Like other retroviruses, HIV virions (figure 1) contain a complex into the nucleus of the host (figure 2). The virus capsid, which consists of (a) the major capsid virion envelope consists of a lipid bilayer membrane, protein, p24; (b) the nucleocapsid protein, p7/p9; (c) the derived from the host cell, and a virally encoded diploid single-stranded RNA genome; and (d) the three tetrameric envelope protein complex, of which each viral enzymes, protease, reverse transcriptase, and subunit consists of two non-covalently-linked membrane integrase. Reverse transcriptase is the hallmark of a proteins, gp120 (the “outer” envelope protein, or SU) and this is capable of transcribing its and gp41 (the “transmembrane” protein, or TM) (figure genomic RNA into double-stranded DNA. This DNA 1). The envelope protein complex facilitates viral entry by copy of the retroviral genome is called a “”. After binding to CD4, the main cellular receptor for all primate integration into the host genome, the provirus serves as a lentiviruses,5 via the outer envelope protein, gp120. The template for cellular DNA-dependent RNA transmembrane protein, gp41, is involved in the fusion of to generate new viral RNA genomes as well as shorter with cellular membrane.6,7 subgenomic messenger RNAs. The unspliced and singly- These viral structural proteins are encoded by different spliced viral RNAs are translated into the protein genes (figure 3). The matrix protein, p17, the major components of the viral core and the envelope proteins capsid protein, p24, and the nucleocapsid protein, p7/p9, and the multispliced viral RNAs into the small are encoded by the first open reading frame (gag in figure accessory/regulatory proteins. 3) and the protease, reverse transcriptase, and integrase The viral capsid is surrounded by a matrix protein by the second open reading frame ( in figure 3). The (p17; figure 1), which is located underneath the virion viral protease is required for generation of individual proteins by proteolytic processing from the gag precursors Lancet 1996; 348: 31–35 and gag/pol precursor proteins.6,7 The envelope precursor protein, gp160, is encoded by Retrovirus Biology Unit, Institut Pasteur, 25 Rue de Docteur Roux, the env gene and processed by a cellular protease into the 75724 Paris Cedex 15, France (Prof F Barré-Sinoussi PhD) two envelope proteins, gp120 and gp41.

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first viral components produced from multiply spliced Retrovirus viral mRNA. The vif and vpu proteins respectively influence the infectivity of cell-free virions and the release of virions from infected cells.12,13 seems to be involved in the replication of HIV in non-dividing cells.14 Membrane fusion Binding of HIV The pronounced variability of HIV isolates was noted soon after the diversity and sequence analysis of the first 15 Receptor isolates from different patients. There is sequence variation even within patients, and this observation led to Uncoating the term “quasispecies” to reflect the presence in infected Reverse individuals of a “swarm” of viruses rather than a single Endocytosis isolate.16 During the course of infection the frequency distribution of individual virus variants changes. Reflecting this evolution of virus variants in vivo, the replication potential of virus isolates and their ability to infect cells increases as the clinical disease progresses.17 Prviral integration The relatively low fidelity of reverse transcriptase, Nucleus combined with the extremely high turnover of virus in vivo (recent estimates put the rate of virus production in the order of 109 virions/day), provides the basis for the Cytoplasm continuous emergence of new virus variants.18–20 Consequently, HIV-1 acquires resistance to all antiviral Assembly drugs rather rapidly21 and escape mutants to neutralising 22,23 Budding antibodies and cytotoxic T cells may emerge in vivo. Whilst drug-resistant virus mutants create obvious Maturation problems for antiviral chemotherapy, the importance of immune escape mutants for the pathogenesis of HIV-1 is not entirely clear. Individual HIV-1 genes differ in their variability. The Figure 2: Life cycle of HIV replication gag and pol genes are much more conserved than env. Tat HIV virions enter host cells after binding to the cellular receptor, CD4, and likewise vary, but to a lesser extent than the and envelope protein complex mediated fusion of the viral lipid envelope and env genes. Within the env gene, constant and variable with the cellular membrane. After entering the cytoplasm and initiation 24 of reverse transcription, the preintegration complex is targeted to the domains have been defined. Some of the more variable nucleus where the completed provirus is integrated into the host regions—eg, the V1/V2 and V3 domains—are the target genome. Production of new virus particles is initiated by the for neutralising antibodies in patient sera and are exposed transcription of new viral RNAs. Full-length RNA molecules require rev 25–27 for their export from the nucleus and provide new viral genomic RNAs as at the surface of monomeric envelope protein subunits. well as templates for the production of the core proteins and viral There is some evidence that sequence variability in these enzymes. Singly-spliced viral mRNAs give rise to new envelope proteins, regions may be due to immune selection, and that this and most accessory proteins (see text) result from the translation of 22,28 multispliced mRNAs. Viral core proteins and enzymes are synthesised as can result in a change in tropism. two high molecular weight precursor proteins in the cytoplasm and At a functional level, HIV isolates can differ in their processed into the individual components by the viral protease. Much of tropism for cells of different lineages. While the CD4 this processing occurs after budding of new virions. The envelope are synthesised as a precursor protein in the endoplasmic molecule is required for efficient entry of all HIV-1 reticulum/Golgi compartments and processed by a cellular protease. variants, some variants are able to infect macrophages and Assembly of new virions occurs at the plasma membrane immediately others show a preferential tropism for T cells.29 before release of new virions. Macrophage-tropic virus variants may be more effective at In addition to these structural proteins, found in all infecting across a mucosal barrier, and subsequent in-vivo retroviruses, all complex primate lentiviruses contain a evolution may lead to the emergence of more T-cell tropic series of accessory proteins. All primate lentiviruses variants.30 In human beings, a minority virus species contain the , rev, vif, and nef genes; HIV-1 and SIVcpz among the variants present in the “infecting partner” contain vpu; HIV-2, SIVsm, SIVmac, and SIVagm seems to be transmitted sexually.31 Thus, virus variants contain ; and all primate lentiviruses with the exhibiting a certain tropism may be required for exception of SIVagm contain vpr. transmission, leading to the de-novo evolution of virus The function of the tat protein8,9 is to upregulate variants with an increased replication/fusion potential in transcription from the viral promoter, the U3 region of each infected individual. This model would explain why the long terminal repeats (LTR) (figure 3) by binding to HIV does not increase its with each passage nascent RNA transcripts. The rev protein promotes the from one individual to the next. export from the nucleus of unspliced or singly spliced The variability of HIV has been exploited to establish viral RNAs which act, respectively, as genomic transmission chains (as in the case of the Florida dentist), RNA/template for the translation of gag/pol proteins and to follow HIV evolution in vivo, and to document the template for envelope proteins. In the absence of rev, no entry of HIV into defined populations (eg, intravenous structural proteins are made. The nef protein seems to be drug users) and its subsequent spread.32,33 required for efficient replication in vivo.9–11 Tat, rev, and Extensive genetic analysis has revealed that HIV-1 nef are not incorporated into virion particles but are the isolates fall into two distinct groups, now designated M

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vpr tat pol tat vpu net HIV-1 SIVcpt HIV-1gag SIVcpt vif rev env LTR LTR rev

gag vif vpr env HIV-2 SIVmac, SIVsm vpx tat nef pol rev LTR LTR rev

vpx env tat SIVagm pol tat nef gag vif LTR rev rev LTR

rev tat vpr nef SIVmnd pol tat rev gag vif env LTR LTR vpr rev tat nef SIVsyk pol rev gag vif env LTR tat LTR

Figure 3: Genome maps of different primate lentiviruses The position of the genes for the individual viral proteins discussed in the text is indicated. and O.34 Most HIV-1 isolates belong to the M group. question began when a closely related virus was identified Within the M group there are at least ten subtypes (A to in wild-living West African monkeys, the sooty J), which are separated from each other by equivalent mangabeys. Over the past several years, SIVs have been genetic distances and differ in their geographic found in diverse species of wild-caught monkeys in distribution. Subtype B is predominant in western Africa.3 They all have the same complex genomic and the USA. Several subtypes exist in Africa.34,35 In organisation as HIVs, and an exceptional level of viral Thailand, subtype B is thought to have been introduced diversity. However, despite a similar genome mainly through intravenous drug use, and subtype E organisation, individual primate species differ mainly through sexual transmission.36 We still do not with respect to the absence or presence of some accessory know whether such a separate introduction of B and E genes (see above). viruses is due to subtle differences in the biological The existence of five distinct groups of primate properties of individual HIV-1 subtypes. lentiviruses was further confirmed by sequence analyses, HIV-1 group O strains have so far been found in from which our current understanding of the origin and 37 individuals originating from Africa. They are sufficiently molecular evolution of HIVs and SIVs derives.42,43 First, divergent from group M strains (aminoacid homology in the phylogenetic trees, constructed from sequence data env of only 55%) to be missed by some serological assays. (figure 4), suggested that primate lentiviruses probably It is widely held that the existence of different HIV-1 evolved from an ancient common ancestor. According to groups and subtypes in different countries would necessitate the development of individual vaccines, by estimated dates of genetic diversification, this analogy with A and B. This assumption is phenomenon may have occurred at least 600–1200 years 44,45 supported by the apparent specificity of neutralising ago. The hypothesis that primate lentiviruses have antibodies in patient sera for individual subtypes.38 been around for a very long time accords with the species However, recent reports suggest efficient cross- specificity found for SIVagm.46 The findings of a fifth neutralisation of HIV-1 subtypes by at least some patient lineage of primate lentiviruses (SIVsyk) and the apparent sera, so whether subtype-specific vaccines will be required evolutionary link between SIVagm and SIVsm led to the remains controversial.39 hypothesis of a radiation of primate lentiviruses from the Cercopithecus monkey species.3,47 The evolutionary trees Evolution of primate lentiviruses also provided evidence for a phylogenetic relation The discovery of HIV-2 in West Africa40 and its between human and monkey viruses (figure 4): HIV-1 similarities with simian immunodeficiency viruses (SIVs), was found to cluster with SIVcpz and HIV-2 with SIVsm. first identified in captive macaques in North America,41 Over the past few years, the assumption of a recent simian raised the possibility of a link between human and origin of HIVs has become more and more convincing, non-human primate lentiviruses. Research into this with an abundance of epidemiological and virological

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Human immunodeficiency virus type 1 variants with increased replicative capacity develop during the asymptomatic have occurred and the origin of HIV-1 group O remains stage before disease progression. J Virol 1994; 68: 4400–08. to be clarified. A similar problem of branching order 18 Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human became apparent for HIV-2 (figure 4) with the immunodeficiency virus type 1 infection. Nature 1995; 373: 117–22. 48 19 Ho DD, Neumann AU, Perelson AS, et al. Rapid turnover of plasma identification of various subtypes. The findings of a virions and CD4 lymphocytes in HIV-1 infection. Nature 1995; 373: human virus as the earliest diverging branch and the 123–26. clustering of SIVsm within only one lineage of HIV-2 20 Coffin J. Genetic diversity and evolution of retroviruses. Curr Topics Microbiol Immunol 1992; 176: 143–64. (figure 4) again raise the question of its origin.42,43,45 In 21 Richmann DD. HIV drug resistance. 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Department of ethics Survey of British clinicians’ views on management of patients in persistent vegetative state

Andrew Grubb, Pat Walsh, Neil Lambe, Trevor Murrells, Sarah Robinson

Summary doctors who thought treatment-limiting decisions could be appropriate thought that such decisions could be Background The best care and management of patients in considered with the first 12 months of the patient being in persistent vegetative state (PVS) has been the subject of PVS. Despite recent case law, less than half the doctors sustained moral and legal debate for a number of years. responding to the survey thought that an advance directive However, the views of clinicians in the UK involved in caring made by the patient should have a decisive influence in for patients in PVS are largely unknown. determining treatment-limiting decisions. Most doctors Methods A postal questionnaire was sent to 1882 would like decisions about withdrawing ANH to be made in consultant members of the British Association of conjunction with family members and in accordance with Orthopaedic Surgeons, the Association of British agreed guidelines but without the need to go to court. Neurologists, the Society of British Neurosurgeons, and the Interpretation There is a broad consensus among doctors British Society of Rehabilitation Medicine. Their views were that treatment-limiting decisions are sometimes sought on various aspects of the management and care of appropriate for patients in PVS, irrespective of whether they PVS, in particular the appropriateness of a decision not to have experience of the condition or of the specialty to treat and a decision to withdraw artificial nutrition and which they belong. However, two thirds of doctors said that hydration (ANH). such decisions can be considered at a time earlier than that Findings 1027 doctors responded (55%) of whom 558 recommended by the British Medical Association. It is not (54%) had experience of managing patients in PVS. Over clear why some doctors thought a decision not to treat 90% of responding doctors considered that it could be could be appropriate while a decision to withdraw ANH appropriate not to treat acute infections and other life- would not be. threatening conditions. 65% of doctors considered that Lancet 1996; 348: 35–40 withdrawal of ANH could be apporpriate. About two-thirds of Introduction Centre of Medical Law and Ethics, King’s College London, Strand, The best management and care of patients in a persistent 1 2 London WC2R 2LS, UK (Prof A Grubb MA, P Walsh BA, N Lambe Ll B), vegetative state (PVS) remains controversial despite and Nursing Research Unit, King’s College London (T Murrells MSc, several consensus statements about definitions and S Robinson BSc) terminology.3,4 There are different approaches to Correspondence to: Prof Andrew Grubb management,5–7 and clinical decision-making is further

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