HIV

0
908





Untitled Document

  • Family Retroviridae
    • Has reverse transcriptase,
    • converts a single-stranded RNA viral genome into double-stranded viral DNA.
    • Retroviridae contain two genera
      • Lentivirus (MCQ)
        • includes HIV-1 and -2
      • human T-cell lymphotropic virus–bovine leukemia virus group (HTLV-BLV group),
        • contains HTLV-1 and -2
    • HTLV-1 is associated ( MCQ)
      • adult T-cell leukemia (ATL)
      • HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP).
    • Retrovirus structure
      • Retroviruses are enveloped particles
      • The viral envelope, is formed from the host cell membrane
        • The full-length protein, called gp160, is cleaved into two peptides by a viral protease. ( MCQ)
          • "gp" indicates that the protein is glycosylated
          • resulting transmembrane protein is called gp41, or TM ( MCQ)
          • resulting surface exposed portion of the protein is called gp120, or SU. ( MCQ)
        • Host cell proteins, including MHC class II proteins, are also found in the envelope.
      • The virion has a cone-shaped, icosahedral core
        • contain the major capsid protein called p24, or CA.
        • outer matrix protein (p17, or MA) ( MCQ)
          • present between the capsid and the envelope
          • directs entry of the double-stranded DNA provirus into the nucleus
          • essential for the process of virus assembly.
      • unlike other viruses, retroviruses are diploid
        • There are two identical copies of the positive-sense, single-stranded RNA genome in the capsid
      • RNA is tightly complexed with a basic protein (p7, or NC)
      • nucleocapsid structure that differs in morphology among the different retrovirus genera.
      • Enzymes within the capsid are the
        • reverse transcriptase
        • integrase (which are required for viral DNA synthesis and integration into the host cell chromosome) ( MCQ)
        • protease (essential for virus maturation). ( MCQ)
  • Human immunodeficiency virus
    • HIV-1 is more virulent, more infective, and more widespread geographically,
    • HIV-2 is not as virulent and is localized exclusively to West Africa.
    • Organization of the HIV genome (A very High yield fact for Exam)
      • HIV RNA genome contains three major genes: gag, pol, and env
        • gag gene ( MCQ)
          • encodes p17 (MA), p24 (CA), and p7 (NC) (core and matrix proteins).
        • pol gene  ( MCQ)
          • encodes reverse transcriptase, protease, integrase, and ribonuclease
        • env gene ( MCQ)
          • encodes gp41 (TM) and gp120 (SU) (transmembrane and sur- face proteins).
    • HIV replication
      • first phase of HIV replication 
        • includes
          • viral entry
          • reverse transcription
          • integration of the virus into the host genome
        • accomplished by proteins provided by the virus
      • second phase of replication
        • includes  synthesis and processing of viral genomes, mRNAs, and structural proteins,
        •  uses the host cell machinery for transcription and protein synthesis
      • Attachment to a specific cell surface receptor
        • accomplished via the gp120 fragment of the env gene product ( MCQ)
        • preferentially binds to a CD4 receptor molecule
        • Thus, the virus infects
          • helper T cells, lymphocytes
          • monocytes
          • dendritic cells
      • Entry of virus into the cell
        • An additional coreceptor, a chemokine receptor, is required for entry of the viral core into the cell
        • A chemokine is a cytokine with chemotactic properties, produced by lymphocytes and macrophages
        • Two chemokine receptors employed by HIV –  CCR5 and CXCR4( MCQ)
        • tropism of particular variants of HIV is determined, in part, by which coreceptor is present
        • Binding to a coreceptor activates the viral gp41 gene product, triggering fusion between the viral envelope and the cell membrane  ( MCQ)
      • Reverse transcription of viral RNA
        • This process takes place in the cytoplasm
        • reverse transcriptase enzyme has no proofreading capacity
        • errors often occur during the conversion of genomic RNA into the DNA provirus
        • This error-prone process gives rise to 1 to 3 mutations per newly synthesized virus particle.
      • Integration of the provirus into host cell DNA:
        • The provirus, still associated with virion core components, is transported to the nucleus with the aid of p17 (MA). ( MCQ)
        • In the nucleus, viral integrase cleaves the chromosomal DNA and covalently inserts the provirus. ( MCQ)
        • The integrated provirus, thus, becomes a stable part of the cell genome and can never be eliminated
      • Transcription and translation of integrated viral DNA sequences:
        • provirus is transcribed into a full-length mRNA by the cell RNA polymerase II. ( MCQ)
        • The genome-length mRNA has at least three functions
        • Some copies will be the genomes of progeny virus and are transported to the cytoplasm in preparation for viral assembly
        • Some copies are translated to produce the virion gag proteins
        • Still other copies of viral RNA are spliced, creating new translatable sequences
      • Regulation:
        • Nonstructural genes encode a variety of regulatory proteins that have diverse effects on the host cell and on viral replication
        • nef and vpu gene products  ( MCQ)
          • down-regulate host cell receptors, including CD4 and major histocompatibility complex class I molecules.
          • These products enable efficient virus replication and viron production
        • Rev and Tat proteins ( MCQ)
          • produced from differentially spliced mRNAs
          • Tat protein causes the host cell RNA polymerase to be more processive by preventing premature dissociation from the DNA template, which results in full-length HIV RNAs.
          • Rev protein interacts with specific viral mRNAs to enable their transport out of the nucleus, bypassing the splicing machinery
      • Assembly and maturation of infectious progeny:
        • Env polyprotein is processed and transported to the plasma membrane by the usual cellular route through
        • the Golgi apparatus and cleaved into SU and TM molecules by a host cell protease.
        • Assembly begins as the genomes and uncleaved Gag and Gag-Pol polyproteins associate with the TM-modified plasma membrane.
        • As the virion buds from the surface, viral protease is activated and cleaves the polyproteins into their component proteins, which then assemble into the mature virion
        • Cleavage is a necessary step in the maturation of infectious virus. ( MCQ)
    • Transmission of HIV
      • Sexual contact
        • HIV, present in both semen and vaginal secretions
        • transmitted primarily as cell-associated virus
        • Transmission occur in the course of either homosexual or heterosexual contact.
        • syphilis and chancroid result in genital ulcerations, may greatly facilitate HIV-1 infection.
        • nonulcerative STDs  also enhance HIV transmission due to replicative syn- ergy between the viral and bacterial pathogens.
      • Transfusions
        • transmitted by transfusion with whole blood, plasma, clotting factors, and cellular fractions of blood.
      • Contaminated needles
      • Perinatal transmission:
        • An HIV-infected woman has a 15 to 40 percent chance of transmitting the infection to her newborn ( MCQ)
        • Transmission occur either
          • Transplacentally
          • during passage of the baby through the birth canal
          • via breastfeeding
    • Pathogenesis
      • progression from HIV infection to AIDS develops in 50 percent of HIV-infected individuals in an average of 10 years ( MCQ)
      • if untreated, it is uniformly fatal, generally within 2 years of diagnosis
      • about 10 percent of HIV- infected individuals have not developed AIDS after 20 years.
    • Phases during development from HIV infection to end-stage AID
      • Initial infection
        • initially infected cells are generally macrophages within the genital tract. HIV disseminates via the blood
        • virus localize in dendritic cells throughout the lymphoid tissue.
        • From the surface of follicular dendritic cells, HIV can then infect CD4+ lymphocytes moving through the germinal centers of lymph nodes.
        • a reservoir of chronically HIV- infected cells develops within the lymphatic tissue throughout the body
        • Some individuals are resistant to some variants of HIV-1 due to a deletion in the gene that encodes the coreceptor (C-C chemokine receptor type 5, or CCR5) for the virus. ( MCQ)
      • Acute phase viremia
        • Occurs several weeks after the initial infection with HIV
        • one-third to two-thirds of individuals experience an acute disease syndrome
        • Large amounts of virus and capsid protein (CA antigen) are present in the blood
        • circulating antibody does not appear until 1 to 10 weeks after the initial infection (seroconversion). ( MCQ)
        • During this window of time, antibody tests will not identify HIV-infected people.
        • Lymph nodes also become infected during this time and later serve as the sites of virus persistence during the asymptomatic period.
      • Latent period
        • acute phase viremia is eventually reduced significantly with the appearance of a HIV-specific cytotoxic T-lym- phocyte response, followed by a humoral antibody response.
        • A clinically asymptomatic or “latent” period lasting from months to many years follows the acute infection.
        • During this latent period, 90 percent  of HIV proviruses are transcriptionally silent ( MCQ)
        • only 10 percent of the cells containing integrated HIV DNA also contain viral mRNA or viral proteins
        • Clinical complications of HIV infection during the latent period –
          • persistent, generalized lymphadenopathy (swollen lymph nodes)
          • diarrhea; chronic fevers; night sweats; and weight loss
          • herpes zoster and candidiasis, may occur repeatedly during this period
      • Progression to AIDS:
        • coinfection with a number of the herpesviruses, such as human her- pesvirus type 6 can transactivate transcription from the silent HIV provirus, increasing HIV replication.
        • This transition is accompanied by the appearance of a CXCR4-tropic virus variant, whereas the infecting variants tend to be CCR5- tropic. ( MCQ)
        • these variants are often highly syncytium-inducing, pro- moting fusion between infected and previously uninfected cells
        • With the CD4+ count falling below 200/ml and the appearance of increasingly frequent and serious diseases and opportunistic infections (“AIDS- defining illnesses”), the patient is said to have AIDS. ( MCQ)
      • End-stage AIDS:
        • Cell types other than CD4+ lymphocytes can be infected by HIV.Infection
        • AIDS encephalopathy, and severe dementia.
          • microglia are the HIV-infected cells present in brain is responsible ( MCQ)
          • This is unrelated to CD4+ depletion but, rather, to an expanded tropism of variant HIV.
        • Wasting syndrome seen in late stages of AIDS
          • HIV-infected macrophages produce various cytokines, especially tumor necrosis factor. ( MCQ)
        • HIV infection of blood cell progenitors in the bone marrow leads to the anemia seen in most AIDS patients.
    • Opportunistic infections in AIDS:
      • nervous system opportunistic infections
        • Toxoplasma, Cryptococcus, JC virus, and mycobacteria
      • eye can be infected with HIV, CMV
      • lungs are primarily affected by
        • P. jirovecci pneumonia ,Mycobacterial infections
      • GI tract illnesses
        • HIV infection. CMV colitis ,Protozoal parasitic diseases, gram-negative enteric bacteria
      • Recurrent infections by EBV, varicella zoster virus, human papillo- mavirus, and herpes simplex virus are common
      • Mucocutaneous candidiasis (oral, esophageal, or vaginal)
      • HIV

  • Malignancies associated with AIDS
    • Kaposi sarcoma
      • most characteristic neoplasm present in AIDS
      • associated with human herpesvirus, type 8 (HHV-8) ( MCQ)
      • involves skin, mucous membranes, and deep viscera
    • CNS lymphomas,
    • body cavity lymphomas associated with HHV-8 infection ( MCQ)
    • EBV associated lymphomas
  • Laboratory identification
    • Demonstration of virus or virus components:
      • Polymerase chain reaction (PCR)
        • Amplification of viral RNA or DNA proviruses
        • most sensitive method for early detection of virus in blood or tissue specimens. ( MCQ)
        • quantitative estimates of viral load
        • amount of viral RNA per milliliter of blood plasma
        • permit evaluation of the
          • stage of the disease
          • effectiveness of a drug regimen
          • prognosis.
      • ELISA (for enzyme-linked immunosorbent assay) testing
        • Done for purposes of initial screening of the blood supply
        • Done for the CA (p24) antigen in serum ( MCQ)
        • can detect otherwise undetectable infection in individuals who are infectious by screening for anti-HIV antibodies.


      Transmission and Prevention of HIV
      The modes of transmission of HIV are numerous. This animation describes the common and less common ways in which HIV can be transmitted from one person to another. While HIV is most commonly spread from an infected person through vaginal or anal intercourse, as well as intravenous blood exposure through the sharing of needles, there are practices and measures that you can take to help minimize the risk of becoming infected.
      HIV and AIDS
      HIV Replication 3D Medical Animation
      Targeting HIV replication

      The replication of HIV 1 is a multi-stage process.

      Each step is crucial to successful replication and is therefore a potential target of antiretroviral drugs.

      Step one is the infection of a suitable host-cell, such as a CD4-positive T-lymphocyte.

      Entry of HIV into the cell requires the presence of certain receptors on the cell surface, CD4 — receptors and co-receptors such as CCR5 or CXCR4.

      These receptors interact with protein-complexes, which are embedded in the viral envelope.

      These complexes are composed of two glycoproteins:

      an extracellular gp 120 and
      a transmembrane gp 41

      When HIV approaches the target cell gp120 binds to the CD4-receptors. This process is termed attachment.

      It promotes further binding to a co-receptor. Co-receptor binding results in a conformational change in gp120.

      This allows gp41 to unfold and insert its hydrophobic terminus into the cell membrane.

      Gp 41 then folds back on itself.

      This draws the virus towards the cell and facilitates the fusion of their membranes.

      The viral nucleocapsid enters the host cell and breaks open releasing two viral RNA-strands and 3 essential replication enzymes:

      Integrase, Protease and Reverse Transcriptase.

      Reverse Transcriptase begins the reverse transcription of viral RNA.

      It has two catalytic domains:

      The Ribonuclease-H active site

      And the polymerase active site

      Here single stranded viral RNA is transcribed into an RNA-DNA double helix. Ribonuclease- H breaks down the RNA.

      The polymerase then completes the remaining DNA-strand to form a DNA — double helix.

      Now Integrase goes into action.

      It cleaves a dinucleotide from each 3-prime end of the DNA creating two sticky ends.

      Integrase then transfers the DNA into the cell nucleus and facilitates its integration into the host cell genome.

      The host cell genome now contains the genetic information of HIV.

      Activation of the cell induces transcription of proviral DNA into messenger RNA.

      The viral messenger RNA migrates into the cytoplasm where building blocks for a new virus are synthesised.

      Some of them have to be processed by the viral protease.

      Protease cleaves longer proteins into smaller core proteins.

      This step is crucial to create an infectious virus.

      Two viral RNA-strands and the replication enzymes then come together and core proteins assemble around them forming the capsid.

      This immature particle leaves the cell acquiring a new envelope of host and viral proteins.

      The virus matures and becomes ready to infect other cells.

      HIV replicates billions of times per day destroying the hosts` immune cells and eventually causing disease progression.

      Drugs which interfere with the key steps of viral replication can stop this fatal process.

      Entry into the host cell can be blocked by fusion inhibitors for example.

      Inhibition of reverse transcriptase by nucleoside inhibitors or by non-nucleoside Reverse Transcriptase- inhibitors is part of standard antiretroviral regimens.

      The action of Integrase can be blocked.

      Protease inhibitors are also part of standard antiretroviral therapy.

      Each blocked step in viral replication is a step towards better control of HIV disease.
      When HIV Becomes AIDS (HIV #2)
      HIV and AIDS are not the same thing, but the virus can lead to the disease. Learn how in this video.
      HIV life cycle: How HIV infects a cell and replicates itself using reverse transcriptase
      Howard Hughes Medical Institute, HHMI’s BioInteractive Animations: „HIV life cycle — How HIV infects a cell and replicates itself using reverse transcriptase and the host’s cellular machinery.” From the 2007 Holiday Lectures „AIDS — Evolution and Epidemic”