(1) HIV Epidemiology (A ratcliffe) Flashcards
HIV the virus- what is it’s structure?
Family: retroviridae
Subfamily : Lentivrinae
Genus = Lentivirus
Single stranded positive sense RNA genome of 9.7 kilobases.
2 strands of HIV RNA- each with a copy of the virus’s 9 genes.
What are the 9 genes in the virus?
• 9 genes- very small virus
o Not a particularly infective virus
o Compared to 500 genes found in bacterium
• 3 = gag, pol, env – contain information needed to make structural proteins for new virus particles
• 6 = known as tat, rev, nef, vif, vpr and vpu, code for proteins that control the ability of HIV to infect a cell, produce new copies of virus or cause disease.
• At either end of each strand of RNA is a sequence called the long terminal repeat, which helps control HIV replication
HIV entry- explain the four steps
- Attachment
- Receptor binding
- Co receptor binding
- Membrane fusion- reverse transcriptase uncoats which makes HIV impossible to eradicate once it is established. DNA of the cell integrates into host genome. Addition of HIV proteins by other genes are used to assemble new proteins and bud from the cell.
What is the primary target of the HIV virus?
Primary target of the HIV virus => dendritic cells in mucosal genital tract -> These dendritic cells transport HIV into lymph nodes => The virus then infects CD4 lymphocytes -> receptors for HIV are CD4 molecules on surface subset lymphocytes. * Co-receptors are also necessary for entry.
Explain how HIV gains entry into a cell- which proteins are used etc
High affinity receptor for HIV-1 that is located on lymphocytes, macrophages and dendritic cells.
• Interaction between gp120 and CD4 is the initial step in viral attachment inducing the conformational change in gp120 required for coreceptor binding “When spaceship comes down on HD4 membrane, in close contact, this is when the fusion can occur.”
• The CD4 binding site is located at the base of the gp120 core
• Following viral attachment, flexible segments of the CD4 molecule allow gp120 to drop down
onto the co receptor, bringing the virus and cell membranes into close contact.
What is important about the envelope glycoprotein gp120 and gp41?
Gp120 constitutes the outer membrane subunit of env protein
• Binds CD4 and chemokine receptors expressed on the surface of T helper lymphocytes (and other cells including cells of the macrophage lineage) and dendritic cells (DC)
Gp41 is the transmembrane subunit by which gp120 is anchored to the viral membrane
- Gp41 contains the fusion protein that is ultimately inserted into the host cell membrane leading to host cell-HIV-1 membrane fusion
Pathogenesis of HIV
Although >98% lymphocytes in lymph nodes, GALT or spleen, the new viruses produced flood the blood and are transported to all tissues within a matter of days. Viraemia may be up to millions virus/mm3. This is the Primary HIV infection.
• Anti-HIV antibodies develop- broadly neutralizing
• Cytotoxic T cells proliferate
o CD8cells
• CD4 count drops – 70-100/year
• Age and genetic actors affect progression
Cytotoxic T lymphocyte responses, helper T cell functions, and humoral responses = some of the acquired factors that modulate the risk of transmission in highly exposed persistenly seronegative individual and could also contribute to spontaneous control of replication in long term non progressors.
The putative protective role of cytotoxic T lymphocyte activity has been suggested in seronegative sex workers and in some long term non progressors.
What is the antibody response to HIV infection?
Antibodies appear late, after primary viraemia is controlled.
Structure of ENV gp120 reveals a cloaked glycoprotein largely masking potential AB neutralization epitopes.
Broad and potent Nab reactivity may involve multiple antibodies against a wide variety of epitopes.
Explain CD8 and cytotoxic lymphocyte responses in HIv infection
Massive expansion of CD8+ CTL in early infection and correlation with control of primary viraemia before appearance of antibodies.
Association of specific HLA alleles with viral loads
CTL escape mutants correlated with loss of immune control of viremia and progression to AIDs.
Explain the cellular immune responses in HIV infected individuals
Evidence suggests that Gag-specific T lymphocyte responses may be relevant for immune control. Gag epitope breadth associated with control of viral replication in chronically infected HIV-1 infected individuals
When can you test for HIV?
Can find HIV virus between 4-6 weeks from infection. New tests are much more effective and pick up HIV-1 antibody and p24 antigen.
Explain the progression of HIV
• Monitored by progressive loss of CD4 count and monitoring HIV viral load
• Host factors influencing progression
o Genetic polymorphisms of multiple chemokine receptors, chemokine proteins and related cytokines
->CCR5 32 -> co receptor which is reduced cell surface expression CCR5
- >Mutations in CCR2-641
• Viral factors
o Attenuated viruses such as nef deleted isolates
o Viruses which use CXCR4 appear more pathogenic
• Highest trisk of transmission are in acute and last stage of disease o Asinacuteyouhavealargeviralload.
How do we define post treatment controlers?
In 2010, a second group of patients who initiated ART during acute infection, and controlled HIV for several years after interruption of ART was identified
o These so called post treatment cotrollers are very rare,and unlike elite controllers, do not show strong HIV specific CD8 T cell responses or have protective HLA alleles
What are elite controllers?
A functional care is achieved spontaneously by a rare group of individuals who naturally control HIV replication without treatment (so called elite controllers)
o These patients are characterised bya favourable HLAprofile and potent HIVspecific CD8 T cell responses that are associated with a low viral DNA reservoir
How is HIV transmitted?
HIV can be transmitted through:
• Unprotected sexual intercourse (vaginal or anal) with an infected person
• Transfusions of contaminated blood
• Sharing of contaminated needles, syringes or other sharp instruments
• The transmission between a mother and her baby during pregnancy, childbirth and
breastfeeding.
HIV continued to be transmitted primarily through sexual contact between men. There was a similar per capita rate of HIV diagnosis in the Aboriginal and Torres Strait Islander and non-indigenous populations. Higher proportions of cases were attributed to heterosexual contact and injecting drug use in aboriginal and torres strait islander population
