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Aids
- 3. 107 cases of Pneumocystis carinii pneumonia reported in the United States before the AIDS epidemic AIDS epidemic has resulted in 166,368 cases up to 1999 HIV and AIDS History of an infectious agent Pneumocystis pneumonia www.freelivedoctor.com
- 4. HIV and AIDS With dissemination to extrapulmonary sites, Pneumocystis carinii tends to produce foci with prominent calcification, as seen in the kidney www.freelivedoctor.com
- 6. Before 1981: 40 - 120 cases per year in United States HIV and AIDS an infectious agent – Kaposi’s Sarcoma 1981-1999: 46,684 definite cases in United States www.freelivedoctor.com
- 12. HIV and AIDS Obvious agent: A virus …… that is now in the blood supply Primary route of transmission: Sex AIDS is a sexually-transmitted viral disease www.freelivedoctor.com
- 13. HIV and AIDS The Cellular Picture In advanced disease: the loss of another cell type CD8+ cytotoxic killer cells Loss of one cell type throughout the course of the disease CD4+ T4 helper cells A fall in the CD4+ cells always precedes disease Suggests an infectious agent A virus But initially difficult to grow Rapidly kills cells on which it grows www.freelivedoctor.com
- 17. HIV and AIDS www.freelivedoctor.com
- 18. HIV and AIDS AIDS Deaths Prevalaence www.freelivedoctor.com
- 19. HIV and AIDS Black White Hispanic www.freelivedoctor.com
- 21. Life Expectancy Sub Saharan Africa www.freelivedoctor.com
- 22. www.freelivedoctor.com Impact of AIDS on life expectancy in five African countries, 1970–2010 Life expectancy at birth (years) Source: United Nations Population Division (2004). World Population Prospects: The 2004 Revision, database. Botswana South Africa Swaziland Zambia Zimbabwe 1970–1975 1975–1980 1980–1985 1985–1990 1990–1995 1995–2000 2000–2005 2005–2010 70 65 60 55 50 45 40 35 30 25 20 4.1
- 23. Botswana Zimbabwe Lesotho Swaziland www.freelivedoctor.com HIV prevalence (%) in adults in Africa, 2005 2.5
- 24. H uman I mmunodeficiency V irus www.freelivedoctor.com
- 26. HIV and AIDS The cellular and immunological picture - The course of the disease virus CD4 cells antibody www.freelivedoctor.com
- 27. HIV and AIDS The cellular and immunological picture - The course of the disease CD8 cells www.freelivedoctor.com
- 29. HIV and AIDS 2. A strong immune response www.freelivedoctor.com
- 30. HIV and AIDS 3. A latent state www.freelivedoctor.com
- 32. HIV and AIDS 4. The beginning of disease www.freelivedoctor.com
- 34. HIV and AIDS Good correlation between number of HIV particles measured by PCR and progression to disease www.freelivedoctor.com
- 35. HIV and AIDS Viral load predicts survival time www.freelivedoctor.com
- 36. HIV and AIDS CD4 cell count is not a good predictor of progression to disease www.freelivedoctor.com
- 37. Cofactors Not all cases of Kaposi’s are associated with HIV Not all HIV infected persons suffer from Kaposi’s 20% of homosexual HIV+ males get Kaposi’s Few IV drug users or hemophiliacs get Kaposi’s Kaposi’s sarcoma associated herpes virus Human herpes virus-8 HIV and AIDS www.freelivedoctor.com
- 38. HIV and AIDS So far it seems that >50% of HIV-infected persons have progressed to AIDS There is NO strong evidence there is any other infectious agent involved than HIV Three Views of AIDS Gallo : Infection by HIV is sufficient to cause AIDS Montagnier : HIV may be harmless in the absence of other co-factors Duesberg / Mullis : HIV is too silent to be the etiologic agent of AIDS. It is a much maligned by-stander www.freelivedoctor.com
- 39. HIV - The Virus Membrane: host derived Retrovirus Three genes GAG – POL – ENV Three polyproteins www.freelivedoctor.com
- 40. HIV - The Virus vaccine problem Retrovirus ENV gene www.freelivedoctor.com Two glycoproteins: gp160 gp120 and gp41 gp41 is fusogen that spans the membrane sugars
- 41. HIV - The Virus GAG gene Group-Specific Antigens Retrovirus Polyprotein www.freelivedoctor.com p17: inner surface - myristoylated p24: nucleocapsid p9: nucleocapsid associated with RNA
- 43. The Genome of HIV Three structural genes LTRs Extra open reading frames are clue to latency These ORFs code for small proteins - antibodies in AIDS patients www.freelivedoctor.com
- 44. HIV - The Virus www.freelivedoctor.com
- 47. HIV - Life History Entry into the cell T4 (CD4+) cells are major target Human HeLa Cell Human HeLa Cell transfected with CD4 antigen NOT INFECTED INFECTED But NOT the whole answer since this does not happen if CD4 is transfected into a MOUSE cell www.freelivedoctor.com
- 48. HIV - Life History Why do CD4-transfected human cells become infected but CD4-transfected mouse cells do not? Human cells must possess a co-factor for infection that mouse cells do not www.freelivedoctor.com Co-Receptors CD8+ Cells MIP-1 alpha MIP-1 beta RANTES Chemokines Block HIV infection of macrophages
- 49. HIV - Life History CD4 CD4 CD4 HIV CCR5 CCR5 chemokine Mutant CCR5 macrophage Chemokine receptors are necessary co-receptors along with CD4 antigen www.freelivedoctor.com
- 50. HIV and AIDS Some people do not get AIDS Long term survivors Exposed uninfected persons The chemokine receptor story www.freelivedoctor.com
- 56. HIV - Life History HIV infection is not manifested as disease for years During apparent clinical latency, virus is being replicated and cleared Latency – Cellular – The problem of memory T4 cells Only activated T4 cells can replicate virus Most infected T4 cells are rapidly lyzed but are replaced Some T4 cells revert to resting state as memory cells which are long-lived Memory T4 cells cannot replicate the virus unless they become activated Clinical Latency www.freelivedoctor.com
- 57. Dynamics of CD4 T cells in an HIV infection Cell death apoptosis etc Uninfected activated T cell Cell death immune destruction www.freelivedoctor.com Chronically-infected memory T cells with provirus Return to resting state Reactivation Uninfected unactivated memory T cell pool Infection Long lived! Long lived!
- 58. Long term latent HIV T4 resting memory cell It may be impossible to cure the patient of HIV Even if combination therapy stops HIV replication www.freelivedoctor.com Immune response T4 activated HIV production
- 59. Inexorable decline of CD4+ T4 cells Of great importance to therapeutic strategy Why do all of the T4 cells disappear? At early stages of infection only 1 in 10,000 cells is infected Late 1 in 40 www.freelivedoctor.com
- 60. But few cells are infected: Early stage of infection 1:10,000 Late 1:40 Why do all T4 cells disappear? 1. PUNCTURED MEMBRANE Virus destroys the cell as a result of budding www.freelivedoctor.com
- 61. Why do all T4 cells disappear? - 2 But syncytia not common Most T4 cells are not HIV+ Could “sweep up” uninfected cells Uninfected CD4 cell Gp120 negative Cells Fuse Killing of CD4 cells 2. Syncytium Formation Infected CD4 cell Gp120 positive www.freelivedoctor.com
- 62. Killing of CD4 cells 3. Cytotoxic T cell-mediated lysis Why do all T4 cells disappear? BUT: Most cells are not infected www.freelivedoctor.com Cytotoxic T cell
- 63. www.freelivedoctor.com Killing of CD4+ cells 4. Binding of free Gp120 to CD4 antigen makes uninfected T4 cell look like an infected cell Complement-mediated lysis Could account for the loss of uninfected T4 cells
- 64. CD8 cell (no CD4 antigen) Macrophage CXCR4 chemokine receptor Why do all T4 cells disappear? Induction of apoptosis www.freelivedoctor.com Binding to CXCR4 results in expression of TNF-alpha on the cell surface ? G protein signal ? Binding to CXCR4 results in expression of TNF-alpha receptor II HIV gp120 chemokine
- 65. CD8 cell Macrophage CXCR4 Why do all T4 cells disappear? Induction of apoptosis www.freelivedoctor.com Death CD8 T cell apoptotic bodies
- 66. Macrophages may be infected by two routes CD4 Fc receptor HIV gp120 binds to macrophage CD4 antigen Virus is opsonized by anti gp120 antibodies which bind to macrophage Fc receptors - an enhancing antibody vaccine problem www.freelivedoctor.com HIV gp120 HIV Anti-gp120
- 67. Macrophages - The Trojan Horse Carry virus into different organs (brain) Non-proliferating mature macrophages sustain HIV production for a long time without being killed by virus Macrophages form a reservoir outside the blood www.freelivedoctor.com Early HIV isolated during infection are macrophage tropic (have a macrophage chemokine co-receptor (CCR5)) Virus probably infects patient via macrophages in semen etc Infection by HIV leads to altered cytokine production “slim disease” Slim disease very like Visna in sheep - also infects macrophages
- 68. Population Polymorphism HIV genome 9749 nucleotides Therefore EVERY new virus has at least one mutation! Every possible single mutation arises daily 1% of all possible double mutations arise daily The HIV that infects a patient is very different from that seen by the time AIDS appears HIV is a retrovirus Retroviruses use host cell RNA polymerase II to replicate their genome vaccine problem Pol II has a high error rate 1:2,000-10,000 www.freelivedoctor.com
- 75. Anti-HIV Strategies H ighly A ctive A nti- R etroviral T herapy HAART: Two nucleoside analog RT inhibitors and 1 protease inhibitor Now also: Two nucleoside analog RT inhibitors and 1 non nucleoside www.freelivedoctor.com
Hinweis der Redaktion
- AIDS is a disease caused by a virus, A RETROVIRUS. Much of our knowledge about the disease and our attempts to counter it are based on this fact We know more about this virus than any other virus Yet despite our burgeoning knowledge base, the way in which the virus participates in disease seems more and more complicated, leading to more and more complicated anti-viral strategies It was very early in the development of the AIDS pandemic that the involvement of an infectious agent became clear and, to see why, we must go back to the very beginning of the epidemic. To the late 1970’s
- Before the AIDS pandemic, Kaposi’s sarcoma was found primarily in elderly Jewish men and immuno-compromised patients
- It was originally suggested that there was an immuno-suppressive factor in semen Now we know this disease as AIDS
- The clusters of infected patients showed that the disease was in groups of sexual partners
- But HIV was difficult to grow from the infected patients blood. It killed the cells on which it grows and it could not be grown on ordinary cultured T4 cells
- Although the obvious agent was a virus, it was difficult to grow. It did not grow on cultured T4 cells, the only cells at that time that were know to be infected by HIV. Cultured T4 cells are resting, unactivated T4 cells. The great step forward made by Gallo and his collaborators was to use interleukin 2 to activate T4 cells. Then they could support HIV replication Gall showed that cells could support the replication of virus but there was no long term production. The assay was reverse transcriptase. Gallo had discovered HTLV-1 and know that it could give a similar cellular picture: Leukemia in some patients and immuno-suppression in others. This immuno-suppression was the result also of the specific loss of T4 cells. Feline leukemia virus also shows immuno-suppression in many cats. Gal also showed that there was reverse transcriptase in the blood of infected patients, suggesting infection by a retrovirus It was clear from the start that it is a major characteristic of HIV that it causes a fall in the number of T4 cells. WHEREVER AIDS OCCURS, HIV PRECEDES IT
- This time course of HIV infection applies to persons not receiving chemotherapy.
- HIV is now NOT replicating in resting T4 cells and most are resting in the peripheral circulation. At this time most replication is in lymph nodes in macrophages and dendritic cells. Symptoms are ‘flu or mononucleosis-like.There is a cellular immune response within weeks. Antiviral antibodies and cytotoxic T cells rise to high levels and persist for years. They are very effective at keeping the virus in the circulation at low levels. The CD8 cells rises transiently while CD4 cells fall but5 again recover (almost at least). The loss of these CD4 cells may result from DIRECT INFECTION of T cells in the circulation. Although antibodies lower HIV in blood, infection persists in the lymph nodes and in macrophages
- Persistent infection with no or minor symptoms: Night sweats, generalized lymphadenopathy, diarrhea Virus persists as provirus in resting memory T cells. Reactivation of cells occurs contributing to overall viral load but this does not at this stage significantly affect CD4 cell number. Nevertheless, CD4 cells drop in number throughout infection
- Also neuroplogical manifestations, lymphoid neoplasms Opportunistic infects occur when CD4 cells drop below 300 cells per cu mm Mechanism of this loss is still uncertain
- Clinically most Kaposi’s is indolent and many infected individuals die of other causes. The AIDS-associated form is much more progressive involving many sites (skin, lymph, lungs, intestine) Human herpes virus-8 or Kaposi’s sarcoma-associated herpes virus found in many AIDS patients. In AIDS anti-HHV-8 antibodies are found only in those that have Kaposi’s or will get Kaposi’s. Blood from hemophiliacs with HIV infection does not show antibodies against the herpes virus
- Clearly there are cases of immuno-suppression without HIV – that is to be expected, diseases of different etiology. Clearly for other diseases such as Kaposi’s, HIV is a cofactor rather than a cause. The data argue for a specific sexually transmitted agent of Kaposi’s in which immune suppression is a DOMINANT COFACTOR
- The establishment that the disease is caused by a virus and therefore the ability to produce antibodies against viral antigens led to the first tests for HIV, the ELIZA and Western blot tests. However, there is a 1 to 2 month time lag before antibodies are produced. This can be overcome by using a test that identifies viral RNA rather than antibodies produced against viral protein e.g PCR. The very fact that we can use an antibody test shows us that there is a good immune response and it is neutralizing antibody which gives hope for a vaccine . But the virus is not completely neutralized which argues that a vaccine may be difficult to develop. The virus goes underground within the cells and because it is a retrovirus , is prone to genetic drift . As it changes it overcomes the immune system. As we shall see retroviral vaccines pose special problems and HIV is more complicated than other retroviruses
- The size of the HIV genome is similar to that of other retroviruses but it is more complex. There is no oncogene but there are extra open reading frames which do code for protein. In all 15 proteins are encoded in HIV and they are made because antibodies to them can be found in patients. These extra open reading frames are not typical of retroviruses such as RSV. These extra open reading frames give a clue to the complex lifestyle of HIV. Note that some of them are encoded in two or more exons so there will have to be multiple splice events to make the final RNA. Could these be a site for intervention in the replication of the virus?
- Syncytia are only possible if fusion occurs at ambient pH, this is very important as the formation of syncytia between infected and uninfected cells can allow spread of the virus without having to travel between cells. This must be borne in mind when thinking about vaccine strategies since humoral antibody will have no effect on this kind of spread. A vaccine must, clearly, be effective against INFECTED CELLS as well as virions. How fusion occurs is not known but involves the fusogen, gp41 which undergoes a conformational change But there is something more than just binding to CD4 antigen for infection. Early on it was known that if we transfect a MOUSE cell with the gene for CD4 antigen, it is NOT infected. Something else exists in a HUMAN cell, that allows infection
- Human HeLa cells are not infected by HIV because they do not have CD4 antigen. When CD4 gene was transfected into the HeLa cells, they became able to bind HIV and were infected.
- What is extra to CD4 in human cells are the chemokine CO-RECEPTORS. It was discovered that infection of human cells could be blocked with high concentrations of chemokines, proteins that are secreted by CD8 cells in many inflammatory responses.
- In long term non-progressors the CD4 cells fall after infection but recover to near normal and remain there, so far for more than 15 years
- A chemokine receptor may be one reason why these people remain healthy. What part this co-receptor plays in the biology of HIV we shall see later. The T cells or macrophages of non-progressors are very resistant to HIV because they have a mutant chemokine receptor. In some rather rare mutations of CCR5 (macrophage co-receptor), it is virtually impossible for the virus to enter the cell. Other long term non-progressors appear to make high levels of chemokines that block the chemokine receptor and therefore block binding of HIV to the cell.
- Because of their work, these women are repeatedly exposed to HIV (remember that their clients are probably infected at a rate of 25% or more). Yet they show no sign of disease after more than 15 years. All of us can present a large number of antigen peptides in association with our class I MHC antigens…but not all peptides can be presented by all people so the antigens to which we can raise an immune response is limited albeit large. All of us can raise antibodies or induce a T cell response to HIV but the actual antigen peptide recognized differs. If an individual is lucky enough to present an HIV peptide than cannot undergo mutation in the virus without loss of viral infectivity, that individual produces an immune response from which the virus cannot escape
- Protease is necessary for cutting up proteins in viral maturation … could be site of chemotherapeutic intervention
- Thus we have a very complex life cycle. In some cells the virus goes latent while in others such as macrophages, it seems not to. Why such a complex life cycle? What is the molecular basis of this?
- Although clearly connected with immune deficiency, wasting and brain diseases (dementia) appear to be linked to macrophage infection and are distinct from the severe immuno-suppression caused by T4 cell depletion
- During infection virus is not totally controlled. This is an inevitable result of being a retrovirus. This is a great problem for a vaccine. During course of the disease, many subtypes arise and the tropism shifts from macrophage to CD4-infecting strains. Also from non-syncytium-inducing to syncytium-inducing. A GREAT PROBLEM FOR A VACCINE