AIDS and Other Immunodeficiencies

1. AIDS and Other Immunodeficiencies By: Luz Arboleda, Sameer Jain, and Ranoo Patel.

2. Overview • Immunodeficiency • Primary Immunodeficiency • Secondary Immunodeficiency • AIDS i.Discovery of AIDS ii.Origin of AIDS Virus iii.Epidemiology & Statistics iv. HIV-1 v. Transmission of HIV-1 vi. Treatment of HIV/AIDS

3. Introduction • The immune system is subject to failure of some or all of its parts. • If the system is not able to protect the host from disease-causing agents or from malignant cells, an immunodeficiency results. • There are two types of immunodeficiency: Primary and secondary or acquired.

4. Primary immunodeficiency results from a genetic or developmental defect of the immune system. The condition is present at birth, though it may not manifest itself until later in life. • Secondary (acquired) immunodeficiency is the loss of immune function that results from exposure to various agents. The most common example is AIDS or acquired immunodeficiency syndrome, which results from infection with the HIV-1. or human immunodeficiency virus 1.

5. Primary Immunodeficiencies • Primary Immunodeficiencies may affect either adaptive (T or B cells) or innate (macrophages or complement) immune functions, which enables us to categorize them according to the type of developmental stage of the cells involved. • So, lymphoid cell disorders may affect T cells, B cells, or, in combined immunodeficiencies, both B and T cells. Myeloid cell disorders affect phagocytic function.

6. Cellular Development in the Immune System Figure 19-1

7. Defects in the lymphoid lineage— May involve B cells, T cells, or both of these Lineages. B-cell immunodeficiency disorders cause recurrent bacterial infections. T-cell deficiency though, can affect both humoral and cell-mediated responses. SCID: Severe Combined Immunodeficiency WAS: Wiskott - Aldrich syndrome Interferon-Gamma-Receptor Defect X-Linked Agammaglobulinemia X-Linked Hyper-IgM Syndrome CVI: Common Variable Immunodeficiency Ataxia Telangiectasia Immune Disorders Involving the Thymus

8. Interaction Between T and B Cells • Defects in cell interaction and signaling can lead to severe immunodeficiency. • A number of primary immunodeficiencies are rooted in defects in these interactions. SCID is an example. Figure 19-3

9. Defects in the myeloid lineage— Defects affect the innate immune functions. Most of them result in impaired phagocytic processes that are manifested by recurrent microbial infection of greater or lesser severity. Reduction in Neutrophil Count CGD: Chronic Granulomatous Disease Chediak-Higashi Syndrome LAD: Leukocyte Adhesion Deficiency • Defects in the Complement Lineage— Many complement deficiencies are associated with increased susceptibility to bacterial infections and/or immune-complex diseases.

11. Treatment of Immunodeficiency • Although there are no cures for immunodeficiency disorders, there are various treatment possibilities. In addition to complete isolation from exposure to any microbial agent, treatment options for the immunodeficiencies include: 1) Replacement of a missing protein 2) Replacement of a missing cell type or lineage 3) Replacement of a missing or defective gene

12. Secondary Immunodeficiencies • Loss of immune function that results from exposure to various agents. • Acquired Hypogammaglobulinemia Recurrent infection that manifests itself in young adults. There are usually very low levels of total immunoglobulin, though T-cell numbers and function may be normal. It is treated with gammaglobulin therapy. • Agent-Induced Immunodeficiency Results from exposure to any of a number of chemical and biological agents that induce an immunodeficient state. • AIDS: Acquired Immunodeficiency Syndrome

13. Discovery of AIDS • AIDS was first reported in the United States in 1981 in Los Angeles, New York, and San Francisco. • The first patients displayed unusual infections by opportunistic agents, such as Pneumocystis carinii, which causes PCP or P. carinii pneumonia, as well as other rare opportunistic infections. • Opportunistic agents are microorganisms that healthy individuals can harbor with no ill consequences but that cause disease in those with impaired immune function. • They also displayed Kaposi’ssarcoma—an extremely rare skin tumor.

14. Origin of AIDS Virus • Within a few years after recognition of AIDS, the causative agent was discovered to be a retrovirus. • Only one other human retrovirus has been described before HIV, the human T-lymphotropic virus I or HTLV-I. • There is also another human virus known as HIV-2, which is less pathogenic than HIV-1. It infects nonhuman primates that are not infected by HIV-1. • Viruses related to HIV-1 have been found in nonhuman privates—such as SIV: Simian immunodeficiency virus. Other animal retroviruses are the feline and bovine immunodeficiency viruses and the mouse leukemia virus. These don’t yield information pertinent to HIV-1. Only the studies made on chimpanzees when infected with HIV-1 can be useful; but they rarely develop AIDS. • Why isn’t there a suitable host to study HIV-1? a) Lack of cell-surface receptors required for entry of virus into host. b) Dependence of HIV on host-cell factors for early events in the replication process, such as transcription and splicing of viral messages.

15. Epidemiology & Statistics • Since its discovery in 1981, AIDS has increased to epidemic proportions. • According to the National Centers for Disease Control and Prevention (CDC), 42 million people are estimated to be living with HIV/AIDS. Of these, 38.6 million are adults, 19.2 million are women, and 3.2 million are children under 15. • An estimated 5 million people acquired the human immunodeficiency virus (HIV) in 2002, including 2 million women and 800,000 children under 15.

16. Epidemiology & Statistics • During 2002, AIDS caused the deaths of an estimated 3.1 million people, including 1.2 million women and 610,000 children under 15. • Women are becoming increasingly affected by HIV. Approximately 50%, or 19.2 million, of the 38.6 million adults living with HIV or AIDS worldwide are women. Compared to accounting for only 6% of the total cases in 1985. • The UN predicts that by 2010, more than 25 million children will have lost at least one parent to AIDS.

17. Global Estimates of HIV/AIDS

18. HIV-1 Virus • The virus that causes AIDS • It is a retrovirus with two copies of single stranded RNA genome • It uses reverse transcriptase to transform its ss-RNA genome into a ds-DNA for integration into its host genome • It has marker proteins (gp120) in the protein coat that allow it to recognize specific cells in the human body • The protein coat also contains MHC-I and MHC-II molecules

19. HIV genome • gag gene codes for nucleocapsid proteins • env gene codes for envelope glycoproteins, i.e. gp41 (transmembrane protein) and gp120 (surface protein) • pol gene codes for enzymes such as reverse transcriptase, protease and integrase • Other genes code for various activators and accessory proteins

20. Complete Activation of HIV • While CD4 is recognized by the virus, it is not sufficient for viral attack; it needs a costimulatory signal. • T cells: coreceptor is CXCR4, which also acts as a receptor for the chemokine SDF-1; there is competitive inhibition between chemokine and HIV for binding; the HIV strain is called T-tropic • Monocytes: coreceptor is CCR5, which is a receptor for chemokines, which also act as competitive inhibitors to HIV; the HIV strain is called M-tropic • T-tropic HIV strains cause syncytia: formation of giant cells as a result of fusion of cells via the gp120 protein on viral coats.

21. Infection of Human Cell with HIV • HIV gp120 surface protein binds CD4 on target cell • Transmembrane component, gp41, binds coreceptor CXCR4 to enhance fusion • Viral genome and other proteins are able to enter the cell via nucleocapsid • RT transcribes the ssRNA genome • The next DNA strand is made, making a double stranded DNA molecule called a provirus • The dsDNA is transferred to the nucleus to be added to the host genome via the viral integrase protein at HIV LTR sites

22. Activation of Provirus • In a latent cell, the integrated provirus must be activates by transcriptional factors to make genomic ssRNA and mRNAs • Genomic RNA is exported • Host ribosomes transcribe viral mRNAs, and the proteins are either with the genomic RNA or part of the membrane • The membrane buds to form a viral envelope • The mature virus is released outside the cell • These latent cells are dangerous because they can remain latent for long periods of time

23. HIV Infected T-Cell

24. Overview of Infection • The viral load is kept at a steady state; half life for infected cells is roughly 1.5 days • In addition to these lytic cells, there are small numbers of latent cells that can persist for long periods of time • Diagnosis for AIDS includes finding the HIV virus in the patient, <200 TH cells/mm3, impaired DTH, and the occurrence of opportunistic infections • Infections that result from the diminished immune system include infections with Candida albicans, flu, tuberculosis, encephalopathy, and other abnormalities of CNS and PNS.

25. Progression of HIV to AIDS

26. Testing for HIV • Enzyme-linked immunosorbent assay (ELISA). This screening test is usually the first test used to detect infection with HIV. If antibodies to HIV are present (positive result), the test is usually repeated. • Western blot. This test requires high technical skills. It is more difficult than the ELISA to perform and interpret accurately, but it is less likely to give a false-positive result because it can distinguish HIV antibodies from other antibodies that may react to the ELISA. A Western blot is usually done to confirm the results of two positive ELISA tests. • Indirect fluorescent antibody (IFA). This test also detects antibodies made to fight an HIV infection. Like a Western blot test, it is used to confirm the results of an ELISA. • Polymerase Chain Reaction(PCR). This test detects the RNA of HIV, rather than detecting antibodies to HIV. Therefore, PCR can reveal an HIV infection before antibodies can be detected. PCR can also accurately determine whether a baby born to an infected mother has HIV.

27. Immunological problems associated with HIV infection

28. Other Immune Evasions Mechanisms of HIV • TC cells are able to generate a response for years until finally they are no longer effective against HIV • The HIV peptides that act as epitopes to the MHC I molecules mutate at a high rate and the TC cells are not able to keep up • Some HLA haplotypes are more susceptible to HIV attack than others • HIV gene products have functions in addition to viral replication functions; some are able to down regulate host cell MHC-I expression so fewer peptides are presented to the defense mechanisms • Tat represses transcription of MHC-I • Vpu keeps MHC-I molecules from leaving the endoplasmic reticulum • Nef selectively internalizes some MHC-I molecules from the plasma membrane, so that the cells have fewer MHC molecules in total. It leaves the MHC-I molecules that will help prevent lysis by NK cells.

29. 3 Points In HIV Cell Cycle Where Replication Can be Stopped • Nucleoside Reverse Transcriptase Inhibitors (NRTIs) • Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) • Protease Inhibitors • All 3 of these treatments are usually prescribed at once. Known as HAART, the combination of all 3 fights the ability of the virus to rapidly mutate.

30. Reverse Transcriptase Inhibitors • Reverse Transcriptase Inhibitors interfere with the reverse transcriptase (RT) enzyme that HIV needs to make copies of itself. There are 2 types of inhibitors each working differently. Type 1: NRTI’s – nucleoside drugs provide faulty DNA building blocks, stopping the DNA chain the virus uses to make copies of itself. Type 2: NNRTI’s- non-nucleoside RT inhibitors bind RT so the virus cannot carry out its copying function Examples Include: AZT, 3TC, Combivir, Nevirapine

31. Protease Inhibitors • Protease Inhibitors (PI), discovered in 1995, block the protease enzyme. When protease is blocked, HIV makes copies of itself that can’t infect new cells. • PI Side Effects: PI’s can cause high blood sugar and consequently diabetes. Another main concern is lipodystrophy, where your body absorbs fats and nutrients in an irregular manner. Latent HIV can hide out in these fat cells.

32. Death rate Death rates per 100,000 population from leading causes of death among persons 25–44 years old, United States, 1987–2000

33. What does the future hold? • Scientists are working on more potent protease inhibitors, less toxic RT inhibitors, as well as 2 new classes of drugs: *Fusion Inhibitors-Drugs which act to block HIV before it enters the human immune cell. This class of drugs works to stop HIV replication at an earlier stage. *Integrase Inhibitors- Aim to block the integration of the virus’s DNA into the cell’s chromosome. 2 different integrase inhibitors are currently in human trials.

34. Can HIV be Vaccinated Against? Challenges -HIV thrives in the presence of circulating antibodies directed against it. - HIV integrates itself into the host genome and may stay dormant for years. All retroviruses prove difficult to remove -HIV mutates and can show up to 109 viruses per day, while the common cold with 100 subtypes has proven to difficult to make a vaccine for

35. Summary of HIV transmission • HIV is a retrovirus with a single stranded RNA genome; it is the virus that causes AIDS • There are two major strains of HIV that infect T cells or monocytes • The gp120 interacts with CD4 on the host cell, but there are coreceptors that are necessary for attack • The viral load of the plasma is a good indicator of the disease course • Many secondary diseases can afflict the patient from the lowered immunity that results from AIDS

36. HIV/AIDS Therapy Summary • 3 primary methods to battle HIV/AIDS - NRTI’s, NNRTI’s, PI’s All 3 combine to form HAART which has proven to be much more effective against HIV’s mutations. • New drugs which eliminate side effects or target different steps in the replication process are under testing. • For now a vaccine still seems to be a pipe dream