Centers for Disease Control August 9, 2004

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HIV CDC site UNAIDS Aids Knowledge Base http://www.cdc.gov/hiv/dhap.htm http://hivinsite.ucsf.edu/insite.jsp?page=kb National Institute of Allergy and Infectious Diseases http://www.niaid.nih.

org/en/default.asp http://www.thebody.com/treat/expdrugs.html HIV Infection and AIDS, FDA related treatment, testing, fraud, prevention,clinical trials http://www.fda.gov/oashi/aids/hiv.

1 HIV CDC site UNAIDS Aids Knowledge Base National Institute of Allergy and Infectious Diseases Combination Antiretroviral Therapy June 1998 Am.Acad.Family Physicians The Body: Gene Therapy for HIV/AIDS HIV Infection and AIDS, FDA related treatment, testing, fraud, prevention,clinical trials Interesting article on HIV therapy written for physicians Centers for Disease Control report s of unusual incidence of pneuomonia caused by Pneumocystis carinii and of skin cancers caused by Kaposi's sarcoma. Patient's immune system was imparied CDC recognized a new disease: Acquired Immune Deficiencey Syndrome which is abbreviated AIDS Two years after appearance of unknown disease the infectious agent was isolated. Now called Human Immunodeficiencey Virus which is abbreviated HIV Estimated that 13 million are infected world wide More than 15,000 new infections daily. Ninety-five percent in developing countries. Nearly 50% are in women. It is estimated that worldwide there are 34.3 million people infected million adults 1.3 million children younger than 15 years old More than 71 percent (24.5 million) live in Sub-Saharan Africa 16 percent (5.6 million) live in South and Southeast Asia. click me for more info HIV1 is the strain in the U.S. In Africa HIV2 is also seen. The number infected (2000) is about 50% greater than what was predicted in Centers for Disease Control August 9, 2004 United Nations estimates there are 36.1 million people infected. 3 million died in 2000 alone 16 to 22 million estimated dead since the Cumulative AIDS CasesThe estimated number of diagnoses of AIDS through 2002 in the United States is 886,575. Adult and adolescent AIDS cases total 877,275 with 718,002 cases in males and 159,271 cases in females. Through the same time period, 9,300 AIDS cases were estimated in children under age 13. Estimated number of deaths of persons with AIDS is 501,669, including 496,354 adults and adolescents, and 5,315 children under age 15. start of the epidemic. At the global level, the number of people living with HIV continues to grow - from 35 million in 2001 to 38 million in An estimated 5 million people acquired the human immunodeficiency virus (HIV) in 2003, the greatest number in any one year since the beginning of the epidemic. In 2003, almost three million were killed by AIDS; over 20 million have died since the first cases of AIDS were identified in 1981.

2 Problems proving that HIV causes AIDS Koch's Postulates cannot be performed. Epidemiological work is difficult because of the long latency (8-10 years from infection to disease). 1. Virus can be isolated from almost all with the disease. Evidence that HIV causes AIDS The Evidence That HIV Causes AIDS 2. Advanced disease correlates with higher virus titer. 3. Asymptotic individuals which have detectable HIV coat proteins later develop the disease. 4. ecipients of contaminated blood subsequently develop AIDS. 5. Needle-stick injuries with HIV contaminated blood often develop AIDS. 6. About 30% of children born to infected mothers are infected with the virus. Those that are infected go on to develop AIDS. But uninfected siblings do not. 7. AIDS does not appear in a new locality without the prior presence of HIV. 8. The single best argument that HIV causes AIDS is that drugs designed to specifically interfere with the viral life cycle suppress symptoms and extend life. HIV is a retrovirus. HIV is a retrovirus. A more specific name for this one is Lentivirus. etroviruses are viruses that have a NA genome which is replicated via a DNA intermediate within the host cell. HIV is similar to NA tumor viruses but is much more complex. Other retroviruses ALV Avian leukemia virus (birds) MLV Murine leukemia virus (mice) virions produced per day during latency period. 1/2 life of virion is about 5-8 hours. During a 10 year period about 4 X10 13 virions are produced. These viruses have a relatively simple mna splicing pattern. ALV has 1 splice donor and 1 splice acceptor and produces 2 different mnas. HIV1 9 genes with 4 splice donor and 6 splice acceptor sites and by the process of alternative mna splicing can produce at least 30 different mnas. To put this in perspective: Current estimate of number of people in the world is 6.65 X It is estimated that the total number of people that have ever lived is less than 110 X 10 9.

3 Structure of the HIV virus A coffin-shaped capsid contains 2 copies of NA genome. It is single stranded. Both are the plus strand. The capsid also contains HIV reverse transcriptase, HIV integrase, HIV Nase and HIV protease. Capsid is made of p24. Protein p17 forms an icosahedral-like container that encloses the p24 sarcophagus. This structure is enclosed by a lipid bilayer. The lipid bilayer was stolen from the host cell. Life Cycle everse transcription complex TC = T, IN, p7, Vpr tiny amount of p17. Nuclear localization Vpr & IN have nuclear localization signals. Are involved in transport into nucleus. The cellular importin 7 protein is involved in this. Importin 7 is a transporter for ribosomal protein and histones. The lipid bilayer contains two very important viral-encoded proteins, gp41 and gp120. Other host-derived proteins may also be present in the membrane. trimer Infection and gp120 & gp41 gp120 and gp41 associate with one another. The complete complex is trimeric (3 copies of both gp120 and gp41). Beta turns are presumably exposed in C3 and C4 regions and are important for CD4 binding. Primary Target:! CD4 helper T cells. The normal role of these cells is to stimulate other macrophages to be more effective in destroying pathogens. They coordinate the immune response. These helper T cells have on their surface a glycoprotein called CD4. The viral protein gp120 binds CD4. The gp120 protein changes shape and exposes a chemokine binding site. Now it binds the chemokine coreceptor. gp41 causes membrane fusion It is clear that the viral p24 sarcophagus enters the cell. The protein coat is removed and the virus's NA genome is reverse transcribed in the cytoplasm into a double stranded DNA molecule. Double stranded DNA molecule enters the nuclease HIV integrase inserts it into the host cell's genome. Now called a provirus. Provirus never leaves the genome. CD4 surface glycoprotein is also found on other cells of hematopoietic origin. It is in high concentration on the surface of mature and immature helper T hymphocytes. It is in low concentration on antigen presenting dendritic cells such as follicular dendritic cells in the lymph nodes and blood dendritic cells, monocytes and macrophages. Therefore, early in the infection HIV can infect these cells but at a lower frequency.

4 There are at least 12 chemokine receptors that work in vitro. Two are know to work in in vivo. 1)! CC5 - macrophages, iv & mucosal membrane transmission. Viruses that can access these typically do not generate syncytiums. Important for the initial infection. Dominates early stage of infection - entry vehicle! 2)! CXC4 - T-cells. Syncytium forming. CXC4 is cytopathic and appears late in disease course. Chemokine receptors CD4 is necessary but not sufficient for HIV entry into CD4+ T-lymphocytes. The chemokines act as coreceptors. ambaut, A., Posada, D., Crandall, K. A. & Holmes, E. C. (2004) Nat ev Genet 5, Alleles that confer resistance - AIDS estriction Genes = AGs CC5 "32 About 1% of Caucasians, European ancestry Blocks HIV-1 in homozygotes. Heterozygotes show slow progression. AIDS estriction Genes = AGS esistant to the virions that 'normally' start an infection. Some people have a 32 bp deletion in this gene (second extracellular loop). The receptor is not expressed on cell surface. Cells from people with these gene are very resistant to infection. Seems to have no adverse affect These people can still get HIV, remember that during the later stages of the disease that the types of receptors that can be used changes. These people can catch a variant that can use the CXC4 receptor. CC2b mutation seems to increase the likelihood of delayed disease progression. CXC4 3' UT mutation About 1% Caucasians It delays the onset and the time of death. It is a point mutation in the 3' UT. Mechanism unknown. Why is the disease more aggressive in some populations? Female sex workers in Nairobi 3.5 years from infection to AIDS More than 3X faster than in Caucasians. Data is starting to emerge that says that in this Nairobi cohort the protective mutation s are not found. eference: Sarah L. owland-jones Survival with HIV infection: good luck or good breeding. TIG 14: Good eference for AGS is Human genes that limit AIDS Stephen J O Brien & George W Nelson. Nature Genetics 36: ANTES is a principal chemokine ligand for CC5. Elevated circulating ANTES levels have been detected in exposed individuals who avoid infection and also in people infected with HIV-1 who have a delayed onset of AIDS. Stephen J O Brien & George W Nelson Stephen Human genes that limit AIDS. Nature Genetics 36:565. AGs are important because They suggest effective therapies. One might tailor the therapy based on the AGs present. Knowledge about them is important for the interpretation of clinical trials

5 How does HIV kill cells? A healthy individual has about 800 CD4 positive cells per ml of blood. AIDS patients often have about 200 CD4 cells/ ml. The virus replicates by budding through the cell membrane. This does not necessarily kill the cells. Cells dies by autofusion, syncytial formation and apoptosis. Other mechanisms may await discovery. How does HIV kill cells? Syncytium formation Autofusion Apoptosis An infected cell T helper cell can direct an uninfected T helper to undergo apoptosis (BYSTANDE APOPTOSIS).. Apoptosis is the process of programmed cell death. During development of an organism it is a normal event to kill off some cells. This is done by telling them to commit suicide. This process is called apoptosis. For instance, in the thymus it is normal to eliminate autoreactive T lymphocytes to establish self-tolerance. Genes of HIV HIV has a number of overlapping genes. gag, pol and env are related to the genes found in other retroviruses. These three encode polyproteins. Genes that overlap use the same region of the DNA and NA but are read differently by the ribosomes. Source of Diversity 0.2 errors per genome via reverse transcription Three recombination events per genome per replication cycle. ATE OF ECOMBINATION IS HIGHEST AMONGST ALL KNOWN OGANISMS. NA Pol II makes mistakes. Viral generation time of 2.5 days. Produces to new virions each day. Most cells have 2 or more proviruses. Dual infection is common. ambaut, A., Posada, D., Crandall, K. A. & Holmes, E. C. (2004) Nat ev Genet 5,

6 everse everse transcriptase does not have any error checking ability therefore it makes many mistakes. 5 3 About 5-10 errors occur during reverse transcription.# everse everse transcriptase does not have any error checking ability therefore it makes many mistakes. About 5-10 errors occur during reverse transcription.# p7 promotes the annealing of tnalys3 tna p7 coats the NA and is a CHAPAONE that promotes all types of interactions between the NA genome & the DNA copy. everse everse transcriptase does not have any error checking ability therefore it makes many mistakes. About 5-10 errors occur during reverse transcription. everse everse transcriptase does not have any error checking ability therefore it makes many mistakes. About 5-10 errors occur during reverse transcription.# p7 promotes the annealing of tnalys3 p7 coats the NA and is a CHAPAONE that promotes all types of interactions between the NA genome & the DNA copy. Up to this point is thought to occur during viral assembly. Prior to infecting the next cell.#

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8 everse Galetto et al JBC 281: Viral recombination Very high replication rates early in infection. Cells very often infected by more than one subspecies. Copy-choice method of viral recombination switching events per each infection cycle At least 10-% of HIV-1 infectious strains are recombinants. ecombination may be a product of the ability of the virus to replicate nicked NA genomes! tna Life Cycle

9 Integration Preferential integration into sites where NA pol II is actively transcribing. Next PP CC5 principle co-receptor for non-syncytium inducing isolates. The ligand for CC5 is usually CD8. A very typical progression is: CC > CC3 and CC2b > CXC and CXC4 As disease advances see appearance of variants that recognize CC3, CC2b. Virions that use these receptors are more pathogenic. Late stages of the disease Chemokine receptor family: CC5, CXC, CXC4, CC2b The CXC coreceptor receptor is used. Virions that use the CXC chemokine coreceptor are cytopathic and syncytium inducing. CXC4 receptor This provides access to a vast number of new targets which were previously unavailable. Skip The progression of receptors may not be valid. This information is from older papers. I have not seen it in more recent papers.

MedChem 401~ Retroviridae. Retroviridae

MedChem 401~ Retroviridae. Retroviridae MedChem 401~ Retroviridae Retroviruses plus-sense RNA genome (!8-10 kb) protein capsid lipid envelop envelope glycoproteins reverse transcriptase enzyme integrase enzyme protease enzyme Retroviridae The