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Dynamics of HIV

Dynamics of HIV. By Bio 475 Seminar Class Fall 1998. Introduction. HIV (Human Immunodeficiency Virus) is the causative factor of the disease known as AIDS (Acquired Immune Deficiency Syndrome) According to the CDC (Center for Disease Control) 1993 definition a person has AIDS when:

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Dynamics of HIV

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  1. Dynamics of HIV By Bio 475 Seminar Class Fall 1998

  2. Introduction • HIV (Human Immunodeficiency Virus) is the causative factor of the disease known as AIDS (Acquired Immune Deficiency Syndrome) • According to the CDC (Center for Disease Control) 1993 definition a person has AIDS when: • his/her CD4+ T-lymphocyte cell count is less than 200/ul

  3. Introduction • his/her CD4+ T-lymphocyte percentage of total lymphocytes is less than 14% • they have any of the many clinical conditions listed including: karposi sarcoma, Pneumonia, and more recently pulmonary tuberculosis, recurrent pneumonia, or invasive cervical cancer

  4. Introduction • The life cycle of HIV includes: • entry • synthesis of viral DNA • integration into host cell genome • transcription • translation • assembly • release

  5. Introduction • Studies are underway in all aspects of the disease including Detection, Transmission and Treatment. • In terms of treatment there are 3 main points of attack • Entry of HIV into cell • Synthesis of viral DNA • Synthesis of viral proteins

  6. Influence of CCR5 and CCR2 Variants in HIV-1 Infection and AIDS Progression William F. Buitrago

  7. Background • Why do some individuals avoid HIV-1 infection after coming in contact with the virus? • Why some people who are HIV-1 sero-positive progress to AIDS unusually slowly?

  8. Specific alleles of the HLA locus are associated with different rates of AIDS progression • This phenomenon accounts only for a small amount of patients who are “protected” from HIV infection or AIDS progression

  9. CCR2 and CCR5 • CCR2 and CCR5 are member of the chemokine receptor family--cellular cofactors required for HIV to enter the cells. • They associate with CD4 to form a functional receptor complex

  10. Hypothesis... • A defect in co-receptors or their expression may protect individuals from infection and/or progression.

  11. What was found... • CCR5 : Major mutation 32 nucleotides missing “CCR5-32” • CCR2: Mutatation A to G substitution (190) Valine for isoleucine (64) “CCR2-64I”

  12. Survival Curve • Purpose... - Determine the dependence of progression to AIDS among +/+, +/32, and 64I/+ patients

  13. Rationale... - If +/32, and 64I/+ alleles confer protection, then +/32, and 64I/+ patients should remain 1993-AIDS for longer periods.

  14. Results... - There is a 2 to 3 year postponement in median time to AIDS outcome - In addition some patients with 32 /32, and/or 64I/64I remain 1993 AIDS free.

  15. The Role of CXCR4 in the Transmission of Feline Immunodeficiency Virus Rachelle Vander Meulen

  16. Rationale • FIV can be used as an animal model to study HIV • Understanding the mechanism of CXCR4 may lead to a possible treatment of late stage HIV

  17. Why study FIV? • A retrovirus of cats similar to HIV • Causes similar pathology to AIDS • Infects wide range of cell types, but the primary receptor is unknown

  18. What is CXCR4? • A chemokine coreceptor with a similar role as CCR5 and CCR2 • Seen in T-cell line adapted and dual tropic strains of lentiviruses • Seen in late disease stages • Forms a complex with CD4 and gp120

  19. CXCR4 and FIV • CXCR4 can act as a coreceptor for FIV • FIV will not infect cells that do not express CXCR4 • Feline HumanMurine • 3201 CrFK Mya-1 AH927 HeLa3T3 • CXCR4 + + + -- + -- • FIV(PET) + + + -- + --

  20. Suppression of CXCR4 • In nature, chemokine ligand SDF-1 inhibits CXCR4 strains • Competitively displace gp120 binding • Bicyclam drug AMD3100 has been shown to be an effective inhibitor of CXCR4 dependent HIV

  21. The Role of Regulatory Proteins Tat and Rev in The Inhibition of HIV Replication By Diarra Greene

  22. Background • Transcription is controlled by Regulatory proteins • 2 major regulatory proteins in HIV are Tat and Rev • Tat and rev are located adjacent to each other on the HIV genome • Tat functions in pre-transcription while Rev functions post- transcriptionaly

  23. Goals • Goals of the 2 studies were • to prove that soluble Tat analogs with mutations it the 41 and 44 amino acids inhibit activation • to determine the effect of Rev in the Presence of an inhibitory factor.

  24. Results • Results of Tat study • of the different amino acid substitutions tested 4144 proved most effective • shorter amino acids(36-50) more effective than longer one (36-72) • Tat peptides (41/44) can inhibit both viral replication and transcription

  25. Results • Results of Rev study • expression of the gag gene used as an indicator of function • gag expression poor in both cell types in the absence of REV • REV increased mRNA levels from p17R.1 four fold

  26. Future Applications • Mutations in both Rev and Tat can serve to inhibit viral replication • analogs of these proteins may be used as a clinical treatment

  27. Association of Mycoplasma penetrans with Human Immunodeficiency Virus Infection Odile Grau, Bruno Slizwwicz, Phillippe Tuppin, Valerie Launay, Emmanuelle Bourgeois, Nadia Sagot, Marinette Moynier, Alain Lafeulliade, Herve Bachelez, Jean-Pierre Clauvel, Alain Blanchard, Elmostafa Bahraoui and Luc Montagnier

  28. Proposal • Grau et. al proposes that microorganisms, specifically M. penetrans, infecting AIDS patients may influence the progression of the disease.

  29. The manner in which Grau et. al. plans to prove this is by investigating the relationships between the presence of antibodies to M. penetrans and the biologic features and clinical status of patients.

  30. Background • M. penetrans is a newly recognized species recently recovered from AIDS patients. • This bacteria of the class Mollicutes are the smallest organisms capable of self-replication. • These prokaryotes, which are mainly characterized by the lack of a cell wall and by a small genome, are parasites of plants, insects, animals, and humans.

  31. Background (cont.) • They are characterized by a flask-shaped morphology, mediates attachment to host cells but also quickly becomes buried in the cell in what appears to be an intermediate step to cell invasion. • In addition, mycoplasmas have been shown in vitro to enhance the cytopathic effect of HIV, and be powerful immunomodulators by inducing the activation of B or T lymphocytes.

  32. Brief Description of Materials and Methods • 154 HIV-seropositive and 405 HIV-seronegative • of the seronegative 350 were healthy blood donors, 40 had clinical sexually transmitted diseases (STDs), and 15 had Kaposi Sarcoma (KS). STD patients were considered because they were at risk of HIV infection through sexual intercourse.(Refer TABLE 1)

  33. Results • M. penetrans antibodies were detected in men only. • M. penetrans antibodies was higher in the homosexual-bisexual transmission group than in other exposure groups. • There was no significant difference between the prevalences of M. penetrans antibodies in homosexual men with or without K.S.

  34. Conclusion • Four conclusions can be drawn from this research: • M. penetrans seropositivity was associated with HIV infection • Serology positive for M. penetrans was associated with homosexual practices among HIV-seropositive persons • The seroprevalence of M. penetrans increased with disease progression • There was no obvious association between M.penetrans and K.S.

  35. Evolution of HumanImmunodeficiency Virus Type-1in Perinatally Infected Infants With Rapid and Slow Progression to DiseaseBy Pilar Dillard

  36. Mother to child transmission of human Immunodeficiency virus type 1 (HIV-1) accounts for more than 95% of the cases of pediatric AIDS. • HIV-1 transmission can occur before birth, during birth or after birth by way of breast milk from nursing mothers. • Early testing results set the parameters at birth that are associated with the rate of progress of HIV-1 disease in children born to infected mothers.

  37. Disease progression clinical classification: Category N: Asymptomatic Category A: Mildly symptomatic Category B: Moderately symptomatic Category C: Severe symptomaticOpportunistic infections, recurrent bacterial infection, cancers,encephalopathy and wasting syndrome. • Testing Period: At birth, monthly up to six months, every 3 months up to 18.

  38. SIGNIFICANT ANALYSIS RESULTS:AT BIRTH: Enlarged spleen and liver, Lower CD4+ cell <30 %, Higher CD8+ %, High Plasma RNA count, PNR or Culture +, P24 antigenemia + • AT TWELVE MONTH:Category C The major differences are in Liver and spleen enlargement (triples), PCR +(double) p24 antigenemia increases 205% and plasma RNA begins to level.

  39. CONCLUSION • Early testing allows the classification and application of early treatment of infected infants. • Early treatment allows infected children to slow down the rate of the disease progression.

  40. Detection of HIV-1 DNA using PCR in patients with AIDS by Tricia Julien

  41. PCR ANALYSIS • An in vitro method which amplifies DNA sequences. • First, DNA is denatured by heating. • Primers complementary to the target nucleotide sequences are annealed by lower the temperature.

  42. PCR ANALYSIS cont….. • DNA is extended by the action of a heat stable polymerase (taq).

  43. RATIONALE & RESULTS • Determine the sensitivity of the PCR assay in detecting HIV-1 DNA. • First test- 93.6% tested positive for the HIV-1 gag DNA sequences. • Second test- those that were initially negative (6.4%) tested positive.

  44. CONCLUSION • PCR is very sensitive if samples are run in duplicate. • Sensitivity can be increased if 2 or more HIV-1 primer pairs are used. • PCR is advantageous- has a faster turn around time, smaller sample required and non-infectious viral amplification.

  45. The Use of A Fixed Infected Cell Vaccine Against F.I.V. and possibly H.I.V. A Brief Summary of two F.I.V. vaccine trials by Tisha K. Hall

  46. Aim of The Experiments • To determine the efficacy of fixed infected cell vaccines (vaccines containing cells infected with the Feline Immunodeficiency Virus) in protecting cats from F.I.V. infection

  47. Methods • Cats are vaccinated • Then challenged with the virus • In 1st experiment: two different cat cell types infected to make vaccine • In 2nd experiment: two different strains of FIV used to challenge cats

  48. Results • Exp. #1: 3 of 19 cats were FIV-negative 25 weeks after challengeUpon rechallenge with FIV, 2 of the 3 remained seronegative • Exp. #2: cats were protected against challenge with FIV/PET strain up to 12 weeks post-challenge, but not against FIV/GLA-8 strain AND protected cats become seropositive after 50 weeks post challenge

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