HUMAN IMMUNODEFICIENCY VIRUS (HIV) AND AIDS

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1 HUMAN IMMUNODEFICIENCY VIRUS (HIV) AND AIDS Mohamed Mahdi MD. MPH. Department of Infectology and Pediatric Immunology University of Debrecen (MHSC) 2015

Patients presented with opportunistic infections such as

2 Historical facts about HIV First presentation in 1981 among homosexual men in San Francisco and New York. Patients presented with opportunistic infections such as Pneumocystis pneumonia and Kaposi s sarcoma. Discovery of the virus in Robert C.Gallo Luc A. Montagnier

3 Historical facts cont mid 90 s was the era of stigma Prejudice against AIDS patients Haemophiliacs Homosexulas Haitians

4 Epidemiology

6 Viral propeties A retrovirus belonging to Retroviridae family, Lentivirus genus. Enveloped, diploid, single-stranded, positivesense RNA virus. Two known HIV species, and multiple subtypes (clades) exist! CRF s

7 Origin of HIV cont.

Origin of HIV The Simian Immunodeficiency virus (SIV) Infection occurs only in primates, around 32,000 years old! Complicated pathogenicity Mutiple serotypes, some serotypes resemble HIV-1 and HIV-2.

8 Origin of HIV The Simian Immunodeficiency virus (SIV) Infection occurs only in primates, around 32,000 years old! Complicated pathogenicity Mutiple serotypes, some serotypes resemble HIV-1 and HIV-2. SIVsm almost identical to HIV-2 found in some mangabey primates. Up to 1999, link could not be be established to HIV-1 In 1999 a University of Alabama research group discovered a serotype (SIVcpz) that was a perfect match for HIV-1. Link was established!

9 The cross-over In an SIV infected primate, multiple serotypes may co-infect the host. Through genetical recombination a distinct virus may come into existance that is capable of inter-species cross-over. The hunter theory: HIV was transmitted to bushmen during hunting activities. Widely accepted The Oral Polio Vaccine theory: In 1950 s The OPV was probably produced in SIV infected chimpanzy kidney cell lines. Contraversal The colonization theory: Colonizers of Africa facing tough environmental conditions, poor sanitation and scarce food resourses may have resorted to monkey hunting, or got into contact with infected At the end of the colonial era they helped spread the virus world wide. Most accepted Other theories

Structure of HIV Genes gag pol env tat, rev, nef, vif, vpr, vpu tev Function codes for P24, the viral capsid; P6 and P7, the nucleocapsid proteins; and P17 a matrix protein Codes for viral enzymes

10 Structure of HIV Genes gag pol env tat, rev, nef, vif, vpr, vpu tev Function codes for P24, the viral capsid; P6 and P7, the nucleocapsid proteins; and P17 a matrix protein Codes for viral enzymes (reverse transcriptase, integrase and protease) Codes for the precursor to gp120 and gp41 enabling the virus to attach to and fuse with target cells Each of these genes codes for a single protein with the same names It is a fusion of parts of the tat, env, and rev genes, and codes for a protein with some of the properties of Tat

11 Structure of HIV Protiens Gag p24 P6,7,17 Reverse transcriptase Integrase Protease gp120 gp41 Transactivators: Tat "Trans-Activator of Transcription" Rev "Regulator of Virion" Vpr "Viral Protein R" Nef Negative Regulatory Factor" Vif viral infectivity factor Vpu "Viral Protein U" Function encoded by the gag gene, and provide structural elements of the virus makes up the viral capsid p6 and p7 provide the nucleocapsid. p17 provides a protective matrix An enzyme transcribes the viral into double-stranded DNA integrates the DNA produced by reverse transcriptase into the host's genome enzyme that cuts proteins into segments binds to the CD4 receptoron any target cell that has such a receptor, particularly the helper T cell when gp120 binds to a CD4 receptor, gp120 changes its conformation causing gp41 to become exposed, where it can assist in fusion with the host cell helps HIV reproduce by compensating for a defect in its genome, allowing transcription of the HIV DNA allows fragments of HIV mrna to be exported from the nucleus to the cytoplasm and provides time-dependent regulation of replication required for virus replication in non-dividing cells such as macrophages and induces cell cycle arrest and apoptosis in proliferating cells, resulting in immune dysfunction Its expression early in the viral life cycle ensures T cell activation and the establishment of a persistent state of infection. It also promotes the survival of infected cells by down modulating the expression of surface molecules ( MHC I, ll, CD4 and CD28) inhibits the cellular protein, APOBEC3G, from entering the virion during budding from a host cell enhancing virion release from the cell

12 Genetic difference

13 HIV life cycle

15 Research targets

16 Pathophysiology Transmission requires contact with body fluids: Sexual intercourse Sexual practices (fellatio/cunnilingus/kissing) are low risk but NOT SAFE! Child birth (25 to 35%) Breastfeeding ( ~ 20 %) Absence of ART in pregnant women = total risk of % for vertical transmission!! Medical procedures Risk is low = < 1%

17 Pathophysiology Infection of host cells begins with binding of virus particles (virions) to host cells. Gp120 and gp41 engage CD4 + cells (T lymphocytes, monocytes, macrophages and dendritic cells).

18 Clinical features Acute retroviral syndrome usually begins within 1 to 4 weeks of infection and usually lasts 3 to 14 days. Non-specific symptons (fever, malaise, rhinorrhea, rash, arthralgia, lymphadenopathy Latency stage (1-20 years).

19 Pathophysiology Direct cytotoxic effects of HIV replication Cell-mediated immune cytotoxicity Thymic damage that impairs lymphocyte production

20 Pathophysiology Decreased CD4+ lymphocytes half-life (2days) Decline of CD4+ lymphocytes (normaly cells/mm 3) Impaired cellular and somewhat humoral immunity (B cells hyperplasia, lymphadenopathy..etc).

21 Acquired Immunodeficiency syndrome (AIDS) CD4 + helper T cells count rapidly starts to decline to < 200/μL. Inversion of the normal CD4/CD8 T-cell ratio Dysregulation of B-cell antibody production. Immune responses to certain antigens begin to decline. Failure to respond to opportunistic infections and normally harmless commensal organisms. Because the defect preferentially affects cellular immunity, the infections tend to be nonbacterial (fungal, viral).

22 AIDS When the immune system is damaged enough that significant opportunistic infections begin to develop, the person is considered to have AIDS. CD4 T-cell count less than 200/microl Occurance of AIDS defining illness:

23 Opportunistic Infections CNS and PNS Impairment Malignancies Wasting syndrome Pneumocystis carinii pneumonia AIDS dementia complex Kaposi's sarcoma Inadequate nutrition Mycobacterium tuberculosis Peripheral neuropathy Lymphoma Untreated infections Oral/esophageal candidiasis Myopathy Non-Hodgkin's lymphoma Metabolic disturbances Oral hairy leukoplakia Myelopathy Cervical malignancies Kaposi's sarcoma CMV hepatitis Toxoplasmosis Genital infections

24 AIDS

25 AIDS

26 AIDS Kaposi s sarcoma (Human herpesvirus 8)

27 Diagnosis HIV antibody testing: Detection of antibodies to HIV is sensitive and specific except during the first few weeks after infection. ELISA to detect HIV antibodies is highly sensitive, but rarely, results are false-positive. Positive ELISA results are therefore confirmed with a more specific test such as Western blot Nucleic acid amplification assays to determine HIV RNA level (viral load). Once infection diagnosed, determine CD4 count and plasma HIV RNA level (VIRAL LOAD)

28 Treatment Anti-retroviral therapy Highly active antiretroviral therapy (HAART) Prophylaxis for opportunistic infections Antibacterials/Antifungals

29 Treatment Therapy should involve combinations of drugs: Two nucleoside-analogue reverse-transcriptase inhibitors combined with either a protease inhibitor or a non-nucleoside analogue reverse-transcriptase inhibitor Or an Intergrase inhibitor! Combination therapy more toxicity : anemia, pancreatitis, hepatitis,, glucose intolerance, osteopenia and osteoporosis

30 Treatment Nucleoside Reverse transcriptase inhibitors Non-neucleoside reverse transcriptase inhibitors Abacavir Zidovudine (ZDV, AZT) Lamivudine (3TC) Stavudine (d4t) Nevirapine (NVP) Delavirdine Efavirenz Protease inhibitors Indinavir Nelfinavir Lopinavir Early inhibitors and Integrase inhibitors Enfuvirtide Raltegravir

31 Pregnancy Labour After birth: mother AZT after 14 weeks single dose nevirapine; AZT+3TC AZT+3TC for seven days After birth: infant Daily NVP until 1 week after breastfeeding has finished

32 Post exposure prophylaxis Short term antiretroviral therapy Following suspicion, initiate within a 3 days period! 2-3 antiretrovirals combination for 28 days. Not 100% protective!

33 End stage AIDS Although antiretroviral therapy has dramatically increased life expectancy for patients with AIDS, many patients still deteriorate and die. Death may result from the following: Inability to take HAART consistently, resulting in progressive immunosuppression Occurrence of untreatable opportunistic infections and cancers Liver failure due to hepatitis B or C Drug resistance

34 Vaccination Theoretically possible. Introduce the Immunogene to generate an immune response Immunogens are captured and presented by cells, such as dendritic cells, triggering cellular and antibody immune responses activation of the adaptive immune responses. Memory T and B cells Vaccine-induced memory cells become activated when the immune system encounters the actual pathogen

35 Vaccination Approaches focusing on the HIV envelope proteins Canarypox vectors (AIDSVAX) USA---Thailand. Mostly Humoral respose was achieved 31.4% vaccination efficacy Approaches to stimulate HIV-specific cellular immunity Adenovirus vectors Phase I, II, III trials Controversy (the Merk trial) Ethical dilemma: More than 850 million USD is spent on AIDS vaccine research annually!!

36 Merck V520 phase II, randomized, multi-center, double-blind, placebo-controlled test-of-concept study in 3000 HIV-seronegative high-risk volunteers HIV testing was conducted ~every 6 months. 49 cases of vaccinated population compared to 33 cases of Placebo group contracted HIV Vaccine neither prevented infection nor lowered viral setpoint. Why?

37 Resistance to HIV/AIDS? Four types of HIV patients: Rapid progressors Develope AIDS with in 2-3 years (10%) Typical progressors Develope AIDS < 10 years Long term non-progressors Develope AIDS years later Resistant patients!

38 Resistance to HIV/AIDS? The commercial sex worker example. 424 prostitutes from Kenya Thailand sex workers Individuals having unprotected sex with HIV+ partners. T-helper responces? Plasma and mucosal IgA?

39 Resistance to AIDS? Prolonged exposure to HIV increased mucosal IgA secretion and T-helper responses! Once exposure ceased, HIV infection developed.

40 Resistance mechanisms Viral factors Deletion of Nef gene Vpr gene mutation Host factors Chemokine receptor 5 polymorphism Environmental factors Co-infection with GB virus C Multivitamin supplimentation

41 Conclusion Education is the key to combat AIDS. Prevention of infection acquisition! The social stigma of AIDS patients. AIDS is manageable to an extent, given access to expensive antiretroviral drugs! More research needed into mechanisms of resistance to infection and even vaccination.

42 Thank you!

Fayth K. Yoshimura, Ph.D. September 7, of 7 HIV - BASIC PROPERTIES

Fayth K. Yoshimura, Ph.D. September 7, of 7 HIV - BASIC PROPERTIES 1 of 7 I. Viral Origin. A. Retrovirus - animal lentiviruses. HIV - BASIC PROPERTIES 1. HIV is a member of the Retrovirus family and more specifically it is a member of the Lentivirus genus of this family.