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BTY328: Virology wstafford@uwc.ac.za

BTY328: Virology wstafford@uwc.ac.za. 18th Aug 10.50- AIDS 19th Aug 9.40- HIV molecular biology 20th Aug 8.30: HIV prevention & treatment . Acquired immune deficiency syndrome.

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BTY328: Virology wstafford@uwc.ac.za

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  1. BTY328: Virology wstafford@uwc.ac.za • 18th Aug 10.50- AIDS • 19th Aug 9.40- HIV molecular biology • 20th Aug 8.30:HIV prevention & treatment

  2. Acquired immune deficiency syndrome • AIDS patients have many diseases, most having more than one disease at any given time. • Collectively the diseases that are expressed in an AIDS patient are referred to as a syndrome. • The number of diseases an AIDS patient has, and the severity of their expression reflects the functioning of that person’s immune system.

  3. Chronicle of the onset of AIDS epidemic in the U.S.A. •1981 June, LA –5 cases of an unusual pneumonia, pneumocystis (CDC)‏ July –41 cases of Kaposi’s Sarcoma, a rare skin cancer August –100 cases of homosexual men dying of rare diseases End of 1981: 121 deaths • 1982: May – immune system disorder known to doctors – around 335 people affected July – 34 cases of a serious immune disorder among Haitians. December – infant dies of AIDS after multiple blood transfusions • 1983: – Pasteur Institute - new virus in patient with symptoms preceding AIDS named it lymphadenopathy-associated virus, or LAV – Women can catch it too – 1476 deaths

  4. AIDS chronicle 1984 – Robert Gallo (US) CDC reports that HTLV may cause AIDS – 3500 deaths – Drug users are getting AIDS 1985 – Blood test made available to blood banks – Rock Hudson admits to having AIDS. Dies in October – Blood supply declared free of HIV virus – Pentagon starts screening recruits- Will reject positives – 6850 deaths 1986 – Women may transmit HIV to men ~12,000 deaths 1987 – Insurers want to test for HIV – WHO makes global map of AIDS cases – 17,000 deaths

  5. AIDS: an infectious agent? Koch's postulates: • 1. Epidemiological association: the suspected cause must be strongly associated with the disease. • 2. Isolation: the suspected pathogen can be isolated - and propagated - outside the host. 3. Transmission pathogenesis: transfer of the suspected pathogen to an uninfected host, man or animal, produces the disease in that host.

  6. HIV causes AIDS • Previously rare diseases (Pneumocystis carinii pneumonia) opportunistic infections have become more common. In the rural Hlabisa District of South Africa, TB increased 360 percent from 1992 to 1998, concomitant with a steep rise in HIV seroprevalence. • Death rates are markedly higher among HIV-seropositive individuals than among HIV-seronegative individuals. Masaka District of Uganda (8,833 individuals). Among individuals ages 25-34, HIV-seropositive people were 27 times more likely to die than HIV-seronegative people. • AIDS and HIV infection are invariably linked in time, place and population group. Virtually all patients with AIDS are HIV seropositive

  7. Individuals from diverse backgrounds- heterosexual and homosexual men and women, haemophiliacs, blood transfusion recipients and injection-drug users and infants have all developed AIDS- the only common denominator being their infection with HIV (NIAID, 1995)‏ • The development of AIDS following known HIV seroconversion observed in blood transfusion cases, in mother-to-child transmission and accidents to heath workers (needle injury from HIV+ patient). • More than a dozen strains of simian immunodeficiency virus (SIV) cause AIDS in macaques (old world monkey). • Isolation of HIV from AIDS patients, and culture in the laboratory. Detection by antibodies (ELISA, Western Blot) and PCR to trace the viral load o finfected patients

  8. AIDS pandemic • In 2007, an estimated 33.2 million people lived with the disease worldwide, and it killed an estimated 2.1 million people, including 330,000 children. • Three-quarters of these deaths occurred in sub-Saharan Africa, retarding economic growth and destroying human capital.

  9. Global HIV infection

  10. Affected groups

  11. AIDS and immune function T-cells and B-cells – Thymus and Bone • B-cells produce antibodies • T-cells – help B-cells make antibodies (helper T-cells)‏ – kill damaged or foreign cells (cytotoxic T-cells)‏ – 2 kinds of helper T-cells (biochemical messengers)‏ – Th2 – help B-cells – Th1 – help cytotoxic T-cells • HIV gradually eliminates Th1 & Th2 cells – HIV has a surface protein gp120 which binds to CD4+ receptor Th1 & Th2 – Immune system keeps producing T-cells, but after 10-15years, the body can’t keep up with the rate of cell death No immune response to infection – AIDS begins......

  12. Typical progression of AIDS

  13. Rapid progressors • A small percentage of HIV-infected individuals rapidly progress to AIDS within four years after primary HIV-infection and are termed Rapid Progressors (RP) (Anzala et al., 1995)‏ • Rapid progression was originally thought to be continent specific, as some studies reported that disease progression is more rapid in Africa (N'Galy et al., 1988; Anzala et al., 1995; Whittle et al., 1992), but others have contested this view (Marlink et a., 1994; French et al., 1999; Morgan et al., 2002).

  14. Long term non-progressors • Individuals who are persistently infected with HIV-1, but show no signs of disease progression for over 10 years and remain asymptomatic are classified as Long Term Non-Progressors (LTNP). (Buchbinder et al., 1994; Cao et al., 1995; Easterbrook, 1994; Levy, 1993). • However, the term LTNP is a misnomer as progression towards AIDS can occur even after 15 years of stable infection (Harrer et al., 1996). • LTNP are not a homogeneous group regarding both viral load and specific immune responses against HIV-1. Some LTNPs are infected with HIV that inefficiently replicates(Deacon et al., 1995; Kirchhoff et al., 1995) whilst others that are infected hav strong and broad set of HIV-specific humoral and cell-mediated responses that seems to delay the progression to AIDS.

  15. Highly exposed persistently seronegative • A small group of individuals prostitutes in Kenya and in The Gambia) are HIV-negative despite being persistently exposed to HIV • Continual transient infection may have occurred(Clerici et al., 1994; Pinto et al., 1995; Rowland-Jones et al., 1995; Fowke et al., 1996).The CTL epitope specificity differs between Highly exposed persistently seronegative and HIV positive individuals(Kaul et al., 2001).The appearance of HIV-1-specific CD8+ cytotoxic T cells (CTLs) early after primo-infection has been correlated with the control of HIV-1 viremia (Koup et al., 1994; Borrow et al., 1994).

  16. Prediction of progression rates • Individuals with a broad expansion of the T cell receptor of CD8+ T cells during primo-infection seem to have low levels of virus six to twelve months later, which is predictive of relatively slow disease progression. (Pantaleo et al., 1997). • However, a few reports have correlated the presence of antibodies against Tat in long term non-pogressors.

  17. HIV subtype variation and effect on progression rates The HIV-1 subtype that an individual becomes infected with can be a major factor in the rate of progression from sero-conversion to AIDS. Individuals infected with subtypes C, D and G are 8 times more likely to develop AIDS than individuals infected with subtype A (Kanki et al., 1999). In Uganda, where subtypes A and D are most prevalent (Kaleebu et al., 2000), subtype D is associated with faster disease progression compared with subtype A (Kaleebu et al., 2002). ‏

  18. Host genetic susceptibility • HIV enters cells through an interaction with both CD4 and a chemokine receptor. • While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV entry. This gene is found in up to 20% of Europeans but is rare in Africans and Asians. • Multiple studies of HIV-infected persons have shown that presence of one copy of this gene delays progression to the condition of AIDS by about 2 years. (Gonzalez et al).

  19. Co-infection and AIDS progression Coinfections or immunizations may enhance viral replication (entry to the cell; reverse transcription and proviral transcription) (Lawn et al., 2001). The expression of Chemokine receptors is inducible by immune activation caused by infection or immunization, thus increasing the number of cells that are able to be infected by HIV-1 (Wahl et al., 1998; Juffermans et al., 2001). Co-infection with DNA viruses such as HTLV-1, herpes simplex virus-2, varicella zoster virus and cytomegalovirus may enhance proviral DNA transcription and thus viral load as they may encode proteins that are able to trans-activate the expression of the HIV-1 pro-viral DNA (Gendelman et al., 1986).

  20. The effect of co-infections on progression rates The impact of co-infections by micro-organisms such as Mycobacterium tuberculosis can be important in disease progression, particularly with those with poor access to medical care(Blanchard et al., 1997). Frequent exposure to helminth infections, (endemic in Africa) shifts the cytokine balance away from an initial Th1 cell response against viruses and bacteria which would occur in the uninfected person to a less protective T helper 0/2-type response (Bentwich et al., 1995). This makes the host more susceptible to and less able to cope with infection with HIV-1.

  21. Defining AIDS • Category A: Acute phase (few weeks). The virus is produced in large quantities by the activated lymphocytes in the lymph nodes, sometimes causing the nodes to swell (lymphadenopathy), or generating flu-like symptoms, or can be asymptomatic. The viral load is greatly curtailed within a few weeks by cell mediated response to HIV-1 as the number of CD8 cytotoxic lymphocytes and Ab increases.The virus population at this stage fairly homogeneous • Category B: Asymptomatic Stage (several years). CD4 numbers decrease at a steady rate (approx 60 cells/year) to around 200-500/ul and immune system weakens due to direct cytopathogenicity by the virus, or apoptosis. The virus population becomes more heterogeneous because of continual selection for specific mutants as a result of immunological pressure.

  22. Defining AIDS • Category C: Symptomatic Phase and AIDS. End stage when infected individual develops AIDS symptoms characterised by a CD4 count below 200/ul blood and increased quantities of virus. Virus population becomes homogenous with increased virulence, expanded cellular host range, ability to cause syncytia. AIDS indicator conditions present: Candida albicans: esophagus and lungs, cytomegalovirus infection of eyes, tuberculosis, pneumocystis pneumonia, toxoplasmosis of the brain, Kaposi’s sacoma

  23. Common infection in AIDS

  24. AIDS: summary * Patients with acquired immune deficiency syndrome, regardless of where they live, are infected with HIV. * If not treated, most people with HIV infection show signs of AIDS within 5-10 years. * HIV infection is identified in blood by detecting antibodies, gene sequences or viral isolation. * Persons who have exchanged bodily flids with HIV positive individual or contaminated blood (sex, intravenous drug use, vaccintions with repeated needle usage, heamophiliacs) become HIV positive and develop AIDS. Most children who develop AIDS are born to HIV-infected mothers. * Monkeys inoculated with cloned SIV DNA become infected and develop AIDS.

  25. Origin of HIV ?

  26. Tracing the origin of the epidemic....to Africa • 1959: Congolese man. Preserved blood sample taken in 1959 from a man from Leopoldville, Belgian Congo (now Kinshasa, Democratic Republic of the Congo). However, it is unknown whether this anonymous person ever developed AIDS and died of its complications. . Another early case was detected that same year, 1959, in a 48-year-old Haitian, who had immigrated to the United States 30 years beforehand. He died the same year, apparently of the same very rare kind of pneumonia. • HIV arrived in Haiti, probably in one person, in about 1966, at a time when many Haitians were working in newly independent Congo. Then in 1969 HIV spread to the US - again in one person - where it circulated, unrecognised, for 12 years. The team thinks it may have remained invisible until it reached gay communities - compact groups that spread the virus efficiently - which led to visible clusters of the disease.

  27. HIV: Origin in Africa..? Cameroon chimpanzees and Hunter theory • A human was bitten by an ape or was cut while hunting one, and the human became infected. HIV most likely originated in wild chimpanzees in the southeastern rain forests of Cameroon or, Democratic Republic of Congo. Immunisation programmes with needle re-use • The jump from chimpanzee to human likely occurred during the French colonial period (1919–1960). Systems of poor conditions (forced labour and poor nutrition) and mass immunisations using one needle on many patients enabled zoonosis and transmission the virus spread.

  28. HIV and its origin in Africa Iatrogenic event (1) Oral polio vaccine hypothesis. Late 1950s research into a polio vaccine in the Belgian Congo prepared using chimpanzee kidney tissue enabling the SIV to infect and adapt to humans. The hypothesis that oral polio vaccine was involved in the origin of AIDS has been investigated and generally rejected by the scientific community. (2)Hepatitis B (HB) vaccine hypothesis. African chimpanzees were used in the manufacture of the HB vaccines during the early 1970s. Human HB viruses cultured in chimpanzees were returned to humans whose infected blood serum was then pooled to develop four different strains of experimental HB vaccine pilot tested between 1970 and 1975 in New York City and Africa.

  29. HIV: Origin in Africa. Hepatitis B vaccine and HIV zoonosis?

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