When did HIV-1 enter the human population? Current evidence for the HIV-1 that is now pandemic (group M): early 20 th century, 1902-1921. Extrapolated t from: - genetic relatedness of viruses isolated over time and - assumptions about the time needed for the observed number of genetic changes to occur. Earliest biological evidence: in serum from blood drawn in 1959 from a man in the city of Kinshasa (formerly Leopoldville) in the country Democratic Republic of the Congo (formerly Zaire, formerly Belgian Congo). He was part of a malaria study. Serum was stored frozen. Fragments of the HIV genome were present in the man s serum. The base sequences of this ZR 59 virus are most closely related to subtype D current M (main) group of HIV-1 Kinshasa, Dem. Republic of the Congo aka Congo (formerly Zaire, formerly Belgian Congo) 1
Modern chimps carrying SIV most closely related to HIV-1 M Leopoldville 1896 Kinshasa 1955 Sharp & Hahn, Nature 455:605 (08) comment on Worobey et al., Nature 455:661 (08) More biological evidence from the same time: in a lymph node biopsy specimen obtained from a female in 1960 in Kinshasa. Fragments of the HIV genome were present in the tissue, which had been fixed, embedded in paraffin, and stored at the Univ. Kinshasa. The base sequences of this DRC 60 virus are most closely related to subtype A of the M group of HIV-1. ***By 50 years ago, group M HIV strains had diversified into at least subtypes A and D. This means: ZR59 and DRC60 probably had a common ancestor at least 50 years before 1959. Conclusion: HIV-1 was spreading among humans at least 60-80 years before AIDS was recognized. 2
3 groups of HIV-1: M = main genotypes pandemic HIV (99% of AIDS cases) Within M group, subtypes A to K differ by sequences within envelope proteins O = outlier (Gabon, Cameroon) N = nonpandemic (Cameroon) DRC 60 HIV-1 N group ZR 59 Modified from Wain-Hobson, Nature 391:531 (98) ZR 59 strain similar to subtype D, HIV-1 group M DRC60 strain like subtype A, HIV-1 group M Another set of evidence: O group HIV-1 existed at that time. Norwegian sailor and family: - Sailor infected sometime during 1961-65 -- ports visited it included d coast of western central laf Africa - Sailor developed rash, pain, swollen lymph nodes 1966 - Wife had recurrent infections 1967 - Daughter born 1967, ill 1969 with recurrent infections - All died 1976. Autopsy samples and serum were preserved. - Later examination revealed O group HIV-1 gene sequences and HIV-specific antibodies. 3
Does HIV fit Koch s postulates as the cause of AIDS? Koch s postulates An organism can be considered to be the cause of a disease if it: 1. is always found in diseased individuals; 2. can be isolated from the diseased individual and grown pure in culture; 3. when taken from the pure culture, will initiate iti t and reproduce the disease upon introduction into a susceptible host; 4. and then can be re-isolated from the diseased individual. Vaccines against HIV How vaccines work Is an effective vaccine feasible? Clinical trials Challenges in testing vaccines 4
How do vaccines elicit immunity against microorganisms? - Imitate natural infection with a pathogen - Stimulate antigen-specific, adaptive immunity: humoral (antibody) and/or cell-mediated immunity. - Establish immune memory (memory T H, memory T C, memory B cells) ***** Existing vaccines do not result in sterilizing immunity (complete protection against any later infection by a virus). Instead, vaccination allows an individual s immune system to control the infection in its earliest stages. Prevents further spread of the virus and damage to the cells and tissues of the body. Problem: once established in the body, HIV has proven impossible to eradicate. Cells with latent infections have silent HIV DNA genomes integrated into cellular DNA, do not provide signals of infection to the immune system, so immune system can t identify and kill the cells. Silently infected cells can later become activated and start to produce virus. Types of vaccines in wide use Subunit (piece of a microorganism) stimulates mainly antibody immunity requires frequent booster shots - tetanus toxoid HIV envelope protein not effective 2005, 2006 (which to use of many envelope proteins in circulation?) Whole, inactivated microorganism stimulates mainly antibody immunity requires frequent booster shots - Salk vaccine against polio (shots) - influenza vaccines (injected) Not considered safe approach for HIV (inactivation might not be complete) Live, attenuated t (weakened) microorganism i stimulates both antibody and cell-mediated immunity longer lasting immunity still need booster shots - Sabin vaccine against polio (oral) - Flumist vaccine against influenza (nasal spray) Not considered safe approach for HIV (weakened virus might mutate and become pathogenic) 5
Which subtypes of HIV-1 (M group) should be used in a vaccine? They are distributed differently around the world B B A, B, AB B, C, BC B, BF AG D F, G, A H, J, K C AE, B C B diagram from International AIDS Vaccine Initiative (2003 data): http://www.iavireport.org/specials/hiv-clademap.pdf newer vaccine approaches being tested Vector viruses expressing particular HIV proteins - mainly stimulate cell-mediated immunity adenovirus expressing 3 HIV proteins did not protect against HIV infection or reduce amount of virus after infection (2007); may have increased HIV infection among vaccinees having immunity to adenovirus (a common human cold virus) Naked DNA coding for HIV proteins injected to elicit immunity - tested in monkey models (SIV) doesn t seem to work well in humans Combination of strategies - vector virus expressing HIV proteins; boost with subunit vaccine canarypox virus (no replication in human cells) expressing 3 HIV proteins, boost with HIV envelope protein. 6 years, $105 million, 16000 volunteers no protection of high-risk groups from infection (fall 2009) 40% reduction in infections among low- and moderate-risk groups no reduction in levels of virus in those who became infected 6
What types of immunity will protect against HIV disease? - Is a combination of antibody and cell-mediated immunity likely to be most effectcive? - Immunity at mucosal surfaces where HIV first enters the body is extremely important Cell-mediated immunity is probably very important. (see The Vaccine reader #78) Some sex workers (the Nairobi prostitutes ) in Kenya remained uninfected despite repeated exposures to HIV. - strong CD8+ T cell responses to HIV - may have to be continuously exposed to HIV for CD8+ cell responses to remain effective - how does this protection work? - could this understanding be used to develop a vaccine? Long-term nonprogressors: 1 in 300 HIV-infected people; HIV-infected for 15-20 yr without developing AIDS; maintain low HIV loads. - what features of their immune system allow this? The International HIV Controllers Study Clinical studies of drugs and of vaccines in humans follow preclinical laboratory work and testing in animals Drugs Vaccines Phase I Safety 20-80 healthy volunteers 1 yr Safety Small # healthy volunteers Phase II Phase III Effective? Side effects? 100-300 patients 2yr Verify effectiveness, learn more about side effects. 1000-3000 patients 3 yr Signs of immunity? Volunteers, healthy Signs of immunity? Effectiveness? Higher-risk individuals Large numbers, years 7
Challenges to conducting HIV vaccine trials to test effectiveness. In developed countries: - low incidence of HIV infection, even in high risk individuals - recruitment and retention challenges for at-risk individuals - distrust of researchers and government among at-risk people -misunderstandings di and distrust of vaccines in general In developing countries: - desperate need to slow the spread of HIV - concerns about exploiting people and unequal partnerships between those who designed the vaccines and those who are doing the testing - concerns that most people in these countries won t be able to afford the vaccine, even if it is effective - need health infrastructure: clinics, labs, equipment, supplies - need to train personnel in lab methods, data analysis, clinical practice, ethics - national authorities and institutional review boards are poorly supported or don t exist at all 8