1. Emerging Diseases Lecture 13: HIV and the End of Optimism 13.1: Overview 13.2: HIV is a Retrovirus 13.3: Human Retroviruses 13.4: Targets of HIV-1 13.5: Antiviral Therapy 13.6: Origins

2. 13.1: Overview June 5, 1981-immune deficiency reported in MMWR Early 1980’s-acquired immune deficiency syndrome linked to a virus 1983-virus isolated in France 1986-virus named HIV Thought limited to male homosexuals. Haitians and heroin users-disease neglected See-”And the Band Played On”

3. 13.2: HIV is a Retrovirus RNA virus that works in reverse Viral RNA is copied over into DNA Reverses the usual direction of copying

4. Retrovirus “life cycle” Reverse Transcription and integration are two key steps. These two steps produce a form of the virus called the provirus.

5. Provirus DNA copy of retrovirus RNA inserted into host DNA Behaves exactly like a regular gene. When active, produces more viral particles. Can cause mutations that lead to cancer. May be passed on through sperm and egg DNA. Endogenous retroviruses are the ones that you inherit from your parents. Most retroviruses are benign and do not cause disease.

6. 13.3: Human Retroviruses-Timeline Year Virus Event 1980 HTLV-I first human retrovirus-Gallo lab at NIH 1981 first CDC report on AIDS (MMWR report) 1982 HTLV-II second human retrovirus 1983 LAV Montagnier lab in Paris isolates virus from pre- symptomatic patient 1984 HTLV-III Gallo lab isolates AIDS-related virus 1984 ARV from San Francisco patient 1985 LAV and HTLV-III are the same SIV-mac a primate retrovirus isolated from macaques 1986 HIV-1 LAV/HTLV-III renamed HIV-1 HIV-2 West African strain-from sooty mangabey monkeys

7. 13.3: Human Retroviruses Both HIV-1 and HIV-2 are classified as lentiviruses (a type of retrovirus) because it takes so long for their symptoms to appear. HIV-2 is “weaker” than HIV-1 and is mainly confined to West Africa. The worldwide epidemic is caused by one group of HIV-1. All other HIVs are primarily African diseases Both are transmitted via body fluids; blood-borne or sexual.

8. 13.4: Targets of HIV-1 Receptor = molecule that virus attaches to CD4 Protein = primary receptor for HIV-1 CD4+ cells = cells that have the CD4 protein on their surface T cells, nervous system cells, other immune system cells. Opportunistic pathogens kill when immune system declines. CCR5 is another important receptor; CCR5/delta32 mutation is a resistant form HIV infection gradually wipes out the immune system and allows opportunistic pathogens to flourish.

9. 13.5: Antiviral Therapy Virus mutates rapidly to become resistant to standard antiviral medications because reverse transcription is error-prone. No one anti-retroviral (ARV) drug can hold the virus in check for long. Combination therapy-the use of several classes of drugs at once-works better. HAART-Highly Aggressive Anti-Retroviral Therapy

10. 13.6: Origins of HIV HIV is closely related to viruses found in other primates: SIV The chimpanzee version of SIV (SIVcpz) is closest of all to almost all HIV-1 Zoonotic disease

11. Evolutionary Tree of SIV and HIV HIV-2 in cluster with SIV-MM HIV-1 in cluster with SIV-CPZ Older tree- incomplete Note HIV-1 Group M

12. Sources of HIV 8 groups of HIV-2: all from sooty mangabey 4 groups of HIV-1 3 from chimpanzee 1 from gorilla

13. SIV jumped into humans at least 12 times to become 4 groups of HIV-1 and 8 groups of HIV-2 But only one of the zoonotic viruses (the M group of HIV-1) spread around the world. What happened?

14. Ideas About the Origins of HIV and How it Spread Cut Hunter-came from wild animal contact via bushmeat- a “natural transfer” Heart of Darkness- brutal colonial regimes disrupted societies and spread disease Used Needles-spread by western medical procedures in colonial Africa Probably a combination of all is correct.

15. Cut Hunter Simplest explanation “bushmeat” as food item Bushmeat exposures to SIV not rare today Blood contact during hunting or butchering

16. Geographic Source of HIV SIV-cpz from southeast Cameroon most similar to HIV-1 M Results from new technologies and many samples

17. When Did the “Jump” Occur? “Molecular Clock” analysis Includes newly discovered samples preserved since 1959 and 1960 Best estimate for jump is 1910 +/- 20 years

18. From Cameroon to European colonies in Congo Basin Via river traffic Reaches capital cities Brazzaville and Kinshasa (Leopoldville) How Did the New Virus Spread?

19. Spreads in capital cities Rapid urbanization Rail and river travel Sex trade Well-established by 1959-60

20. Unsterile Injections Reusable syringes available by 1930 Mass injections against sleeping sickness, malaria, other diseases Sex workers required to be examined at clinics Vaccines, antibiotics But no way to sterilize syringes before reuse!

21. Congo Independence Colonial infrastructure collapses UN peacekeepers Humanitarian aid workers from Haiti HIV returns with workers mid 1960s

22. Spread to US and beyond Via blood products (the Vampire of the Caribbean) Sex tourism Likely introduced by one person Almost all infections outside sub-Saharan Africa traceable to this one transfer