Are you HIV Resistant?

1. Are you HIV Resistant? By: Ashley Arnett Advisor: Dr. Grimes

2. Introduction • Since the 1980’s many people have been infected with HIV. • However, not everyone who is exposed to the virus gets sick. • Scientists have carefully studied people who seem resistant to the HIV infection. • The very rapid evolution of the HIV virus makes it extremely difficult to treat. But, scientist are pursuing all avenues to learn methods to impede the infection.

3. HIV/AIDS • In June 1981, the first cases of what was later called acquired immunodeficiency syndrome (AIDS) in the United States were reported. • Since 1981, the HIV epidemic has continued to expand in the US. • Approximately 1 million people are living with HIV/AIDS in US. An estimated 25% of whom are unaware of their infection.

4. Background • Two incidents have indicated that the natural resistance to HIV-1 infection, while rare, does exist. • First there are individuals who have been exposed to HIV, sometimes repeatedly and over long periods of time who have remained HIV-negative. • These people were commerical sex workers, infants born to positive mothers, health care workers and IV drug users.

5. Background • Second, there are individuals who have been infected with HIV but whose disease has not progressed or has progressed extremely slowly compared to the average experience. • What is different about these people???

6. What’s different about these People? • The individuals who seem to have complete natural resistance to the HIV virus are homozygous for the CCR5-delta32 gene. • The individuals who are termed “slow progressors” are heterozygous for the CCR5-delta32 gene.

7. CCR5 • HIV-1 needs two receptors to gain entry into human cells; the CD4 receptor found on some cells of the immune system, and the chemokine co receptor used by most circulation strains of HIV-1 (CCR5). • Once HIV has bound to CD4 and CCR5 and the area of the virus is exposed that can fuse with the human cell, it permits entry of the viral genetic material into the cell.

8. CCR5-delta32 • CCR5-delta32 is a polymorphism in the gene encoding CCR5 in which a 32 base pair has been deleted. • The distribution of CCR5-delta32 varies geographically. • The frequency of the mutation is about 10% in Europe and nearly absent in Africans and East Asians. • In the United States, about 1% of Caucasians have at least one copy of the gene.

9. HIV resistance? Why is the CCR5-delta32 mutation so frequent in Northern Europe? It is possible that this gene provided resistance to previous epidemics. If true, people with CCR5-delta32 mutation would have been more likely to survive and pass it down to their offspring.

10. HIV Resistance • Two different diseases were widespread in Europe when this mutation is believed to have arisen. • Resistance to bubonic plague )also called the Black Death) might have influenced CCR5-delta32 distribution. • Recent findings name smallpox immunity as another strong possibility.

11. The Black Death • In 1665, the black plague hot a small village in England called Eyam. The town quarantined itself to keep the Black Death from spreading, • A year later half of the townspeople were dead. • In 1996, researchers tracked down rhw descendants of the half that lived. • They found the mutation called CCR5-delta32. • The mutation was already known to be the special component in mysteriously HIV resistant individuals.

12. The Black Death • The Black Death was one of the most deadly pandemics in human history, killing about 40% of the European population. • Today, what we call the Bubonic plague is caused by the bacterium, Yersinia pestis. • Scientist now suggest the actualy cause to be mixed with a virally borne hemorrhagic fever. • This may be different from what you have learned about the Black Death because in Europe the graves are crawling with Yersinia pestis. Both diseases probably co-existed, but the virus being the one to cause most of the deaths and the CCR5 mutation.

13. The Bubonic Plague

14. Smallpox • An acute infectious disease caused by a virus. No one has contracted smallpox since 1977 and was declared ericated from the Earth in 1980. • It was estimated that the official figures reported to WHO represently only 2% of the true incidence. • Poxviruses infect lymphocytes via a close relative to CCR5, so cross-resistance could have occurred.

15. Smallpox

16. Smallpox vs. Black Death • Smallpox was not as catastrophic as the Black Death, but it did primarily kill children which usually do not make it into historical accounts. • The Cumulative effect of small scale smallpox epidemics over 700 years killed far more than the Black Death Pandemic • The intermittent nature of the plague was caused at least in part by indirect transmitting between rodent reservoirs via fleas. • Smallpox was transmitted directly between humans resulting in a more contagious transmitting.

17. Research • Scientist studying HIV first learned about the gateway blocking capacity of the CCR5 mutation in 1996. • Several drug companies, then quickly began exploring the possibility of developing pharmaceuticals that would mimic delta32 by binding to CCR5 and blocking the attachment of HIV.

18. Research • Previous methods of treatment interfered with HIV’s ability to replicate after the virus has already entered the cell. • This new class of HIV treatment, called the early inhibitor or fusion inhibitor drugs seeks to prevent the virus from ever attaching at all. • These pharmaceuticals are still in relatively early stages of development, but certainly stand as a hopeful new method of approaching HIV treatment.

19. HIV Therapy

20. Early Inhibitors/ CCR5 antagonist • Maraviroc is an entry inhibitor. Specifically, maraviroc blocks the chemokine receptor CCR5 which HIV uses as a co-receptor to bind and enter a human helper T cell. • Maraviroc was developed by the drug company Pfizer. On April 24, 2007 the U.S. FDA recommended approval for the new drug, and the drug received full FDA approval on August 6, 2007 for use in treatment experienced patients.

21. Summary • CCR5-delta32 has a specific impact on the function of T-cells. The mutation is widely dispersed throughout Northern Europe and in those of European descent. • It has been hypothesized that this allele was favored by natural selection during the Black Death or during small pox outbreaks. • The allele has a negative effect on T cell function, but appears to protect against smallpox. Plague and HIV.

22. Research For Up-to-date information about current clinical trails and research information. • http://www.aidsresearch.org/?gclid=CNqaufbE4pICFR_NIgodak486Q WARNING: Please do not partake in risky behavior and assume that you can not contract HIV just because your grandmother is British…You may be disappointed 

23. References • Cohn, SK., Weaver, LT. “The Black Death and AIDS: CCR5- Delta 32 in genetics and history.” QJM, 2006 Aug; 99(8) 497-503 • Duncan, CJ. et. al. “Reappraisal of the historical selective pressures for the CCR5 Delta 32 mutation.” Journal of Medical Genetics, 2005 Mar; 42(3):205-8 • Duncan, CJ. et. al. “What caused the Black Death?” Postgraduate Medical Journal, 2005 May; 81(955):315-20 • Duncan, CJ., et. al. “Frequency analysis of the delta 32 CCR5 HIV resistance allele in a medieval plague mass grave.” 2006. • Galvani, AP., Staltkin, M. “Evaluating plague and smallpox as historical selective pressures for the CCR5- Delta 32 HIV resistance allele.” Proceedings of the National Academy of Sciences of the United States of America, 2003 Dec; 100 (25):15276-9 • Guilherme, A., et. al. “CCR5 receptor gene and HIV infection.” National office of Public Health Genomics, 2002. • Hedrick, PW. Verrelli, BC. “Ground Truth” for selection on CCR5 Delta 32,” Trends in Genetics. 2006 Jun; 22(6):293-6 • Hummel, S., et al. “Detection of the CCR5 delta 32 HIV resistance gene in Bronze Age skeletons.” Genes and Immunity, 2005; 6, 371-374 • Lu, Y., “Genotype and allele frequency of a 32 base pair deletion mutation in the CCR5 gene in various ethnic groups: absence of mutation among Asians and Pacific Islanders.” International Journal of Infectious Disease. 1999 Summer; 3(4):186-91

24. References • Nelson, M., et. al “The role of CCR5 and CCR2 polymorphisms in HIV-1 transmission and disease progression.” Nature and Medicine, 1997; 3, 1160-1162 • Quillent, C., et. al. “HIV-1 resistance phenotype conferred by combination of two separate inherited mutations of CCR5 gene.” Lancet, 1998 Jan; 351(9095):14-8 • Silva, E., et. al. “HIV and the CCR5 delta 32 resistance allele.” FEMS Microbiology Letters, 2004 Dec; 241(1)1-12 • Smoljanovic, M. et. al. “Historic exposure to plague and present day frequency of CCRdde32 in two isolated island communities of Dalmatia, Croatia.” Croat Med J. 2006, Aug; 47(4):579-84 • Styer, KL. et. al. “Study of the role of CCR5 in a mouse model of intranasal challenge with Yersinia pestis.” Microbes and Infection, 2007; 9 (9):1135-9 • Zhang, C. “Distribution of the CCR5 gene 32 basepair deletion in Chinese populations.” Anthropologischer Anzeiger, 2002 Sept; 60(3): 267-71