By David N. Leff
Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.
Four thousand years ago, a gene expressing the CCR5 receptor underwent mutation. Six scientists at the National Cancer Institute¿s Laboratory of Genetic Diversity reported this discovery in 1997. They pointed out that people carrying this gene mutation are immune against HIV infection, and therefore AIDS-proof.
Then in 1998, one of the six co-authors announced that this same CCR5 mutation had emerged seven centuries ago, coinciding with the Black Death (bubonic plague) pandemics that ravaged Europe in the 1300s. The plague pathogen, Yersinia pestis, also utilized the mutated CCR5, conferring HIV immunity ¿in ancestral Caucasian populations.¿ So did the smallpox virus, Variola major, which was also rampant in the Middle Ages. Thus, present-day populations of European descent have those pandemic diseases of yore to thank for their moderate ¿ compared with Africa ¿ susceptibility to HIV infection and AIDS death.
That total homozygous immunity, conferred on their offspring by both parents carrying the mutation, is rare and newsworthy on the modern HIV/AIDS scene. If only one parent passes on the mutant gene, partial immunity results, with full-blown AIDS delayed for two years on average. No mutation at all leaves the HIV-positive individual no protection at all.
That¿s the horrendous situation in sub-Saharan Africa ¿ where more than 20 percent of the population in some countries is infected with HIV. A paper in the Proceedings of the National Academy of Sciences (PNAS), dated Aug. 28, 2001, paints this picture in an article titled: ¿The coreceptor mutation CCR5D32 influences the dynamics of HIV epidemics and is selected for by HIV.¿ Its authors are microbiologists and immunologists at the University of Michigan at Ann Arbor.
They note that 19 million people have died of AIDS since discovery of HIV in the 1980s. Another 5.4 million individuals were infected with the virus in 1999. ¿The staggering rate at which the epidemic has spread in sub-Saharan Africa,¿ the PNAS paper observed, ¿has not been adequately explained.¿ It suggests that host genetics ¿ as well as currently adduced heterosexual transmission and economics ¿ can account for the African AIDS crisis, because the CCR5 mutation rate ¿is almost zero.¿
CCR5 is a host-cell chemokine receptor also used as a coreceptor by certain HIV strains acquired during sexual transmission. That 32-base-pair deletion in its gene frustrates HIV¿s break-and-enter assault on its main target cell, the immune system¿s CD4-flagged T lymphocyte.
The co-authors zeroed in on national HIV/AIDS prevalence data for Malawi, Zimbabwe and Botswana, where HIV infection rates range from 11 percent to 20 percent. They used mathematical models to assess HIV transmission in those and non-African populations with or without heterozygous or homozygous mutations. ¿The absence of this mutant CCR5 allele in Africa,¿ they concluded, ¿could explain the severity of HIV disease as compared with populations where the mutation is present.¿
The paper concludes: ¿This information can influence the design of treatment strategies as well as point to the urgency for education and prevention programs.¿
Adeno-Associated Virus Turned Mutant p53 Tumor-Promoter Into Tumor Suppressor
Dubbed ¿guardian of the genome,¿ the tumor-suppressor gene p53 encodes a protein that binds DNA, and interferes with cell division. If that cell is cancerous, the p53 protein has done its tumor-suppressing job. However, half of all malignant tumors harbor mutated p53, now a tumor-promoting oncogene. It pushes cell division, the very definition of malignancy. That makes p53 a dream target for designing anticancer drugs. It holds out the prospect of treating multiple tumor types with one and the same chemotherapeutic compound.
But like the classic recipe for frying fish ¿ ¿First catch your fish¿ ¿ to develop putative anti-p53 drugs aimed at cancer, first target your tumor. Of many experimental baited hooks along these lines, one of the latest uses the small, innocuous, human adeno-associated virus (AAV) as bait. AAV mimics damaged DNA. A paper in Nature dated Aug. 30, 2001, reporting this ploy bears the title: ¿Virus-mediated killing of cells that lack p53 activity.¿ Its authors are at the Swiss Institute for Experimental Cancer Research in Epalinges, Switzerland.
That virus selectively clicks on apoptosis ¿ programmed cell death ¿ in cells carrying defective p53. When a dividing tumor cell senses AAV¿s pseudo-DNA damage, it grabs a Kevorkian gift certificate and commits suicide. Injection of AAV in tumor-bearing mice, the Nature paper reported, reduced their cancers.
Antioxidant-Mimicking Compound Improves Vascular, Neural Functions In Diabetic Rats
Diabetes mellitus comes in two persuasions, neither of which is a respecter of patients. Type I diabetes, the juvenile-onset version, destroys its own insulin, so condemns its victims to a lifetime of insulin shots (soon inhalations or pills?) several times a day. Type II, which emerges in adulthood, makes insulin, but can¿t metabolize it properly. Diet and exercise are the therapies of choice.
However, over both types looms a pitiless dual verdict: vascular abnormalities and diabetic neuropathy. These complications often don¿t arise until 25 years after the patient¿s initial diagnosis. Then they attack eyes, feet and kidneys, resulting in leg amputations, blindness and organ transplants.
Some 16 million Americans suffer these consequences at an estimated socio-economic cost approaching $100 billion a year. The cause and prevention of these complications have been unclear.
Now preclinical in vivo efficacy studies confirm that a major factor in vascular dysfunction and subsequent nerve damage is an excess of free oxygen radicals. The British Journal of Pharmacology, in its September 2001 issue, reports these trials under the title: ¿Effect of M40403 treatment of diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve.¿
M40403 is the superoxide dismutase mimetic, a proprietary antioxidant developed by MetaPhore Pharmaceuticals Inc. in St. Louis. The paper¿s authors, at the University of Iowa in Iowa City, administered the drug intravenously to diabetic rats and found marked improvement in vascular and neural function.