Resistance to HIV/AIDS

It has taken a while for the general public to know that for any drug, no matter how effective it is as advertized by the pharmaceutical company who developed it, it may not work for everyone who takes it. It is however an ancient knowledge that for any infectious disease, no matter how deadly it is, it seldom kills every human being who gets exposed to it.  Now, we know the reason behind both facts is the same: the genetic make-ups of each human being are different. So for drugs, we need to pick up the concept of “personalized treatment” as it has always been practiced in Chinese and other eastern medicine. And for diseases, we need to map our own personalized risk profiles. The question is where to look.

For HIV/AIDS researchers, they knew exactly where to look, because among the HIV high-risk populations, some small percentage showed either resistance or delayed development of AIDS. In 1996, their luck struck, when a deletion form of gene CCR5 was shown highly enriched in this HIV resistant group. Knowing the prime suspect, several group of scientists demonstrated that in order for HIV virus to infect a T-cell, it required a co-receptor to gain entry into the cell (see below) so that they can start propagating itself. CCR5 just happens to be one of the major co-receptors. The mutant form of CCR5 discovered in HIV-resistant population has a 32-base pair deletion at codon 175 and results in a reading frameshift after amino acid 174, which adds 31 novel amino acids before it hits a stop codon. This mutant allele, called CCR5-del32, cannot perform its normal functions, nor can it serve as the co-receptor for the most common sub-type of HIV, the HIV-1. Therefore, those who carry a single copy of CCR5-del32 allele would have delayed development of AIDS; and those who carry both copies of CCR5-del32 allele would not develop AIDS at all.

When scientists started to check the allelic frequency of CCR5-del32 in current population, they found that CCR5-del32 seems to be restricted to European, West Asian, and North African populations. The allele frequency exhibits a north–south cline with frequencies ranging from 16% in northern Europe to 6% in Italy and 4% in Greece. A recent refined map put Sweden, Finland and areas around St. Petersburg (Russia) as the regions with highest allelic frequency of CCR5-del32 tested. Since HIV became a pandemic only in the mid-1990’s, its selective pressure is too soon to be accounted for this geographic distribution pattern. Using the Coalescence Theory, a group of scientist estimated the origin of the CCR5- del32 allele to be around 700 years ago. And it just happened that from 1346 to 1352 (650 years ago), Europe was devastated by Black Death, while the bubonic plague claimed the lives of 25%–33% of the Europeans. Therefore, the plague (bacillus, Yersinia pestis) was an obvious candidate attributed for the enrichment of CCR5- del32 allele frequency in European populations.

Later genetic evidence has put the origin of CCR5- del32 allele back in time as early as the Mesolithic-Neolithic transition period (5,000 years ago) in Scandinavia. What’s interesting (and puzzling) is that the allelic frequency of CCR5-del32 found in the teeth DNA of ancient human remains in Sweden is about the same as that of the modern-day Swedish population.

Aside from the origin mystery, it is clearly true of the “benefit” by carrying the mutant CCR5- del32 allele. Like HIV, many infectious microorganisms such as the Yersinia pestis, Shigella, Salmonella, and Mycobacterium tuberculosis, all attach the macrophages. Having a mutant CCR5- del32 allele could have helped fighting those infections.