The Start

It started with the simple observation that certain individuals seemed to have a degree of resistance to HIV-1 virus. For instance, about 15 percent of the hemophiliacs who received blood transfusions never contracted the virus, and about 1 percent of the individuals that test HIV-1 positive, remain healthy and free of the AIDS virus. Scientists began to postulate that perhaps there was a mechanism in the human body that prevented the AIDS virus from taking hold. However, they realized that it was not something that applied to the general population but only a small percentage. So they turned to mother nature's blueprints, DNA, to answer this question. Is there something in our genetic code that hinders the progress of HIV to AIDS and perhaps prevents HIV-1 from taking hold in the first place?

The Search

The first step in viral infection is for the virus particle to bind the cell wall surface and then enter the cell by fusion (see diagram). Scientists first identified the molecule called CD4, which is present primarily on cells of the immune system, as the receptor which binds a virus envelope protein called gp 120. This discovery in the mid 1980's provided understanding of how the virus binds to the cell surface, but biding alone was insufficient for the virus to gain entry into the cell. Therefore, a second coreceptor molecule was required for the virus to get into the cell. The search for this coreceptor lasted almost 10 years.

A Breakthrough

The breakthrough started with the discovery in December, 1995 by Robert Gallo, that suppressive factors which would block invitro infection by HIV-1, were chemokines. Chemokines are small proteins which are responsible for attracting cells to injured or diseased tissues. The discovery that chemokines could suppress infection naturally led to a rapid series of discoveries demonstrating the role of chemokine receptors as the coreceptor for HIV-1 infection.

An explanation

The first coreceptor for HIV-1 was discovered on T lymphocytes now called the CXCR4 chemokine receptor. This molecule enabled T-tropic viral isolates to gain entry into T-cells. Shortly thereafter, the chemokine receptor know as CKR5 was discovered to be the major coreceptor for HIV-1 virus entry into macrophages. These viral isolates are referred to as M-tropic and represent the primary type of virus transmitted by sexual contact and present in the early stages of HIV-1 infection.

The Discovery

At nearly the same time two groups began to discover a mutation in the CCR5 gene which might be responsible for resistance to HIV-1. These groups showed data that illustrates that individuals with a CCR5 defective gene have much greater resistance to HIV-1. In fact, in some cases, where individuals are homozygous (that is they have the defect in both of their CCR5 genes), their cells are extremely resistant to infection with the virus in.vitro, and infection can only be achieved using over 1000 times more virus than ordinarily required.

The Explosion

This discovery has created an explosion in chemokine receptor research. Already scientists are utilizing this discovery in treatment and perhaps developing a vaccine for HIV-1.