Family Matters
One of the most compelling observations made by gene hunter Francis Plummer in his Nairobi study is a pattern of "family clustering" of apparent HIV immunity -- as well as susceptibility . Early on, Plummer found that female sex workers coming to the Pumwani clinic had several relatives, including brothers and uncles, who remained uninfected, despite exposure to the virus. If a woman is resistant, he found, her blood relatives have a 50 percent chance of being fully or partly resistant as well. Plummer came to his conclusions after ruling out outside factors such as behavior or ethnicity, disease history, and other genetic influences like gene mutations (see main story).

His preliminary data suggests that the resistant Kenyan families represent what's called an autosomal dominant gene model, meaning, he says, "It's in every generation and you have about a 50 percent chance of inheriting it from your mother or father if they have the gene."

The same inheritance pattern may prove true for people with HIV who get sick very quickly. In other families of sex workers Plummer has studied, HIV has affected every adult family member and caused very rapid illness. Here, too, he's ruled out other factors that might explain this phenomenon.

Plummer thinks that in every individual, different factors come together to determine their response to the virus: a genes-plus-environment or nature-plus-nuture perspective. Along with antibodies like IgA (see main story) and cellular immunity and family clusters, Plummer's group is looking at an immune mechanism called Major Histocompatibility Complex, or MHC, a kind of immunological alarm clock that tells your body when you've been exposed to an outside organism.

MHC molecules are present on the surface of all cells, and their job is to distinguish cells that belong to the body ("self") from outsiders ("nonself"). When a virus infects a cell, certain parts of the virus (viral proteins) will normally be carried to the surface of the cell. They get recognized by MHC and wham-a signal is sent to other immune soldiers like CD8 T cells (T-suppressor) who attack the infected cell (see main story; also Immune Control of HIV).

That's really a super-simple version of what's actually a complicated chain of events. Another key actor in the CTL immune story appears to be something called a human leukocyte antigen, or HLA, receptor. A science textbook will tell you that an antigen is any substance -- a foreign protein, toxin, bacteria, or tissue cell -- that can induce a specific immune reponse and react to other products of the immune system like antibodies.

The HLA receptors are the immune soldiers actually responsible for carrying bits of HIV (called peptides) up to the surface of the cell by binding with the viral fragments. HLA receptors fall into two categories: Class I HLA receptors trigger CD8 T-cell responses (and thus CTL activity); class II HLA receptors trigger CD4 T-cell responses. These HLA receptors determine how much of the virus will be present on the cell surface: the more of HIV's structure that can be seen, the stronger the immune response. Got that?

For now, we're missing many of the details of who does what, when, and how -- the quarterback's playbook -- but we do know that different genes influence the type and structure of different class I HLA receptors and thus the CTL immune response.

One way to imagine it is that the HLA receptors are showing immune CD8 T-cells a description of a wanted criminal: If the HLA receptors reveal only the culprit's clothes, those can be changed to elude detection. The virus can do this by mutating its envelope genes to look different. But if the HLA receptors present a fuller picture of the culprit -- its full structure, or shape, genes, etc. -- the immune system has a greater chance of identifying and attacking the virus. People with the broadest CTL response will be most likely to resist HIV infection.

Plummer suspects that inherited HLA traits have helped create a strong CTL response in some of the Nairobi sex workers and a poor CTL response in rapid progressors. Those who quickly succumb to the virus have HLA receptors that bind to fewer HIV peptides than women who resist HIV. Compared with individuals who appear immune to HIV, rapid progressors can't "see" the culprit as well, so their immune responses can't protect them. The key now is to determine whether, with new drugs or other approaches, we might somehow mimic the action of HLA receptors to induce cellular immunity or slow down the virus.

-ACD, RJ