HIV Virology

What type of virus is HIV?

It's a retrovirus and it belongs to a sub-family of retroviruses called Lente from the Latin for "slow". What then makes it a retrovirus is that when the virus starts to get into the cell and ultimately enters the cell, the RNA genome is essentially converted - the proper word is "transcribed" but we won't get into that - into a DNA copy of itself. Strange. Now why does a virus want to do that? Very strange reaction. When it was discovered it was unique in all biology because genetic information had gone from DNA to DNA. When cells divide you have DNA going to both daughter cells, right? You duplicate the DNA. And then when you make a protein, you go DNA through an intermediate, messenger RNA finally to make a protein. Going backwards? RNA to DNA? That gave rise to the name retrovirus, catalyzed by a very specific enzyme called reverse transcriptase. Reverse because it's RNA to DNA. Not known in biology before. Why did the virus want to do that? What a waste. No. Because the DNA that's made gets to move from the centre of the cell, the cytoplasm, into the nucleus of the cell, where it integrates into the chromosomal DNA of our cells that it infects. What does that mean? It means the cell is infected forever. But what happens when the cell divides? The viral genes are going to be duplicated with our cell DNA so the daughter cells will have the viral genes as well as the cell genes, and on, and on, and on. So that means the individual is infected forever. These kinds of viruses don't tend to leave a species once they enter for a very long period of time. Hence, we're stuck with HIV and an individual is infected forever and needs therapy forever. For his life. That's what's special about HIV. It's a retrovirus.

What makes HIV a challenging virus?

The forever part is the essence of this problem. Even scientists I think sometimes we tend to forget that or sometimes I hear my colleagues forgetting it. We worry about the variation. It's the foreverness that is the key here. It's makes therapy have to be lifelong. That creates problems doesn't it because people can get drug resistant by being treated for so long or drug side-effects, toxicity, from needing therapy lifelong. So the job of the scientist is never over because we need new drugs based on new basic science because we know this virus may become resistant in this or that person to the existing drugs. In the clinic here in Baltimore where we follow over 4000 patients, my colleague, Dr. Redfield tells me that fifty percent are resistant to the current drugs, multi-drug resistant. Worse fifteen percent of new patients never receiving therapy who got infected in the region here are multi-drug resistant HIV.

What are 'helper T cells'?

A subclass of a general category of cells of our immune system known as lymphocytes. There are two general categories of lymphocytes, T cells and B cells. B cells make antibodies. T cells take part in a host of immunological functions that are non-antibody mediated. For example, some T cells can kill virus-infected cells. Some T cells can kill certain cancer cells. The helper T cell gives signals to killer T cells, for example, to be active in what they're doing. It gives signals to other parts of the immune system and responds to signals from other parts of the immune system to do this or that function. It helps B cells make antibodies. Probably, if I'm not mistaken, that was the original use of the term "helper," for helping the B lymphocyte make its antibodies. It's located in the blood but has origins from a primitive cell of the bone marrow that gets to the thymus gland.

Why is the helper T cell also called the 'CD4 T cell'?

The helper T cell today is more commonly referred to as the “CD4+” T cell. This is a new terminology based on the presence on a surface membrane of a cell of certain proteins. In one case of T cells, it's called CD4. Many of the killer cells, it's CD8. They're just different proteins on the surface of the cell that people empirically discovered when a technique was developed some few decades ago that enabled us to define molecules on cell surfaces.

How does HIV infect our helper T cells?

It's a multi stage process. And it has two receptor molecules that it interacts with. One begins the process, and one is the gate for HIV to enter. The one that begins the process is called the CD4 molecule. CD4 interacts with a protein on the surface of the virus, known as the envelope protein, as a scientific name known as GP120. And it just means it's a protein that has sugar, glycol protein. It means a sugar coated protein if you will. So that sugar coated protein interacts with CD4. Forming like a docking. The two meet, grasp, and when that happens, this structure on the virus. The envelope protein called GP120. We'll picture my hand as the virus. Each of the fingers are this GP120. Now my fist will be the cell. The knuckle will be CD4. It grabs onto that, that's the beginning. When it grabs CD4. When it grabs CD4, this interacting molecule, this finger, this envelope protein, will undergo a change in its shape to find the true gateway into the cell. Which is another molecule. Scientists give funny names called CCR5. I know you'd rather me say Jack, and Jim, and Jane. But it's called CCR5. When it gets on CCR5, the process of getting into the cell truly begins. Ultimately leading to the fusion, a fusion phenomenon, of the membrane of our cell, of our helper T cell. With a membrane of a virus, remembering when that virus picked up that membrane by budding off the surface of our cells in the past. When they come together properly there's a series of chemical interactions that occur, not completely understood today. In which then the guts of the virus enter into the cytoplasm of the cell. The central component to the virus enters. Which it contains the viral genome or the RNA. And contains the capacity to make DNA from that RNA. And that happens, that DNA goes into the nucleus of the cell, so it gets sewed into our DNA, establishing the infection.

How does HIV replicate?

Now you say, how does the virus come back out? Where does the virus go? It's hidden in the DNA form. But when that DNA uses cellular machinery, for the most part, as well as some of its own proteins, but cellular machinery is needed, then the DNA will remake the virus. It will code for viral RNA, viral proteins, and they're remade with a lot of signaling going on and a lot of biochemical regulation going on. And these molecules accumulate underneath the cell surface. And they cause the cell surface to protrude, and that's the budding phenomenon. And the virus pinches off to complete the cycle of replication, or reproduction.

How does HIV spread throughout the body?

HIV spreads in 2 manners one as a free virus in our plasma that's in our blood stream, and presumably also get into lymphatic system which is like the bloodstream and is carried throughout the body where it'll infect other target T-Cells or other cells of the immune system called macrophages. It infects a cell in the brain that is believed to be derived from macrophages called microgleal cells. HIV also can spread within cells; so within T-Cells, within macrophages, those cells move about the body not only in the blood stream but they can enter certain tissue spaces for example within the lymph nodes within the spleen and some other sites where the T-Cell make viruses under appropriate conditions.

Can the immune system destroy HIV?

Our immune system does destroy HIV it creates antibodies that complex HIV and reduce it. It does make killer T cells that can fight virus infected cells. HIV establishes itself permanently and build variable strains or what is called a micro variance of the original strain that can avoid those antibodies and killer T cells. Infection is forever even though you block a lot of virus with antibodies and kills off some infected cells, you don't kill of all of them. Sometimes our genes are silent and there's no way our immune system can see it. That cell can get to a locus where the immune system can't see it. Whether it be in the brain or in a region where local antibodies or killer T cells are hard to get to, new strains of virus and new variants come out. The immune system can't keep up the variants.

Is HIV deadlier than other viruses?

It's not as "deadly" and "killing" right away as some viruses. Take Ebola for example. No comparison. But HIV is far more dangerous than Ebola, because Ebola will never spread in a population significantly. I think talking about vaccines for it, as was done at NIH was a little... Who's going to get vaccinated for Ebola. Even in Africa, this occurs when you don't know it, suddenly and sporadically. The only epidemic you're going to see in this country is if somebody in a plane gets it. Well, the plane will have it, and it will be very deadly. People will be dead in weeks, right. Much more deadly than HIV. But in contrast, it has no "grains." HIV is much more subtle. HIV will stay around. HIV will infect a much bigger population, and it won't go away. Ebola, you're going to see the person dead before your eyes. You're not going to go that close if you don't have to without proper preparation. So it doesn't spread. You take care of the bodies. You bury the bodies. You're sad, but you're alive. It's not going to go all over the place. It's easy to identify. So it's not as deadly in the sense of acute killing, but it has a high proportion of people who get infected that die, as Ebola does, like smallpox, like rabies. A high percentage of people untreated will die. So in that sense, your point is right. Most viruses don't kill with such a high percentage, but it's just that it doesn't go away. It stays there a long time, progressively, insidiously is impairing your immune system, until uh oh. You've reached a threshold, and all kinds of things you could fight off, you can't anymore.