Natural History of HIV Infection

What medical scientists call the natural history of an infection is simply the chronological story of what the microbe does once in the body, and what the body does in response.

Transmission of HIV

HIV is transmitted—that is, the virus enters the body—almost invari­ably by sexual contact, by blood-to-blood contact, or through preg­nancy.

Once HIV enters the body, it attaches itself to the walls of CD4 cells at certain sites, called CD4 receptors (which give CD4 cells their name). After HIV attaches to a CD4 receptor, it enters the cell. At this point, in a complicated series of events, the virus becomes part of the cell’s genes. Genes are composed of DNA, the molecule responsible for directing the cell’s reproduction. HIV is a virus and has only RNA, a molecule that is actually the mirror image of DNA but which cannot produce new viruses. HIV, however, is a retrovirus, meaning that it has a protein called reverse transcriptase, which allows the viral RNA to make a mirror im­age of itself. That is, reverse transcriptase allows viral RNA to turn into viral DNA. The viral DNA then directs the infected cell to produce, not new CD4 cells, but new HIVs instead. The virus eventually destroys the CD4 cell, and the new viruses that have been produced then infect other CD4 cells. The viruses grow rapidly in number, they spread throughout the body extensively, and the destruction they cause is massive. In the first week of infection, concentrations of viruses in the blood reach 1 bil­lion per milliliter, higher than at any other time during the disease.

Acute Infection

The first symptoms of HIV infection, sometimes called acute HIV infec­tion or primary HIV infection, occur about 1 to 4 weeks after the virus was transmitted. Probably at least 50 percent and possibly 80 percent of all people with HIV infection have the symptoms of this early, acute HIV infection. Some people, who have the same explosive growth in the num­ber of viruses, have no clearly defined symptoms; they are said to be asymptomatic, and the reason is unknown.

Many of the symptoms of acute infection are nonspecific; that is, they are also symptoms of many common viral infections. Symptoms in­clude fever, sweats, malaise, fatigue, achiness, joint pain, headaches, a sore throat, trouble swallowing, and enlarged lymph glands. Some peo­ple have a major illness, somewhat like mononucleosis, with a prolonged fever, night sweats, fatigue, and weight loss of 15 to 20 pounds. Some people have a rash consisting of red spots or splotches over the chest, back, and abdomen. Some have evidence of infection of the brain: se­vere headaches, mood changes, personality changes, irritability, and confusion. Occasionally, people lose the use of their arms or legs for a short time, then regain use again.

Because some of these symptoms resemble those of infectious mononucleosis, the acute infection stage is sometimes referred to as a mononucleosis-like syndrome. Mononucleosis, however, is caused by an entirely different virus, and with acute HIV infection the blood test for mononucleosis is negative.

Some people with HIV infection have no recollection of an acute infection stage, some mistake it for a common viral infection or flu, and some people feel sick enough to go to a physician.

All people recover from acute HIV infection, as a result of their im­mune responses. The recovery is accompanied by the disappearance of symptoms and a rapid decrease in the viral load.

Acute HIV infection is important to recognize, because it’s the time when the concentration of viruses is highest and the risk of transmission is greatest; therefore it should also be the best time to learn about pre­vention. But acute HIV infection often is not recognized: for it to be rec­ognized, people would have to have symptoms severe enough to see a physician, and the physician would have to be alert enough to the pos­sibility of acute HIV infection to measure the viral load (which is high at this stage) and test for the presence of antibodies to HIV (which are essentially absent at this stage). If acute HIV infection were more easily recognized, this might be the best time to treat HIV. Early treatment would help prevent transmission, and it might favorably alter the prog­ress of the HIV infection: the former is probable, but the latter is com­pletely unknown.

Seroconversion

At the time of acute infection with HIV, the body has not yet made antibodies to HIV. Antibodies, proteins produced primarily by certain white blood cells called B lymphocytes, attack substances foreign to the body, including viruses. The fact that symptoms are present even though the blood test to detect antibodies to HIV is negative is not un­usual. In most other infections, symptoms precede the body’s produc­tion of antibodies, and the symptoms disappear once antibodies are produced.

The body usually takes several days or weeks to recognize a foreign substance like a virus, and then it produces antibodies to attack the sub­stance. Six to ten weeks after HIV has entered the body, antibodies to HIV appear in the blood in sufficient concentration to give a positive blood test. Physicians call this appearance of antibodies seroconversion. That is, the result of a test for antibodies in the blood serum converts from negative to positive. Over 95 percent of people have positive HIV tests by three months after transmission, and over 99 percent have pos­itive tests by six months.

Antibodies against most viral infections, once they appear, eliminate the virus and then stay in the body to protect against future infections by the same virus. Virtually all people with HIV infection develop anti­bodies against HIV. These antibodies, along with other immune system mechanisms, reduce the concentration of HIV but do not eliminate HIV. Besides antibodies, the other immune defenses that seem important are the CD8 cells. CD8 cells are lymphocytes that include a subset called CD8-38 cells, which are programmed to attack HIV by hormones called cytokines produced by the CD4 cells. This means that a good immune response requires that CD4 cells recognize HIV and then produce cyto­kines to goose the CD8-38 cells, which then destroy HIV. A goal of early treatment is to preserve this function of the CD4 cells before HIV de­stroys it. This goal makes sense, but despite extensive study, it has been hard to carry out.

The problem with all this is that most people with acute HIV infec­tion never see a doctor, and even if they do, the doctor does the diag­nostic tests only 25 to 30 percent of the time.

Asymptomatic Period

For several years after seroconversion, people with HIV infection feel good. Because they have no symptoms of the infection, this period has been called the asymptomatic (meaning “no symptoms”) period. Dur­ing this period the person will be unaware of the HIV infection unless a blood test shows antibodies to HIV. About 70 to 80 percent of the peo­ple who presently have HIV infection are in this asymptomatic period.

For many years, we thought that during the asymptomatic period HIV was resting and not reproducing. We now know this is not the case. HIV is reproducing at an amazing rate, every day making an average of 10 billion new viruses, and every day destroying a comparable number of CD4 cells. And every day, the body produces enough new CD4 cells to nearly offset the loss. But the body, in the long run, can’t quite keep up. The average net loss of CD4 cells is fifty per milliliter of blood per year, accounting for the gradual decline in CD4 cell counts over the years. Most CD4 cells are in lymph nodes, but we measure their counts in blood because blood is easy to obtain and because the counts in the blood reflect the counts in the entire body. So the CD4 count becomes a good barometer of the immune system.

The actual rate of decline, however, is highly variable. About six months after the virus is transmitted, the amount of HIV in the blood— the viral load—reaches a “set point,” a point at which, without treat­ment, it may stay for several years. If HIV’s set point is high, the immune system is not controlling the virus well; the CD4 count falls quickly and the time before AIDS occurs is short. If the set point is low, the CD4 count falls slowly and the time to AIDS is long. This relation between the set point and the progress of the disease makes sense: the viral load is a direct reflection of how fast HIV is multiplying and how well the im­mune system is controlling it.

We also know that treatment makes a decisive difference in the rate of the infection’s progression because treatment resets the set point. The drugs directed against HIV keep the virus from reproducing in the test tube; and the drugs, when given to people, measurably decrease the amount of virus in the blood and do so within hours. In most people who can take treatment successfully, 99 percent of the virus will be elim­inated within four weeks; and within four to six months, most of these people will have “no detectable HIV.”