Since it was ﬁrst described in 1981, acquired immunodeﬁciency syndrome, or AIDS, has killed more than 20 million people worldwide. The Joint United Nations Programme on HIV/AIDS estimates that nearly 40 million people are infected with human immunodeﬁciency virus (HIV), the virus that causes AIDS. Every year, 5 million people become infected with HIV and 3 million people die of AIDS. On December 1 of each year, people in every nation observe World AIDS Day to increase awareness of the global epidemic.
|This graphic shows the World Health Organization estimates for the distribution of people with AIDS by region. Sub-Saharan Africa has been hit hardest by the disease and accounts for nearly two-thirds of the AIDS cases in the world. Benjamin Reese / Adapted from UNAIDS|
| HIV is a retrovirus that attacks the CD4+ helper T cells of the immune system, leaving those carrying it more susceptible to infection, such as is seen in AIDS patients. Here HIV is magniﬁed under a microscope. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus|
HIV causes AIDS by disabling the immune system. It infects and kills CD4+ helper T cells, cells that control almost every weapon in the immune system’s arsenal, including antibodies, cytokines, killer cells, and phagocytes. HIV can also infect macrophages and dendritic cells. You could say that HIV launches a preemptive strike on the body by knocking out its defense system.
HIV Is a Retrovirus
Viruses multiply by taking over the protein-making machinery of a cell. The instructions for making proteins are carried in a cell’s genes as DNA. The cell transcribes (transfers) the instructions to RNA and uses the information in the RNA to link amino acids in a speciﬁc order to make proteins. When a virus infects a cell, it forces the cell to copy the virus’s genes. Instead of making its own proteins, the cell makes viral proteins.
“Reverse transcriptase” linked to the RNA strand allows the virus to reproduce. Benjamin Reese / Adapted from NIAID, NIH
Retroviruses such as HIV are unique. They carry their genetic information as RNA and transfer it to DNA. They insert their DNA into the DNA of the infected cell, so that it becomes part of the cell’s own genes.
|Retroviruses such as HIV invade a host cell and use an enzyme called reverse transcriptase to transcribe their own RNA into DNA. This DNA then inserts itself into the DNA of the host cell, which proceeds to reproduce it. Once the virus’s DNA has been replicated a new virus “buds” from the side of the host cell and ﬁnds a new cell to infect. Trudy Nicholson|
Retroviruses are the only organisms known to transfer information from RNA to DNA, a process that requires an enzyme called reverse transcriptase (RT). This enzyme, found only in retroviruses, helped scientists ﬁrst identify HIV. It is also an important target for antiretroviral drugs.
The Three Clinical Phases of HIV Infection
Two to four weeks after infection with HIV, most (but not all) victims get ﬂulike symptoms—fever, body aches, and swollen lymph nodes. This acute phase of the infection lasts two to four weeks. During the acute phase, the virus infects and kills huge numbers of CD4+ T cells, and many copies of HIV are present in the blood.
Then comes a “latent phase,” a phase usually without symptoms. The latent phase can last more than ten years. The number of CD4+T cells in the blood may reach near-normal levels, and then slowly fall again. HIV becomes practically undetectable in the blood, but lurks in other parts of the body, such as the lymph nodes.
Eventually, the infection progresses to the third and ﬁnal phase: AIDS. The number of CD4+ T cells falls to fewer than 200 cells per cubic millimeter of blood (compared with 800–1,200 in healthy people). People with AIDS are susceptible to infection by organisms that are usually harmless to people with normal immune systems. As AIDS progresses, these opportunistic infections become more frequent and the amount of HIV in the blood increases. People with AIDS can develop certain cancers and problems with their nervous systems, which include memory loss, clumsiness, and depression. Ultimately, the immune system is completely destroyed, and the patient dies of overwhelming infections.
Destruction of the Immune System
Scientists do not completely understand how HIV causes such devastation of the immune system. Some researchers think that the initial damage caused by the acute infection is so great that the immune system cannot recover. Others believe that continuing viral activity causes a gradual deterioration of the immune system.
HIV kills infected CD4+ T cells and can kill uninfected CD4+ T cells in several ways. Some cells may be tagged for destruction by the immune system when free-ﬂoating viral proteins stick to them, while other cells receive an incorrect signal to self-destruct.
Even cells that survive may no longer function properly, because HIV infection can cause chronic ac tivation of the immune system. Chronic activation wreaks havoc, reducing antibody production and increasing the number of cells that self-destruct. Chronically activated cells can overproduce cytokines, part of the immune system’s chemical response to an ivader. The dramatic weight loss seen in many AIDS patients, for example, is caused by too much of the cytokine TNF-alpha. Immune activation stimulates the virus because HIV replicates more effectively in activated cells.
Two Types of Immunity
We have two broad types of immune response: humoral immunity and cellmediated immunity. Humoral immunity involves antibodies, which block viruses from entering and infecting their targets. Cellmediated immunity eliminates cells already infected by a virus. During the humoral immune response to HIV most of the antibodies made are ineffective, mainly because the virus escapes by mutating so that the antibodies no longer recognize the HIV. Cellmediated immune responses show greater promise against HIV because T cells recognize more parts of the virus that do not change.
Roadblocks to a Cure
Despite more than 20 years of intensive research, no one has discovered a cure for AIDS. Because an antiviral drug must attack the virus without inhibiting normal cell functions, many AIDS drugs interfere with the reverse transcriptase enzyme that is unique to retroviruses. Others interfere with another virus-speciﬁc protein, protease, which the multiplying virus uses to assemble new virus particles.
RT makes many mistakes when it copies HIV’s genes. These mistakes, or mutations, cause changes in viral proteins. The mutations occur so often that many different forms of the virus exist in the population— and even within an infected person. By mutating frequently, HIV becomes a “moving target” for the immune system and for scientists seeking to develop vaccines and treatments for AIDS. An effective immune response against one form of the virus may be useless against a mutated form, and vaccine developers have been frustrated by the mutation rate because they must design a vaccine that will be effective against all forms of the virus.
|An AIDS researcher examines a test sheet. There is no known cure for the disease, caused by the retrovirus HIV, but researchers are constantly investigating ways to attack it. Bill Branson|
Because of HIV’s high mutation rate, drugs that are quite effective at ﬁrst often become ineffective as the virus mutates into a drug-resistant form. To overcome the problem of drug resistance, three or more drugs can be used in combination. This procedure, called highly active antiretroviral therapy, or HAART, can prolong the latent phase of infection and delay the progression to AIDS.
A cure for AIDS has also been elusive because HIV is an elusive virus. Viral DNA becomes part of the human cell’s DNA. Even if the virus is not actively multiplying, its DNA is present in an infected cell. This is called latency, and a latent virus is essentially invisible both to the immune system and to antiviral drugs. Infected macrophages can act like Trojan horses, carrying the virus to the brain and other tissues. In the brain, the virus is less exposed to the immune system and antiviral drugs because the blood-brain barrier prevents many antiviral cells and molecules from entering the brain.
An incomplete understanding of how to coax the body to ﬁght HIV has hindered vaccine development. To make an effective vaccine, researchers need to know which parts of the immune response can protect against HIV infection. For AIDS and many other infectious diseases of global signiﬁcance, such as malaria and the human papillomavirus (which causes cancer of the cervix), scientists must learn how to generate strong cell-mediated immunity, not just humoral immunity (explained in “Two Types of Immunity.” Scientists need to ﬁgure out how to use parts of the virus to stimulate immune responses that will be effective against HIV.
With the aid of genetic engineering, scientists are developing several vaccines to ﬁght HIV. These include the DNA and vector vaccines that will be described in “Research Advances: Recent and Prospective”. Many of the rules of the immune system must also be worked out to allow for the injection of a safe form of a vaccine to lead to protective immunity, particularly cell-mediated immunity.
HAART has been very effective, helping infected people live longer and healthier lives. Scientists continue to study new treatments to boost the immune system and kill or inhibit the virus. For example, some drugs may keep the virus from multiplying by blocking its initial attachment to cells. Although research on HIV and AIDS has not yet produced a cure, it has increased our understanding of viruses and the immune system, opening doors to new treatments for AIDS and many other diseases.