Author : Frederick (Rick) Hecht, MD, is Professor of Medicine at the University of California, San Francisco, in the Division of HIV/AIDS at San Francisco General and the UCSF Osher Center for Integrative Medicine.

2009-02-18

HIV

Human Immunodeficiency virus

Human Immunodeficiency Virus (HIV) is the virus that causes the Acquired Immunodeficiency Syndrome (AIDS). Although some people can have HIV infection for years without apparent damage to the immune system, most people with HIV progress to AIDS over a period that typically ranges from 6 to 12 years. In AIDS, the immune system is unable to function properly, and without treatment this advanced stage of HIV disease is uniformly fatal. HIV is a retrovirus that can splice itself into human chromosomes and remain hidden from the immune system within the genetic material of immune cells. There is no known cure for HIV, but there are now a variety of highly effective antiretroviral drugs. These drugs can halt HIV replication and prevent or even reverse damage to the immune system by HIV. The key ways HIV is transmitted are through sexual contact and use of contaminated needles (for example those used for injecting drugs). It is not transmitted through casual contact.

The HIV Virus

Viruses have been called “obligatory intracellular parasites.” They are so simple that there is debate about whether they should be considered living entities. They lack basic components needed to replicate themselves. In order to replicate, they have evolved so that they are extremely well adapted to hijacking systems within the organism they infect to serve the virus rather than the host. Essentially, the virus replaces the blueprints used by normal host cell functions with directions to replicate the virus instead.

HIV is a member of an unusual family of viruses: the retroviruses. The “retro” part does not mean that these viruses are fashionably nostalgic, but instead refers to the fact that these viruses take a step that reverses the natural order of genetic processes. In other living organisms (and even viruses if you don’t count these as living organisms), DNA serves as the main “storage media” for genetic information. A copy is made into a slightly different “media,” RNA, which serves as the working blueprint for assembling proteins. This is a one-way step: DNA to RNA. Retroviruses reverse this process. They infect the cell in RNA form, but carry a special enzyme, reverse transcriptase (RT). RT turns the natural order on its head by taking the RNA form of HIV and creating a DNA copy. The DNA form of HIV gets spliced into the host chromosome (which is made up of DNA). Then, when the host cell makes RNA copies of the DNA in the chromosome, instead of making blueprints for its own proteins, it makes HIV viral RNA.

Lifecycle

Understanding the lifecycle of HIV is more than just an academic exercise: it is key to truly understanding how current HIV treatments work. Each of these treatments are been based on understanding what HIV must do to reproduce, and developing methods to disrupt each step, wherever possible.

Figure: An HIV virion (green and red) binding to a CD4+ T-lympocyte (from Frontier HIV)

To replicate, HIV faces a series of challenges. First it must accomplish cell entry. Human cells are guarded by an external cell membrane, which has as one of its many functions keeping dangerous intruders (like viruses) out. To cross this barrier, HIV uses external receptors that are designed to interact with the outside world as a docking station and passageway into the cell. HIV binds to two different receptors in the process of cell entry. The first is the CD4 receptor. This is a receptor that is a distinctive feature of the key target cells for HIV: the CD4+ T lymphocyte (more about these cells soon). HIV has two glycoproteins on its envelope (outside covering), with the somewhat dry names: gp120 and gp41 (gp stands for glycoprotein). The job of gp120 is to bind to the CD4 receptor while gp41 essentially helps hold gp120 in place. When the viral gp120 binds to human CD4 molecule, it sets off a change in the conformation of proteins in the HIV envelope. This change in the shape of envelope proteins allows the virus to bind to a second receptor (referred to as a co-receptor for cell entry). HIV uses one of two molecules as a co-receptor: CCR5 or CXCR4. Both of these are chemokine receptors, used by the cell to help direct it to places in which other immune cells are sending off chemoattractant signals (chemokines). Which co-receptor HIV uses is an important issue as it determines viral tropism (the types of cells it can infect), which is covered later. For now, the key issue is that once HIV has bound to both CD4 and a co-receptor it sets off a series of dramatic events that sound a little like a Hollywood horror movie. gp41, which is normally coiled up, springs open, exposing previously hidden structures (peptide fusion domains) that harpoon the human cell membrane and begin to fuse the viral envelope to the unfortunate cell's membrane.

Figure: HIV lifecycle. HIV binds to the CD4 receptor and CCR5 or CXCR4 co-receptors in order to fuse with the cell membrane (step 1). The HIV RNA is released into the cell, along with viral enzymes (step 2). One of these enzymes, reverse transcriptase, builds a DNA copy of the original viral RNA. In the DNA form, the virus can be integrated into the human cell's DNA (genetic material) and becomes a "provirus" (viral genetic material in the host chromosome that forms a blueprint for new virus production). This step (3) is done by the viral enzyme integrase. An active virus is transcribed into RNA by human cell enzymes (step 4) and forms new parts of the virus. Thousands of new virions (complete viruses) are assembled together in an infected cell and bud off to infect a new cell (step 5). From the Gladstone Institute of Virology and Immunology

Once fusion has occurred, the inside of the virus enters the inside of the cell and springs into action. There are two key types of ingredients inside an inner protective coating (the nucleocapsid): the viral genetic material, which contains all the genetic information needed to make HIV, and a set of viral enzymes that are necessary for HIV to accomplish the next steps in its mission. A special enzyme that we have already discussed, reverse transcriptase (RT), plays its key role next. It “reverse transcribes” the HIV RNA genetic material, eventually producing a double stranded DNA version of HIV that is ready to be spliced into the host chromosome.

The next key task for HIV is to get the DNA version of the virus into the nucleus of the cell (where the chromosome lies). This is not a simple task: the nuclear membrane has pores (or openings) that are about half the normal diameter of the HIV DNA complex. HIV must perform some complex squeezing and contortions to get into the nucleus. How HIV accomplishes this task is not completely understood, but some of the key players in the whole process have been identified. The HIV integrase protein is one of the essential elements. Integrase forms a complex with the HIV DNA and several other proteins and helps shepherd the DNA into the human cell nucleus. Once inside the nucleus, integrase, just as it name suggests, integrates the HIV DNA into the human chromosomal DNA. At this point HIV has successfully become part of the doomed cell’s genetic material, and can function just as a gene that was inherited from a parent- but in this case the gene, instead of leading to something useful like brown eyes or insulin, turns the cell into an HIV production factory that ultimately lyses most infected cells as hundreds of virions bud from the cell.

To complete its lifecycle, several key steps remain. Most genes in any particular cell nucleus are inactive (for example, you don’t want brown eye pigments being made in the pancreas, or insulin being produced in the eye). HIV must turn on what is known as transcription of its genes in order to express its genes. This is done by the HIV Tat gene. Once transcription is turned on, RNA copies of the DNA version of the virus (known as “pro-viral DNA) are made and go out of the nucleus into the rest of the cell. Here they serve as templates for producing all the key viral proteins.

Once the viral proteins have been produced, they migrate to the outer regions of the cell, next to the cell membrane. Through a series of additional steps, they become packaged together, and then wrapped in a combination of the human cell membrane, peppered with viral glycoproteins to form a new virus envelope. The whole package buds off the cell membrane and finally is released from the cell.

Only one step remains to make a fully mature virus, once budding has occurred. Some of the viral proteins are produced as one long protein containing multiple different proteins. To become mature, this “precursor polyprotein” must be cut in multiple places to form the final active proteins. This job is performed by HIV protease, a protein that can bind to a specific sequence in the precursor polyprotein and snip the protein in just the right place to reveal the finished proteins. At this point, the mature new HIV virus (called a virion) is ready to find a new cell to infect, and the viral lifecycle is complete.

How does HIV cause AIDS?

A new immunodeficiency syndrome that had appeared in homosexual men was first described in 1981. This immunodeficiency syndrome was eventually named the Acquired Immunodeficiency Syndrome (AIDS). The patterns of how the disease spread (or epidemiology) suggested that it was caused by an infectious agent, and seemed very similar to viral infections such as hepatitis B. These clues set off an intensive search for the potential cause of AIDS. In 1985, three different groups described a virus that they had identified as the likely cause of AIDS. Each group identified what appeared to be the same virus, one that was eventually named Human Immunodeficiency Virus (HIV).

A series of subsequent discoveries helped to confirm that HIV was the cause of AIDS. Two findings are perhaps the most convincing that HIV causes AIDS. First, the discovery of the HIV virus permitted the development of an HIV antibody test that could detect infection with HIV. Essentially everyone with the clinical picture of AIDS turned out to have HIV infection. Secondly, the discovery of HIV led to the development of treatments that specifically block HIV from replicating. These treatments have proved extremely effective in preventing and even reversing the development of AIDS-associated illnesses in persons with HIV.

While there is very strong scientific evidence that HIV causes AIDS, how exactly HIV causes immunodeficiency remains an area of active investigation; there are many answers but a few important questions remain. The hallmark of immunodeficiency in HIV is the loss of CD4+ T-lymphocytes. These cells are a key part of the immune system and orchestrate responses by other parts of the immune system. The loss of CD4+ T-lymphocytes leads to immunodeficiency (lack of certain immune responses), which leaves the affected person vulnerable to infections and certain cancers.

At first it would seem obvious how HIV causes loss of CD4+ T cells. As discussed in an earlier section, HIV uses the CD4 receptor to enter cells. It is clear that HIV mainly infects CD4+ T-cells, and that most (but not all) infected cells die within 1-2 days once they are infected. In most HIV infected people, more than a billion new viruses are produced each day [1], and the daily number of newly infected cells may be in the millions. So where is the mystery?

Even with the loss of large numbers of CD4+ T-cells each day, it appears that the body should be able to make enough new cells to replace those killed by HIV. Detailed studies suggest that there is both a fairly rapid turnover of CD4+ T cells and a gradual loss of the ability to replace lost CD4+ T cells [2]. Another puzzling part of the picture is that HIV’s closest cousin, Simian Immunodeficiency Virus (SIV), in some of its natural hosts such as African Green Monkeys and Sooty Mangabeys, have high levels of viral replication- but do not lose CD4+ T cells. This has been termed a “non-pathogenic SIV infection.” The same viruses in other monkeys, such as Macaques, get both viremia and loss of CD4+ T cells- in other words a pathogenic SIV infection that closely resembles HIV (note that this example of immunodeficiency caused by SIV is also one more important piece of evidence that HIV causes AIDS). One of the features that distinguishes SIV infection in Macaques is that they get high levels of T cell activation, while the natural hosts with non-pathogenic infection do not. It also turns out that T cell activation is a key feature of HIV infection. It predicts loss of CD4+ T cells and disease progression more accurately than measuring the amount of HIV virus in the blood [3, 4].

In the face of a deadly infection, it would seem that having immune cells that were active would be a good thing. Why would T cell activation be a bad thing in HIV? To answer this question it is important to know a little about T cell activation. In the body’s defense system, activation of these lymphocytes appears to be designed as a response to a short term infection rather than to an infection that doesn’t go away, like HIV. Activating potent immune cells is a two-edged sword: it helps fight an infection, but too much immune activation can cause damage to the body, and may result in auto-immune diseases. Probably in part to guard against the hazards of immune activation, activated T cells, especially activated CD4+ T cells, tend to self-destruct after they have done their job. Scientifically, this is call apoptosis or programmed cell death. In addition, activating these T cells doesn’t tend to do much to HIV. Among other things, HIV can mutate or change rapidly to escape detection by the immune system as soon as effective responses are organized (more about how HIV evades immune responses later). To make matters worse, activated CD4+ T-cells are the ideal targets for HIV infection- they are most easily infected by HIV, and activation seems to turn on all the functions HIV needs to replicate well.

To put together a picture of the havoc wreaked by HIV on an activated immune system, one might imagine the following: you are engaged in a war with an alien enemy from outer space that hides inside humans. The alien is able to turn its victim’s bodies into factories to produce more aliens. After a few days, the victim’s body splits open and hundreds of new aliens pour out. The humans encasing the aliens look normal unless subtle clues that something is wrong are recognized. As soon as you troops learn to recognize the signs that a human has been taken over, the aliens are able to put on a new disguise. To make matters worse, when commanding officers engage in a battle, they are somehow compelled to wave a red flag that advertises their location as ideal targets for alien invaders and are often taken over. With the leadership disrupted, the troops can’t quite figure out where to shoot, and often start firing heavy weapons in random directions. As a final blow, if your officers escape becoming alien infant chow, those that are most excited about participating in battle often commit suicide within days after leading an attack.

Unfortunately, this dismal picture is not far from what actually appears to occur in HIV infection. The combination of excessive immune activation for years, together with direct killing of CD4+ T cells by HIV, results in increased turn over of these cells and a gradual sapping of the ability to keep replacing lost cells.

Stages of HIV

Up to 80-90% of people develop a brief period of symptoms that resembles common viral infections shortly after becoming infected by HIV [5, 6]. These symptoms typically begin 1 to 4 weeks after infection and last from a few days to a few weeks. Common symptoms include fever, rash, severe fatigue, muscle and joint aches, and a sore throat. The only way to distinguish them with certainty from other viral illnesses is to perform testing, which is covered in the next section. This period of symptoms occurs before immune responses are well organized against HIV, and the symptoms typically resolve as the levels of virus begin to drop as the immune system fights the virus. This initial stage of HIV infection is called primary or acute HIV infection.

After primary HIV infection, there is a period of infection in which most people experience no symptoms from the infection. Normal CD4+ T-cells counts are above 500 cells/µl. Most people experience no symptoms of HIV infection until the CD4+ T-cell count falls below 350 cells/µl (Table 1). Between 200 and 350 cells/µl, infected persons may begin to experience mild symptoms that may not be easily recognized as related to HIV if the infection is undiagnosed. These symptoms include mild fatigue, and increased risk of developing shingles (herpes zoster), thrush (yeast infection of the mouth), bacterial pneumonia, and tuberculosis. Occasionally, Kaposi’s sarcoma (a type of cancer) may occur while CD4+ T-cell counts are still above 200 cells/µl.

Once the CD4+ T-cell count falls below 200 cells/µl, serious opportunistic infections and cancers begin to occur, especially once the CD4+ T-cell count is below 100 cells/µl. Without any treatment, the median time from infection to these AIDS-defining illnesses is about 10 years, though many people may progress either more or less rapidly.

The immune deficits that occur with HIV infection result in a wide range of complications that can affect every part of the body. Most of these complications result from infections that take advantage of a weakened immune system, but some involve cancers and auto-immune problems; some problems also appear to represent direct effects of HIV. Detailed guidelines from expert panels for treatment and prevention of opportunistic infections can be found at http://www.aidsinfo.nih.gov/Guidelines

CD4+ T-cell counts are a component of the disease staging classification from the United States Centers for Disease Control and Prevention (CDC) [7]. The diseases noted in Table 1 with round bullets represent those that are considered AIDS-defining clinical conditions in the CDC criteria. In addition, current CDC criteria define someone with a CD4+ T-cell count below 200 cells/µl as having AIDS even if one of these complications has not yet developed. The World Health Organization (WHO) has provided an alternative system for classifying HIV disease for use in resource limited settings in which CD4+ T-cell counts are not available [8].

Table 1: Common HIV-related complications and AIDS defining conditions by stage of immunosupression (see also knol on AIDS)

CD4+ T-cell count range	Typical Conditions
> 500 cells/µl	Normal range, no symptoms except during primary infection (first few months)
350 to 500 cells/µl	Usually no symptoms. May have a slightly increased risk of tuberculosis and long periods of time in this range may modestly elevate the risk of cancer and heart disease.
200 to 350 cells/µl	Increased risk of: Shingles (herpes zoster) Bacterial pneumonia Oral candidiasis (yeast infection of the mouth) and vaginal candidiasis Fatigue Oral hairy leukoplakia Tuberculosis * Kaposi's sarcoma Mycobacterium tuberculosis *
100 to 200 cells/µ	Cervical cancer, invasive * Lymphoma, Burkitt's or immunoblastic Pneumocystis carinii pneumonia (PCP) Toxoplasmosis of brain · Coccidioidomycosis outside the lungs · Cryptococcosis outside the lungs · Histoplasmosis outside the lungs · Pneumonia, recurrent
< 100 cells/µl	· Esophageal or bronchial candidiasis (yeast infection) · Cryptosporidiosis greater than 1 month's duration · Cytomegalovirus infection of retina, esophagus or intestines · Herpes simplex: chronic ulcer lasting more than 1 month or esophagitis · Lymphoma originating in the brain · Mycobacterium avium complex (MAC) · Progressive multifocal leukoencephalopathy (PML)

Conditions are listed by the CD4+ T-cell count range in which they commonly first occur. The risk of most conditions increases as the CD4+ T-cell count drops. Round bulleted conditions indicate AIDS defining clinical conditions using the 1993 CDC definitions * = a condition in which the CD4+ T-cell count must be < 200 cells/µl and the HIV antibody test must be positive to meet criteria for a clinical AIDS-defining condition.

HIV Testing

HIV antibody tests can detect whether someone has antibodies directed to the HIV virus. They are now central to diagnosis of HIV infection, and allow diagnosis before AIDS-related complications have developed. Several different types of antibody tests are available. Standard blood tests are usually performed with two different steps. The first step is an Enzyme Linked Immunosorbent Assay (EIA, also called an ELISA). This is a test that can be performed rapidly to detect antibodies. If the EIA is negative, no further testing is done and the person is considered uninfected. If the EIA is positive, a second confirmatory test is performed. This is usually a Western blot test, which detects antibodies to specific parts of the HIV virus. Only if both the EIA and Western blot are positive is the individual considered HIV infected. If the Western blot is completely negative, the person is also considered HIV negative. If the Western blot is positive for antibodies to some parts of the virus, but not to 2 of 3 key parts, it is considered “indeterminant” and further testing is usually suggested.

Because HIV tests are detecting antibodies directed against the virus, it take some time after infection has occurred before the test turns positive (detects antibodies). Early HIV antibody tests took several months after infection to turn positive. Tests that are currently used for HIV testing typically turn positive about a month after infection has occurred [9]. After this time, they detect nearly everyone with HIV infection, and have a very low rate of false positive tests (positive results in someone who does not have HIV).

Despite the shortened window period between infection and seroconversion (development of a positive blood or serological test) on current HIV antibody tests, most persons with acute HIV symptoms will have negative results on conventional antibody tests. In this situation, diagnosis requires detection of viral antigens (parts of the virus, rather than antibodies against the virus). This can be done using p24 antigen tests, or viral nucleic acid amplification tests (NAAT), such as viral load tests. Earlier p24 antigen tests had excellent specificity (rare false positive tests in persons without infection), but only had a sensitivity of 80% for pre-seroconversion acute HIV[10, 11] (this means that 80% of people with acute HIV symptoms and actual infection will test positive). While viral load tests used for monitoring HIV infection are highly sensitive for acute HIV in persons with symptoms, the specificity ranges from 97 to 99% [10, 11]. This means that in a moderate risk population undergoing testing, a substantial proportion of positive tests will represent false positive tests. Although most false positive viral load tests will produce results with low viral copies (less than 3,000 copies/ml), these quantitative tests have not been approved by the FDA for diagnosis of HIV infection, in part because of the issues with false positive tests. A qualitative nucleic acid test, Aptima (Gen-Probe, San Diego), has recently been approved by the FDA for diagnosis of acute HIV, and a related assay has been used for blood donor screening since 2002. In addition, p24 antigen tests have been improved.

There are 3 different "generations" of HIV antibody tests that are used now. In the US, the standard antibody test for HIV is a 2nd generation test (using an improved version of the EIA antibody tests used in the original 1st generation tests). 2nd generation tests detect IgG antibodies, which take several weeks to develop after an infection. 3rd generation tests can detect IgM as well as IgG antibodies, a second type of antibody that develops first after a new infection, but fades after a few months. These tests are used primarly in testing blood donations. So called “4^th generation” antibody tests combine antibody detection with very sensitive p24 antigen detection. These tests can diagnose HIV infection starting only a couple of days after viral load tests (typically 1-2 weeks after infection), and appear to be positive in most people with acute HIV. They are not licensed yest for use in the US, but are being used in parts of Europe and Brazil.They are likely to be licensed soon for use in the US.

Transmission and prevention

HIV is not an easily transmitted virus. The virus is reasonably fragile and skin is an effective barrier. To cause infection HIV has to pass through a break in skin, or through mucous membranes (the lining of internal organs such as the vaginal wall). It is not transmitted through casual contact such as sharing eating utensils or touching someone with HIV. The most common ways that HIV is transmitted [link to HIV article] are through sexual contact and through sharing needles or other equipment used to inject drugs. It can also be transmitted from mothers to infants. This can occur while the fetus is still in the uterus, but the greater risk is during childbirth. Cesarean section reduces the risk of transmission to an infant during birth. Giving HIV drugs to the mother before and during childbirth can reduce the risk of transmission to an infant from about 25% to less than 2%. HIV can also be transmitted through breast feeding. This risk can be reduced two ways. Bottle feeding eliminates this risk. In the developing world, this is often not practical, and can increase the risk of other infections. Recent data suggest that the risk of HIV transmission through breast feeding is greatest when infants are fed solid food or even water or animal milk before age 6 months. An alternative formula feeding in settings in which formula feeding is difficult or impossible is to exclusively breast feed infants until the age of 6 months.

Use of condoms by men has been shown to reduce the risk that men will transmit HIV to male or female sexual partners. Condoms also reduce the risk to men of acquiring HIV infection if they have sex with an infected partner. The success of male condoms has led to efforts to provide female condoms that can be used in the vagina (or in the anus). Though these appear to work, they are much less widely used than male condoms.

For drug users, a key effort has been to provide sterile needles for drug injection by persons who are not ready to stop drug use. Although these have been controversial because of concerns that they may encourage drug use, there is now strong evidence that they reduce the risk of HIV infection (and other infections) in drug users, and have little, if any, effect on frequency of drug use. Needle exchange programs may actually be effective in providing services that ultimately encourage entry into drug treatment.

Efforts to prevent HIV have focused on five areas: (1) behavioral interventions designed to reduce risk behaviors for HIV transmission, (2) male circumcision, (3) treatment of other conditions that may increase risk of HIV transmission, such as sexually transmitted diseases, (4) microbicides that can be placed in the vagina and protect women from becoming HIV infected through sex, and (5) vaccines.

Epidemiology

The United Nations program on HIV/AIDS (UNAIDS) has estimated that in 2007 there were 33 million people living with HIV worldwide, 15 million of whom were women. There were an estimated 2.5 million new infections in 2007, and 2.1 million deaths.

Figure: A global view of HIV infection. From the World Health Organization

Though AIDS is a worldwide problem, Sub-Saharan Africa is the most seriously affected region. AIDS is the leading cause of death in this region. The overall prevalence of HIV infection in Sub-Saharan Africa is about 5%, compared to about 0.8% worldwide; in the worst hit countries, the prevalence of HIV infection is over 30%. In Sub-Saharan Africa, most transmission appears to be through heterosexual sex.

In North America, the prevalence of HIV infection is estimated to be about 0.6% while in Western Europe it is 0.3%. Although some HIV transmission in both regions is heterosexual, injection drug users and men who have sex with men are the hardest hit populations.

Figure: The Estimated number of persons living with HIV/AIDS in the US. From the US Centers for Disease Control and Prevention

Treatment

Treatment for HIV with anti-retroviral medications has been remarkably successful. Initial treatment approaches in the late 1980's and early 1990's used a single drug. These slowed the progression of the disease for months, but the benefit soon waned. Studies showed that single drugs only partially blocks HIV replication. As long as HIV continues to replicate in substantial quantities, drug resistance emerges and undermines the effectiveness of HIV medications. The key advance in HIV treatment was the development of more than one class (or type) of drug treatment, a treatment approach that was widely introduced in developed countries in 1996. This allowed the combination of three or more medicines, with at least two different classes. To overcome this combination of drugs, HIV must develop multiple mutations simultaneously- a feat that even this wily virus seems incapable of accomplishing easily. Current antiviral therapy for HIV has the goal of driving virus in the blood below the limits of detection of current viral load tests (40 to 75 copies/ml). These drug combinations are sometimes referred to as “drug cocktails” or Highly Active Anti-Retroviral Therapy (HAART).

The use of combination anti-retroviral treatment has dramatically changed the course of HIV infection. A recent study found that the mortality rate of persons with HIV in countries where HAART was available between 2004 and 2006 was only 6% as high as it was before 1996[3]. This type of data, combined with that of clinical trials of different HIV treatments, has produced highly convincing evidence of the effectiveness of current HIV treatment.

There are currently five classes of drugs for HIV that target different stages of the HIV life cycle. Early antiviral therapy for HIV used only one or a combination of two drugs. It was only partially effective. This occurs in part because HIV replication is not very precise. Many (perhaps most) new virions have one or more mistakes or mutations. While many of these mutations are harmful to the virus, some confer resistance to particular drugs. When drug pressure is applied that is only partially effective (still allows some virus to replicate), there is a selective advantage for virus with drug-resistance mutations. This mutated virus can quickly outgrow the non-drug resistant virus, and render a particular drug ineffective. This process of selection of drug resistant virus often occurs within weeks or a few months of starting a single HIV drug- an example of evolution that occurs before our eyes.

Antiviral therapy for HIV can now increase the CD4+ T cell count back to a normal range in most patients, though this may take several years. In some patients treatment is not fully effective due to drug resistance or the challenge of taking medication every day, which not all patients follow through with. In patients in whom treatment is successful, it is likely that they can live close to a normal lifespan, although they need to continue treatment.

For years, treatment of HIV was available almost exclusively in the developed world. Starting around 1991, Brazil began making HIV treatment broadly available, and some middle income countries have followed this example. More recently there has been a concerted effort to disseminate HIV treatment to the developing world. This has lead to broad availability of HIV treatment in many countries. In 2001 an estimated 240,000 persons in low income countries were receiving HIV treatment. By 2006 this number had increased to about 2 million.

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTI)

These were the first class of drugs developed. Nucleosides are the building blocks of DNA and RNA. The HIV reverse transcriptase [link to RT section] is not has precise as the human enzymes that assemble RNA and DNA. The NRTI drugs are analogues of nucleosides- they look similar to RT, but don’t work like the real thing. When RT tries to use one of these false building blocks, it stops (terminates) the work of the RT enzyme, which gets stuck-- similar to a zipper that runs into a misaligned tooth in the path.

The drugs in this class are abacavir (Ziagen, ABC), didanosine (Videx, ddI), emtricitabine (Emtriva, FTC), lamivudine (Epivir, 3TC), stavudine (Zerit, d4T), tenofovir (Viread, TDF), and zidovudine (Retrovir, AZT, ZDV) (note that the first name in parentheses is the brand name, the second is the abbreviation). These drugs are used in nearly all HIV treatment regimens, usually as a combination of two. Several combination pills are available. Truvada combines tenofovir and emtricitabine, while Epzicom combines abacavir and lamivudine. Both of these combinations are once daily drugs.

Non-nucleoside reverse transcriptase inhibitors

These drugs also target RT, but do it in a different way than the NRTI drugs. Instead of working as a false building block (nucleotide), they directly gum up the RT and stop it from working. There are now four drugs approved by the FDA in this class: delavirdine (Rescriptor, DLV), efavirenz (Sustiva, Stocrin, EFV), etravirine (Intelence, TMC 125), and nevirapine (Viramune, NVP). Efavirenz in particular, and nevirapine to a lesser degree, are commonly used foundations of an NNRTI-based regimen, which is one of the recommended first line drug combinations by a US Department of Health and Human Services (DHHS) guideline panel [link]. Both of these drugs can be given once daily, though nevirapine is usually given twice daily. Etravirine is a newly approved drug that is effective against virus that is resistant to other drugs in this class.

Protease inhibitors

These drugs stop the action of the protease enzyme, which HIV needs to produce a fully mature virus. Drugs in this class include atazanavir (Reyataz, ATV), darunavir (Prezista, DRV, TMC 114), fosamprenavir (Lexiva, Telzir, FPV), indinavir (Crixivan, IDV), lopinavir/ritonavir (Kaletra), nelfinavir (Viracept, NFV), ritonavir (Norvir, RTV), saquinavir (Invirase, SQV), and tipranavir (Aptivus, TPV). Atazanavir and lopinavir/ritonavir are recommended as preferred agents in a protease inhibitor-based starting regimen. Darunavir and tipranavir are recently approved drugs that are active against virus that has become resistant to other drugs in this class.

Fusion inhibitors

Enfuvirtide (Fuzeon, ENF, T-20) is the only approved drug in this class. It blocks fusion of HIV with the cell membrane. It is quite effective, but must be given as a subcutaneous injection, and thus is usually reserved for treatment in persons with virus that is resistant to other drugs.

Integrase inhibitors

Raltegravir (Isentress, RAL) is the first drug to be approved in this class, which blocks the integrase enzyme and prevents HIV from being spliced into the human chromosome. These drugs appear to be highly effective against HIV and have few side effects. Though they may become first line agents as we gain experience in using them, they are currently recommended for persons with drug resistant virus.

Chemokine Coreceptor Antagonists

Maraviroc (Selzentry, Celsentri, MVC) is the first drug to be approved in this class. This drug blocks CCR5, which the virus uses as a co-receptor for cell entry. It is not effective against virus that can use CXCR4 for cell entry (X4 virus). Although the drug is quite effective against the right virus, like other new agents it is currently reserved for drug resistant HIV.

When to start

Current DHHS guidelines recommend starting therapy in persons whose CD4 count is below 350 cells/µl, in persons with HIV associated nephropathy (kidney disease), persons being treated for hepatitis B virus who also have HIV, and pregnant women. There is some debate about starting treatment when the CD4 count is higher, and future guidelines may raise this threshold to a higher count.

What to start

Table 2 summaries the current DHHS guidelines for what to start in persons getting their first treatment regimen.

Origin of HIV

Elegant research has provided strong evidence that HIV evolved from a similar virus, Simian Immunodeficiency Virus (SIV). The two viruses are closely related genetically. There are different variants of SIV that infect different primate species (monkeys and apes). HIV is most closely related to the SIV that infects chimpanzees. Chimpanzees in the wild are elusive and live in remote areas- and don’t easily offer themselves for blood samples. To look at this issue more closely, researchers have developed methods to detect antibodies to SIV and amplify SIV virus from fecal material collected from the forest floor [12]. By looking at the minor variations in SIV in chimpanzees, researchers have shown that the main type of HIV (group M) appears to have evolved from SIV infecting chimpanzees in a specific area of southern Cameroon. Two other major groups of HIV-1 virus have been identified. Group N is a rare type of HIV-1 identified mainly in persons in Cameroon. Group N HIV-1 appears to have originated in a second circulating stain of SIV in chimpanzees. This second strain of SIV infects chimpanzees also located in Cameroon but separated geographically from the area in which chimpanzees infected with the SIV linked to group M HIV live. Group O HIV, though much less common that Group M, is found throughout West Africa, and sporadic cases have been reported in other areas, mostly linked to persons coming from West Africa or likely to have been infected from persons in this region [link http://www.fda.gov/bbs/topics/ANSWERS/ANS00747.html]. Group O HIV-1 appears to have originated from a variant of SIV that is found in gorillas in central Africa [13]. For an excellent scientific summary of the research on the origin of HIV, a talk by Dr. Paul Sharp on this topic is available online from the 2006 Conference on Retroviruses and Opportunistic Infections.

What we refer to as “HIV” usually means HIV-1 (whenever this is not specified in this article, “HIV” means “HIV-1”. A second type of HIV, HIV-2, does not progress to severe immunosuppression as quickly or frequently as HIV-1. HIV-2 is mostly found in West Africa. It appears to have come from SIV in another primate species, Sooty Mangabeys [14]. Taken together, this research suggests that SIV from chimpanzees, gorillas, or mangabeys has crossed from the natural primate hosts into humans at least four times, founding HIV-1 group M, N, and O infections as well as HIV-2.

This research provides strong evidence that HIV-1 originated from SIV that infected chimpanzees and gorillas in central Africa. How did SIV get from these primates to humans? While this is not known for certain, the theory with the most support is the “hunter theory.” Chimpanzees and gorillas are hunted in parts of Africa as “bush meat.” It is easy to imagine that in the process of butchering a chimpanzee, a nick from a bloody knife, or blood on the hand of a hunter with a cut or wound would allow entry of the virus into a human host. In support of this theory, a study of hunters in Cameroon has found that some of them are infected with other retroviruses previously known only to infect primates [15]. This provides evidence that contact with non-human primates during hunting and butchering of primates is probably leading to on-going introduction of retroviruses from non-human hosts into humans.

While it is not known for certain when HIV first crossed into humans, there are now good estimates of when HIV-1 began to spread in humans. Sophisticated analyses of the rate at which HIV evolves genetically and comparisons of the variation of currently circulating HIV variants have allowed an estimate of when the last common ancestor of HIV-1 group M infections probably occurred. This analysis estimates that HIV-1 group M began to spread among humans somewhere around 1931, with a range in the estimate between 1915 and 1941 [16]. Most likely, HIV-1 was confined to a small area initially. How it spread is not completely certain, but it is highly likely that increasing travel within Africa, as well as international travel, helped to disseminate HIV-1 globally.

HIV Vaccine

No effective HIV vaccine has been developed, despite the investment of millions of dollars of research efforts. At present, the news on development of HIV vaccines is discouraging. A large trial of one of the more promising vaccine candidates was halted in September 2007 before the planned end of the study when a check of the data showed the vaccine was very unlikely to be effective. Subsequent analysis has suggested that the vaccine might even have increased the risk of infection in some participants- an issue that is currently subject to much debate and research.

Figure: HIV-1 generally manages to evade antibody neutralization. Its gp120 glycoprotein (red) has one potential weakness: the site of binding (yellow) for the CD4 receptor. Certain antibodies (green) may be able to exploit this potential weakness to neutralize HIV-1. From the National Institute of Health, Peter Kwong's lab

Why has it been so difficult to develop an HIV vaccine? To understand this, it is important to understand how the virus evades immune responses. A key element of most effective vaccines is the ability to produce antibodies that are able to prevent a virus from successfully infecting cells (referred to as neutralizing antibodies). Antibodies to a virus are often made that are not “neutralizing.” For example many of the antibodies to HIV that are detected on HIV antibody tests are to parts of the virus that are not exposed when the virus is intact (for example p24 antigen). These antibodies target incomplete parts of the virus that are released or “dead” virus, in which the outside has been disrupted- thus providing no protection. Neutralizing antibodies have to target the outside of the virus, or envelope. The envelope has a variety of clever and highly effective means of escaping from neutralizing antibodies. Much of the envelope has no good targets for antibodies to attach to. Parts of the envelope to which antibodies can attach (antigenic regions) are often protected by a “glycan shield” [17]. This shield consists of glycans (sugar-like molecules) to which antibodies can’t attach to well that stick out from the outside of the viral envelope and block the ability of antibodies to reach their target. Through mutations in the viral envelope gene, these sugar-like molecules can shift around the outside to the virus. As soon as antibodies begin to effectively target anything on the outside of the virus, mutated versions of the virus in which the antibody is blocked by a variation in the glycan shield are rapidly selected. This means that the virus is not only well protected against most effective antibodies, but that there is tremendous variation in the outside of the virus. Antibodies that work against one person’s virus are unlikely to work against another person’s virus. This problem of evolution of the outside of a virus is seen in viruses like influenza. Differences in the outside of influenza viruses force vaccine makers to produce different vaccines each year in an effort to target the type of virus most likely to be circulating. While this causes problems for influenza vaccines, the variation in the outside of HIV is much greater, enormously magnifying this problem. The current hunt for a neutralizing antibody vaccine focuses on finding conserved areas of the outside of the virus that result in “broadly neutralizing antibodies”- an antibody that neutralizes many different variants of the HIV virus.

Because of the variability of the outside of the virus, other approaches to vaccines have been tried. The second potentially important type of immune response that could be used in a vaccine is called cell-mediated immunity. A specific type of lymphocytes, CD8+ T lymphocytes, can identify cells as being infected and kill them (cytotoxic T-lymphocytes or CTLs). Infected cells display small sections of the virus on the outside of the cells. This display of parts of the HIV virus happens as part of standard identification process in which sections of proteins found within a cell must be shown on the outside of the cell to pass inspection and assure immune cells that they are not infected or defective cells. Cells that reveal parts of the HIV virus that the CTL recognizes as a problem during this inspection trigger CTLs to carry out a death sentence. CTLs can recognize and target parts of the inside of the virus that don’t vary nearly as much as the envelope. These were exactly the type of responses that the vaccine in the STEP trial was designed to produce. A limitation of these responses is that they only work once a cell is already infected- they can’t prevent a cell from becoming infected in the first place. They work more like a fire extinguisher to put out a fire once it starts, in the hope of preventing it from spreading. Like the response to a fire, cell mediated immune responses not only turn on a fire extinguisher, they tend to set off alarm signals in the immune system that rush more immune cells to the area. It is theoretically possible that this rush of immune cells to an area with HIV might provide some attractive targets for HIV to infect. In this analogy, if the fire does not get extinguished quickly, some of the additional immune cells that respond to the alarm might function more like fuel than fire extinguishers. The STEP trial results have raised concerns that CTL based vaccines may not work to prevent new HIV infections unless we can understand what went wrong and somehow develop approaches that avoid these pitfalls.

Resources

AIDS info: http://www.aidsinfo.nih.gov.

This is a Web site maintained by the US Department of Health and Human Services. It is an excellent source for high quality, up to date information on a variety of AIDS issues, in particular treatment guideline documents from expert panels. It also provides information on clinical trials and both patient and physician oriented information on HIV drugs.

HIV Insite: http://hivinsite.ucsf.edu/

This website provides information on HIV treatment, prevention and policy from the University of California, San Francisco. This is generally a source of high quality information on HIV. Much of the website is targeted toward health care professionals, but it has a specific patient/public section as well.

The Body: http://www.thebody.com/

This is a website with comprehensive information on HIV, oriented toward patients and the general public.

References

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Hellerstein M, Hanley MB, Cesar D, Siler S, Papageorgopoulos C, Wieder E, et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med 1999,5:83-89.
Bhaskaran K, Hamouda O, Sannes M, Boufassa F, Johnson AM, Lambert PC, Porter K. Changes in the risk of death after HIV seroconversion compared with mortality in the general population.
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15. Wolfe ND, Switzer WM, Carr JK, Bhullar VB, Shanmugam V, Tamoufe U, et al. Naturally acquired simian retrovirus infections in central African hunters. Lancet 2004,363:932-937.

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