Acquired Immunodefiency Syndrome

by Michelle Reidy and Jennifer Rhodes

This page was prepared as a course assignment in the undergraduate course BI 348, Immunobiology at Skidmore College.

AIDS (Acquired Immunodeficiency Syndrome) was purified and identified in 1983 by Robert Gallo and Luc Montagnier. The cause for concern over this disease occurred when young, homosexual men in New York and California were coming down with strange strains of pneumonia. This prompted extensive research among biologists and doctors around the world. The disease spread to about 750 more cases in the United States, 100 in Europe and many in Africa. Researchers found that in all of the cases, the T4 cell count was dramatically low causing infections that would not occur in healthy people (or opportunistic infections). (Greenfield, Singh, Tallack 472)

The origin remains unknown, however researchers speculate it began in the 1950s in the jungles of Africa where the disease migrated from primates to humans. It is the first known virus of its kind, typed a retrovirus. This means that it is made out of RNA in place of DNA and in essence “works backwards” in infecting cells. The identification of this fact helped scientists to patent drugs to treat AIDS patients, and in 1987, AZT was approved by the Food and Drug Administration. It functions by inhibiting the transcription of the virus’ RNA to DNA in its course of viral replication. In 1995 came the approval of protease inhibitors which prevents HIV from infecting new cells by blocking the enzyme protease which is necessary in viral reproduction. Today, researchers are working to develop a vaccine so that this epidemic may be eventually eradicated as is the virus’ known as a small pox and polio. (Greenfield, Singh, Tallack 472)

How Does One Get AIDS?

Three modes of transmission have been found to cause AIDS. They include sexual intercourse with an infected person, contact with contaminated blood and transmission from mother to child before or during birth as well as in breastfeeding (Encarta). Being that the virus is present in vaginal fluid and semen, intimate contact with a mucus membrane such as the vagina, rectum or mouth pose entry points through openings in the membranes allowing the virus to gain entry into the body. Aside from mucosal membranes, vaginal secretions can transmit the virus through breaks in the man’s penis (Encarta). In contracting AIDS from contaminated blood, drug users who use syringes for drug administration are at a higher risk in the event that they share needles. Doctors have also been known to infect themselves accidentally. Incidents have occurred where they [the doctors] stick themselves with needles that had just penetrated into infected patients or by carelessly exposing a cut to infected blood. Tissue transplants (including blood and blood component transfusions) have also been a culprit in spreading AIDS. Donations of such tissues are now screened for AIDS (and many other diseases), but this only became a law in 1985. (Encarta)

The last known mode of transmission, or mother to child transmission, has been known to occur while in the womb (although this is highly unlikely), but more often occurs during birth. During this event, a child is generally delivered through an environment rich in vaginal secretions, and in most cases involves a lot of blood. Breastfeeding is also cause for concern, and accounts for 90% of the causes of childhood AIDS due to transmission from the mother. HIV is secreted into breast milk and in drinking the infected milk, the child can contract the virus. (Encarta)

It is important to note that one cannot get AIDS from casual contact with an infected person. This is due to the fact that AIDS is in general a very unstable virus and dies quickly in the outside environment. Causal contact involves acts such as hugging, shaking hands, kissing or sharing dishes. AIDS is also not known to be caused by sneezing, coughing and bug bites from bugs that previously bit infected persons (Encarta).

The Phases of Infection and Associated Symptoms

There are several phases of the HIV infection that characterizes the symptoms an infected individual may be experiencing. After infection, there is a progressive depletion of CD4 cells, and generally, within 10 years, 50% of untreated people will develop AIDS (Andreoli 846). The rate of progression of the virus is not influenced by the mode of transmission however it is influenced by the plasma viral load, a count obtained 8 to 12 months after infection. For example, an individual with a plasma viral load of greater than 30 thousand HIV RNA copies/ml has a 25% chance that he/she will develop AIDS within 3 years whereas someone with a viral load of 10-30 thousand HIV RNA copies/ml has a 6-24% chance of developing AIDS in the next 3 years. (Andreoli 846)

During the asymptomatic phase, the CD4 count is greater than 200 cells/mm3 (the normal count is 600-1,500 cells/mm3), however these levels are depleting. During this time, thrombocytopenia (a decrease in the number or platelets, or blood clotting factors) often sets in do to autoimmune platelet destruction. Mucotaneous manifestations may become more frequent like genital herpes simplex virus (HSV-2) and shingles. There is also a 30-60% occurrence of lymph node enlargement due to the new antigen entering the body, as well as the accumulation of standard viruses that healthy people can combat with ease. (Andreoli 846)

As immunodeficiency advances one reaches the symptomatic phase. The CD4 cell counts drop below 200 cells/mm3. At this stage, a range of infections may start occurring, each depending on the geographic region where the person is located. Some opportunistic infections (infections that occur in people who have compromised immune systems) include Pneumocystis carinii pneumonia, Kaposi’s sarcoma and non-Hodgkin’s lymphoma (Andreoli 846). During the stage of severe immunodeficiency, the CD4 levels drop to less than 50 cells/mm3. Without antiretroviral therapy, the average person will pass within the next 24 to 36 months (Andreoli 847).

It has also been found that there are sex specific manifestations. Women tend to experience the brunt of these manifestations for unknown reasons. The sex specific manifestations include a frequent recurrence of Candida vaginitis, recurrent genital ulcers caused by HSV-2 and cervical dysplasia/neoplasia caused by the human papillomavirus (Andreoli 847).

Acquired immunodeficiency syndrome (AIDS) is characterized by a severe reduction in CD4 T cells. This insult to the immune system leads to increased susceptibility to life threatening infections that do not affect healthy individuals. These secondary infections are of the cause of death in AIDS patients. The human immunodeficiency virus (HIV) is the virus known to cause AIDS. There are two strains of HIV: HIV-1 and HIV-2. HIV-1 is the main cause of AIDS and HIV-2 is known to cause a much slower progression to AIDS (Parham, 2005).

You can get infected with HIV by having unprotected sex with an HIV+ person, sharing a needle with an HIV+ person, by being born to an infected mother or having the breast milk of an infected mother. Once contracted, the Human Immunodeficiency Virus (HIV) can bind to the CD4 receptor on helper T cells, macrophages and dendritic cells. The gp120 envelope glycoprotein on the virus binds to the CD4 receptor. The co-receptor is a normal cytokine receptor on the host cells which also binds to gp120 envelope glycoprotein on the virus (Parham, 2005). The specific co-receptor that HIV binds to is dependant upon the variant of HIV. The HIV variant that is spread horizontally from person to person binds to the CCR5 co-receptor found on macrophages, dendritic cells and CD4 T cells and is known as the macrophagetropic HIV variant (Parham, 2005). The HIV variant that infects activated CD4 T cells binds to the CXCR4 co-receptor and is known as a lymphocyte-tropic variant (Parham, 2005). Macrophagetropic variants can cause infection when only a minimal amount of CD4 receptors are present. Because of this and the fact that macrophages and dendritic cells are among the first cells encountered by the virus they are often the first cells infected (Parham, 2005). The viral phenotype often switches to the lymphocyte-tropic variant later in the progression of the infection and that corresponds with a decline in the CD4 T cell count.

Once HIV binds to the CD4 receptor the gp41 envelope glycoprotein enables the virus to fuse its envelope with the cell membrane and empty its contents into the T cell (Parham, 2005). Being a retrovirus, the genetic information is contained in two RNA strands. The virus has an enzyme called reverse transcriptase that transcribes the RNA strands into DNA. The viral DNA is then transported to the nucleus where the viral enzyme integrase incorporates it into the host cells DNA. The viral DNA can now be transcribed by the host cell to make messenger RNA. The mRNA is then translated into the proteins needed for more HIV viruses. The translated mRNA forms one long protein that needs to be cleaved into smaller functioning proteins. This is accomplished by the viral enzyme protease. These smaller proteins are then assembled into new HIV viruses that leave the cell by exocytosis. The new HIV viruses infect more CD4 T cells and the disease spreads throughout the body. The number of T cells decreases and the immune system is weakened. This eventually progresses to AIDS which is characterized by a CD4 T cell count of 200 per ml among other symptoms.

A few weeks after infection with the HIV virus there is usually a seroconversion illness, the symptoms of which resemble the flu. The body is attempting to fight the infection at this point, producing anti-HIV antibodies and activating cytotoxic T cells. During this stage there is a significant drop in the CD4 T cells which is then brought back to almost normal levels due to the immune response (tthhivclinic.com). An asymptomatic stage follows that can last for up to 10 years. During this time the CD4 T cell count continues to slowly diminish at rate of 40-80 CD4 T cells per mm3 ( www.tthhivclinic.com). A symptomatic period follows which progresses from skin and mouth infections to more serious cancers and neurological conditions. This advances into AIDS which is defined by the Center for Disease Control as having any of 25 different secondary infections and a CD4 T cell count lower than 200 cells per mm3 as well as other key components (www.cdc.gov).

An immunodeficiency is when a part of the immune defense system is either defective or inactive. HIV leads to an immunodeficiency by killing CD4 T cells which are critical to the immune response as helper T cells which stimulate B cells as well as macrophages. There are a few mechanisms by which HIV kills CD4 T cells. The budding of the viruses from the infected cells causes a disruptance in the membrane that leads to the death of the cell. HIV also causes the formation of syncytia which is a large cell that results from an uninfected cell fusing with an infected cell (www.niaid.nih.gov). Uninfected cells are also killed when free gp120, the envelope glycoprotein of HIV, binds to their surface and marks them for destruction by antibody dependant responses (www.niaid.nih.gov). It has been proposed that superantigens may bind to CD4 cells stimulating clonal expansion of nonspecific cells that will become anergic. Research has also shown that HIV affects the precursors for CD4+ T cells in the bone marrow and thymus thus reducing the ability to repopulate (www.nhaid.nih.gov).

AIDS Diagnosis

HIV can be diagnosed by a simple blood test that tests for the presence of HIV antibodies. HIV does not show any physical symptoms and the antibodies may not show up in blood tests for 3 to 6 months. The western blot and ELISA are the two blood tests used to determine the level of HIV antibodies.

Treatment

When AIDS first emerged there were no drugs to treat either the HIV virus or the opportunistic diseases that plagued AIDS patient. Over the past ten years drugs have been developed for both.

There are two classes of drug that treat the HIV infection that have been approved by the FDA. The first class is nucleoside reverse transcriptase inhibitors. The virus' genetic information is contained in two strands of RNA. To incorporate this into the host cells DNA it must be converted to DNA using the viral enzyme reverse transcriptase. By inhibiting reverse transcriptase the virus is not able to infect the cell. These drugs only help to prevent healthy T cells from becoming infected; they do not help already infected T cells. They help slow the spread of the disease but can not completely stop it. These drugs include: AZT, ddC (zalcitabine), ddI (dideoxyinosine), d4T (stavudine), 3TC (lamivudine), abacavir (ziagen), and tenofovir (viread) (www.aidsmeds.com).
Neocleoside reverse transcriptase inhibitors work to prevent the virus RNA to be converted to DNA by attaching to the reverse transcriptase enzyme and impeding its functioning. Nucleotide reverse transcriptase inhibitors act the same as nucleoside reverse transcriptase inhibitors except unlike nucleoside RTI's they are already in an activated form. Nucleoside RTI's must undergo a chemical change to become active.

The second approved class of drugs is protease inhibitors. These drugs help stop the spread of the virus at later stages. Once incorporated into the host's genome, the viral DNA is transcribed and translated producing one long protein that needs to be cut up by protease to form the proteins for the virus such as reverse transcriptase and the capsid. Protease inhibitors block protease from cutting up the protein and the new virus cannot form correctly. These include: Ritonavir (Norvir), Saquinivir (Invirase), Indinavir (Crixivan), Amprenivir (Agenerase), Nelfinavir (Viracept), and Lopinavir (Kaletra) (www.aidsmed.com).

Because the HIV virus can mutate quickly it becomes resistant to any one of the drugs easily. Therefore a combination of both nucleoside reverse transcriptase inhibitors and protease inhibitors are used to treat HIV. This combination is known as highly active antiretroviral therapy (HAART). Generally the drug cocktail consists of one protease inhibitor and two NRTI's. While HAART has proved to reduce the amount of AIDS related deaths it is not a cure. HIV remains present in the body particularly in lymph nodes, testes, retinas of the eyes and the brain (www.aidsmeds.com, www.mydna.com).

Researched Treatments

Entry inhibitor drugs prevent the HIV virus from entering the CD4 T cell. Some entry inhibitors block the CD4 site or the CCR5 site on the T cell. Others block the gp120 or gp41 proteins on the surface of the HIV virus. Only one entry inhibitor has been approved by the FDA, Fuzeon (t-20) which blocks the gp41 site on the virus. Others are being researched that block T cell receptors (www.aidsmeds.com). Integrase inhibitors will block integration of the virus RNA that was converted to DNA to be integrated into the cells DNA (www.aidsmeds.com). Integrase is the third of HIV's three enzymes and therefore is a critical target for treatment. The process of integration is a multi-step process and integrase inhibitors are being researched that affect integration at different points (Kresge, 2002). Antisense antivirals and transcription inhibitors will block the transcription of mRNA into proteins (www.aidsmeds.com).

Immune based therapies try to help the immune system fight the HIV infection. One such therapy involves making cytokines. Cytokines are involved in the regulation of the immune system. Interleukin 2 is a cytokine that stimulate the production of T cells. Proleukin is a drug that creates aldesleukin, a synthetic form of IL2 to help promote T cell development; this drug is approved for cancer patients (www.netdoctor.com). There are many side effects of this drug such as fatigue, weight gain, low blood pressure and decreased kidney and liver function (www.netdoctor.com). Other drugs are being researched that produce a different version of IL-2 that will result in fewer side effects. Other cytokine producing drugs are being researched as well. Therapeutic vaccines are another form of immune based therapy. These vaccines attempt to train a person's immune system to fight a virus after they have already been infected (www.adismeds.com). The Salk vaccine is the best candidate so far. Dr. Jonas Salk, known for the discovery of the polio vaccine suggested that the immune system must be able to suppress HIV since people can remain asymptomatic for years. Therefore he proposed that a therapeutic vaccine be used to strengthen the immune system so it can continue to fight the infection (www.imnr.com). AIDS causes a reduction in hormone levels which can lead to a variety of health issues such as weight loss, fatigue and loss of bone mineral density (Garcia, A. et al, 2002). Hormone replacement therapy may help to return the body to a more healthy state at which it is better able to fight the infection. HE2000 is being studies as a similar hormone to DHEA which is the human growth hormone. The human growth hormone will hopefully help the thymus to produce more T cells (www.aidsmeds.com).

Where Treatments Works

(courtesy of Owen Wallace @ www.chemsoc.org)

Opportunistic Infections

AIDS patients have an extremely weakened immune system that cannot fight off infections that would pose no threat to a healthy immune system. These infections are known as opportunistic infections. The agents of opportunistic infections are those that are present in, on or around the body and are kept under control in healthy people (Parham, 2005). Most infections can be treated if caught early but some can prove deadly. AIDS does not kill people; the opportunistic infections are the cause of death. Opportunistic infections usually signal the transition from HIV to AIDS. The CD4 T cell count is usually below 200 cells per mm3 (normal is around 1000 cells per mm3) when these infections begin to infect patients.

Opportunistic infections fall into six main categories; bacterial, fungal, protozoan, and viral infections, cancers and neurological disorders. Cancers that afflict AIDS patients are usually caused by a virus or are lymphomas which affect the cells of the immune system. Neurological disorders are caused directly by the HIV virus which can penetrate into the brain and nervous system (www.aidsmeds.com). The severity of the infections increases with the progression of the disease. There are many opportunistic infections that are a risk to AIDS patients; some are more common than others and will be the primary focus here.

Candiditis is an overgrowth of the fungus Candida albicans that normally inhabits the body (www.aidsmeds.com). Oral and esophageal candiditis are common in early symptomatic stages of the HIV infection. The symptoms include white patches in the infected area, dry mouth, difficulty swallowing and altered taste (www.aegis.com). Vaginal candiditis, also known as a yeast infection, can occur in the middle stages of the HIV infection. Shingles is another common opportunistic infection seen at this stage of the HIV infection. Shingles is a viral infection caused by the varicella-zoster virus (chicken pox virus) (www.aegis.com). Once a person has the chicken pox, the virus remains dormant in their system. HIV patients are not able to keep the virus dormant and it will reoccur as shingles which are extremely painful. These infections are rated category B by the Center for Disease Control. Category B infections are those that are attributed to the HIV infection and a compromised immune system function. They are those infections that have a clinical course and the treatment is complicated by the HIV virus (Center for Disease Control and Prevention, 1993).

Kaposi's sarcoma (KS) is a common cancer seen in the late stages if HIV. It is caused by a combination of a viral infection and the compromised immune system. This cancer leads to lesions on the body that, depending on location, can affect eating, breathing, and other vital functions (www.aidsmeds.com). There is research that suggests that KS is not a cancer but a dysfunction in the formation of blood vessels (www.aegis.com). Angiogenesis is the formation of new blood vessels. It is common during wound healing and is also seen in cancers as a means to supply the tumor with blood. KS may be abnormal angiogenesis caused by a lack of regulation (Marco, 1994). KS is one of 25 AIDS defining infections (Center for Disease Control and Prevention, 1993).
Tuberculosis, TB, is the most common opportunistic infection. It is a bacterial infection caused by Mycobacterium tuberculosis. It is spread via the air from person to person. TB is usually the first opportunistic infection seen in the HIV virus progression (www.aegis.com). The infection usually occurs in the lungs and other lymph tissue. Multi-drug resistant TB is a common problem in AIDS patients who fail to take the full course of antibiotics for the TB infections. This leads to death in 80 % of infected people and usually within months (www.aegis.com). The Center for Disease Control considers TB to be an AIDS defining infection (Center for Disease Control and Prevention, 1993).
Pneumocystis Carinii Pneumonia (PCP) is a common infection that is caused by a parasite or possibly a fungus (www.aegis.com). The infection is commonly in the lungs but can also affect the spleen, liver, bone marrow and lymph nodes. The symptoms include fever, dry cough and difficulty breathing (www.aegis.com). PCP is the number one killer of people with AIDS and it is suggested that people with a CD4 T cell count under 200 see their doctor and take anti- PCP medication to prevent the infection (www.thebody.com).The Center for Disease Control and Prevention consider PCP to be an AIDS defining infection (Center for Disease Control and Prevention, 1993).
Mycobacterium Avium Complex (MAC) is a bacterial infection that infects about 50 % of AIDS patients (www.thebody.com). The bacterial that causes this infection is common in soil; it is not unusual for a person to have some of the bacteria in their system. This infection is usually seen when the patient has less then 50 CD4 T cells/ mm3 (www.aegis.com). Soil bacterial can also cause other life threatening infections such as Mycobacterium Kansasii. Soil fungus is also responsible for infections such as Aspergillosis, Coccidioidomycosis, and Histoplasmosis (www.aegis.com).

There are other secondary diseases that inflict AIDS patients. Canker sores are a common problem. Thrombocytopenia is when the platelet count in the blood drops. This low platelet count leads to difficulty in forming blood clots which makes the smallest cuts life threatening. Wasting syndrome is another common affliction. It results in a loss of body and muscle mass (www.aidsmeds.com).

Most opportunistic infections can be treated if caught early enough. AIDS patients commonly will take medications that help to prevent these infections before they even occur due to the severity of the infections.

Quantifiable cytotoxic T lymphocyte responses and HLA-related risk of progression of AIDS

By Scherer, Almut; Frater, John; Oxenius, Annette; Agudelo, Juliette; Price, David A.; Gunthard, Huldrych F.; Barnardo, Martin; Perrin, Luc; Hirschel, Bernard; Phillips, Rodney E.; McLean, Angela R.; The Swiss HIV Cohort Study

It has been found that patients with higher viral loads of HIV help indicate who will progress to full blown AIDS more quickly. For example, patients with lower levels of HIV at the beginning of their infection are said to live longer without complications as compared to those who higher viral loads and develop AIDS sooner with more symptoms. A second finding is that patients with certain HLA class I supertypes have longer asymptomatic periods than individuals without these supertypes. The patients with the lower viral loads also have greater amounts of T cells (for the HIV virus attacks and kills T cells), as opposed to those with higher viral loads. Due to the fact that the HLA class I molecule is only able to present a limited range of broken down antigens, the alleles that one has for the HLA molecules has a great deal to do with the responses mounted. Those who are heterozygous for the HLA class I molecules are at an advantage for they are able to present a greater the range of peptides and are able to promote more cytotoxic T lymphocyte (CTL) responses. It can then be implied that the greater range of alleles one has for their MHC class I molecules (as well as the quantity of T cells) is what determines the outcome of one's viral control.

The less common of the nine major supertypes (HLA B58 and HLA B62) yield lower viral loads (and a greater CTL response) whereas the more common supertypes (HLA A2 and HLA B7) yield higher viral loads (and a lower CTL response). The rare alleles for the supertypes seem to be the more advantageous to the infected individual for the reason that HIV is known to form escape mutations to escape the immune system, and if it resides in a host with less frequent HLA supertypes, it has a better chance of being killed. These escape mutations are maintained in transmission from one person to another, however if he/she has a new/rare allele for the HLA molecules, the virus will be more effectively combated.

The study at hand tested three questions. 1) Do HLA alleles associated with slow disease progression elicit detectable CTL responses in a higher proportion of patients than HLA alleles associated with rapid disease progression? 2) Do rare HLA alleles elicit CTL responses in a greater proportion of patients than more common HLA types? 3) Do rare HLA supertypes elicit CTL responses in a greater proportion of patients than more common HLA supertypes?

The course of action included testing 84 patients using SSITT or the Swiss-Spanish Intermittent Therapy Trial. This therapy functioned by halting the administration of AIDS drugs to patients for short periods of time and the CTL responses were detected by IFN-? enzyme-linked immunospot assays (ELISA). CTL responses were found by coating a plate with the antigen, adding the patients' serum to the dish, adding a conjugate binding molecule to bind to the bound cytotoxic cells, then adding a substrate to act with the second binding agent. The intensity of the substrate is quantified and the darker the color, the more cytotoxic cells bound to the antigen (Benjamini, Sunshine, Leskowitz 126). All patients were tested for their HLA types and for the amount of HIV-specific CTL's present. Their HLA types were then matched up against a panel of known peptide epitopes, and a percentage was taken as to how many patients' HLA types elicited CTL responses to each epitope.
It was found that only one peptide (named KAF) elicited CTL responses in all patients with the B57 allele, for each HLA supertype varies greatly in its ability to elicit responses. As quoted from the paper "the capacity of a given HLA allele to elicit a detectable anti-HIV response can be defined as the average frequency with which optimal epitopes, restricted to a particular HLA allele, elicit responses in patients carrying that allele". The highlights of this frequency showed that the B18 allele had the capacity to elicit CTL responses 85% of the time but was only found in 30% of the patients, whereas A2 was found in almost 40% of the patients but only elicited a response 18% of the time.
In response to the first question, it was found that there is an inverse relationship between the relative hazard of disease progression and HLA capacity to elicit CTL responses. In other words, the lower the amount of CTL responses one had, the greater the relative hazard of disease progression was fount. In answering the second question, rare alleles elicit a greater amount of CTL responses compared to the common alleles. For example, B44 is found in approximately 21% of individuals and elicits responses to 20% of the known antigens. B13 on the other hand is found in approximately 5% of individuals and elicits responses to almost 75% of the known antigens. And lastly, the third test yielded results that conclude that patients with rare HLA supertypes have a greater chance of binding to known peptides restricted by the HLA's in that supertype. In other words, CTL responses measured in patients with homozygous HLA alleles recognize only a small proportion of epitopes.

Interleukin -2 induces CD8+ T cell-mediated suppression of human immunodeficiency virus replication in CD4+T cells and this effect overrides its ability to stimulate virus expression
By Kinter, Audrey L.; Bende, Steven M.; Hardy, Elena C.; Jackson, Robert; Fauci, Anthony S

Interleukin -2 is a cytokine that is naturally produced by the immune system. It is the primary T cell growth factor. It can enhance antigen specific proliferation and cytolytic and oncolytic activity. IL-2 therapy has been shown to increase the CD4+ T cell count in the majority of patients who have greater then 200 CD4 T cells per ml of blood. The amount of virus present in the blood, however, was not reduced. This experiment studied whether IL-2 had antiviral activity which could explain how the CD4+ T cell population can grow and the viral replication is contained. The effects of IL-2 and IL -12, a similar cytokine, were studied.

They found that IL-2 stimulates the production of HIV in peripheral blood and lymph node mononuclear cells (PBMC and LNMC) when there are no CD8 T cells. To determine this, the cell populations of both unfractioned and CD8+ depleted PBMC and LNMC were tested for successful isolation of the HIV virus represented by the presence of the p24 antigen or reverse transcriptase activity. Subjects exposed to IL-2 showed no or little isolation of HIV virus in the unfractioned populations. The CD8+ depleted populations, however, showed a high level of isolation of the HIV virus. This suggests that IL-2 is stimulating the expression of HIV in the absence of CD8 T cells. IL-12 also showed a higher isolation ratio in the CD8+ depleted populations but not to the same effect as IL-2.

They showed that IL-2 can also function to increases the efficiency of CD8+ cells to suppress the HIV virus. The reverse transcriptase activity was measured in different ratios of CD8+ and CD8 depleted PBMC populations. In every case when CD8+ cells were present and treated with IL-2 little or no reverse transcriptase activity was seen which means that the virus was suppressed. CD8 cells in IL-12 showed more reverse transcriptase activity than CD8 cells with no cytokines indicating that IL-12 is still enhancing the expression as opposed to suppressing it.

There is a different receptor for IL-2 on CD4 and CD8 cells. The researchers compared the proliferation of CD4 and CD8 cells in the presence of IL-2, IL-12 and no cytokines to examine the effects on the two types of cells. This served as a control to ensure that the cytokine was successfully binding to and activating T cells. Cells in the presence of IL-2 showed the most proliferation, with the CD4 and CD8 cells being almost the same. Cells in the presence of IL-12 showed a decrease in CD8 proliferation as compared to the CD4 cells.
The research also showed that IL-2 increased the suppression in activated CD8+ cells. CD8 cells were stimulated in the presence or absence of IL-2. The activated cells expressed CD25+ and CD8+. These activated cells were mixed with CD4 cells in the presence and absence of IL-2 and IL-12. The percent inhibition was determined based on the reverse transcriptase activity. Cells in the presence of IL-2 showed a high inhibition of HIV that decreased only as the ratio of CD8 to CD 4 cells decreased.

IL-2 was found to stimulate the HIV virus in the absence of CD8+ T cells. It also stimulates CD8+ cells to suppress the HIV virus and this outweighs its stimulation of the virus expression. IL-2 was shown to be more effective than IL-12 which is a similar cytokine. Because CD8+ cytolytic and nonlytic HIV suppression may be regulated differently it is possible that IL-12 can not stimulate the nonlytic suppression. HIV causes a dysregulation of cytokines such as IL-2 which may cause the reduction in the ability of CD8+ cells to suppress the HIV infection. This is not the only cause of the loss of function seen in CD8 and CD4 cells. IL-2 treatment has only worked in patients in the early stages of the disease who still have intact, functioning CD8+ cells. The disease leads to the loss of CD8 cells and the addition of IL-2 cannot help to maintain or enhance the CD8 population. At late stages of the diseases it may even have a detrimental effect by inducing the expression of the HIV virus on CD4 cells in the absence of CD8 cells. This leads to the main question of whether IL-2 therapy will enhance the ability of CD8+ cells to suppress the viral infection. Further research and testing will hopefully bring some answers to this important question.