Taking Lessons from the CCR5Δ32 Mutation for Patient Treatment

I’m Lindsay Sween, and welcome to this installment of the AIDS Pandemic blog and podcast.

Human immunodeficiency virus type 1 (HIV-1) invades a CD4+ (T4) cell through the attachment of the viral protein gp120 to its primary cellular receptor, CD4, and to a transmembrane chemokine coreceptor, usually CCR5 or CXCR4. Agrawal et al. (2007) explain that the removal of 32 base pairs from the CCR5 gene results in the CCR5Δ32 mutation, which produces a shortened, nonfunctional protein that cannot act as a coreceptor due to the fact that it is no longer expressed on the cell membrane. Thus, individuals homozygous for the CCR5 mutation (also known as CCR5 -/- individuals) are extremely resistant to contracting HIV-1, while heterozygous people (aka CCR5+/- people) express fewer CCR5 proteins on the surface of their lymphocytes than wild type individuals, which slows the transition of HIV infection to AIDS. The CCR5Δ32 mutation confers HIV-1 resistance by two mechanisms: the mutated protein cannot be expressed on the lymphocyte surface, and it actively downregulates CXCR4 coreceptor production by causing the formation of heterodimers between CCR5 and CXCR4 proteins that then get trapped in the endoplasmic reticulum.

As explained by Nazari and Joshi (2008), individuals with the CCR5Δ32 mutation appear perfectly healthy in all other areas of their immune systems, which seems to indicate that the CCR5 chemokine receptor is not absolutely essential for immune function. Thus, with no selective pressure against the CCR5Δ32 mutation, Agrawal et al. (2007) report that Caucasians carry the mutation relatively frequently, with about 1% of individuals being homozygous for the mutated allele and approximately 10% of the population being heterozygous. Individuals of purely African or Asian descent, however, almost entirely lack the CCR5Δ32 mutation.

Figure 1. The CCR5Δ32 mutation results in a nonfunctional protein that cannot serve as a cell surface coreceptor for M-tropic (aka CCR5-tropic or R5) HIV viral isolates and, thus, confers some resistance to HIV-1 infection. The immune cells are still fully receptive to T-tropic (aka CXCR4-tropic or X4) viral isolates, which could bind to their coreceptor, CXCR4 (aka fusin), and transmit HIV-1 infection.
From: Samson, Michel. “Human immunodeficiency virus (HIV).” Access Science Online.
McGraw-Hill.
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There is now a new antiretroviral drug called maraviroc, which was approved by the U.S. Food and Drug Administration U.S. Food and Drug Administration in August 2007 and mimics the natural CCR5Δ32 mutation by acting as an antagonist for the CCR5 receptor and preventing the viral envelope protein gp120 from binding to it. Lieberman-Blum et al. (2008) report the results of two Phase IIb/III clinical trials, MOTIVATE 1 and 2, in which the effects of treatment with 300 mg of maraviroc once or twice daily were compared to placebo treatment in patients who were already being treated with HAART and still had primarily R5 HIV-1 infection. Maraviroc was found to decrease viral load by a greater percentage than placebo. Of the patients receiving maraviroc once or twice daily, 43.2% and 45.5%, respectively, had virus particle counts of less than 50 copies per milliliter, as opposed to 16.7% of patients in the placebo group. After the 48 weeks of the studies, patients demonstrated average viral load reductions of -1.68 log10 copies/mL for the once daily group and -1.84 log10 copies/mL for the twice daily group compared to -0.78 log10 copies/mL for the control group.

Figure 2. Most patients given maraviroc once or twice daily had lower HIV-1 viral loads and higher CD4 cell counts at the end of 48 weeks and had a long time period until treatment failure than did patients taking placebo.
From: Gulick, R.M., Lalezari, J., Goodrich, J., Clumeck, N., DeJesus, E., Horban, A., Nadler, J.,
Clotet, B., Karlsson, A., Wohlfeiler, M., Montana, J.B., McHale, M., Sullivan, J., Ridgway, C., Felstead, S., Dunne, M.W., van der Ryst, E., Mayer, H. 2008. Maraviroc for Previously Treated Patients with R5 HIV-1 Infection. The New England Journal of Medicine 359: 1429-1441.

As would be predicted by the absence of adverse health problems in individuals lacking functional CCR5 receptors due to the CCR5Δ32 mutation, maraviroc produced few severe side effects for the immune system by blocking the CCR5 surface protein. According to Lieberman-Blum et al. (2008), 21 of 426 (4.9%) individuals taking maraviroc and 11 of 209 (5.3%) individuals taking placebo had poor health outcomes that lead them to stop taking their medication and quit the trials. Most patients (92.3%) reported at least one side effect, which included upper respiratory illness, cough, fever, and abdominal pain. The primary concern with the use of antiretroviral drugs that block the CCR5 receptor is that the HIV virus will evolve into X4 or R5X4 variants that will then evade the drug’s action. For the individuals who were not benefitted by maraviroc, 54.4% of the once-daily patients and 55.2% of the twice-daily patients demonstrated virus that had changed from the R5 strains to either X4 or R5X4 strains. When the researchers performed phylogenetic analyses of the viral envelope proteins in these strains, however, they found that the new X4 or R5X4 strains had developed from preexisting viral particles of these strains that had been missed in the screening process before the beginning of the drug trials and had not resulted from R5 mutation during the course of drug treatment. Thus, these clinical trials suggest that maraviroc could be a good possibility for “salvage therapy” for those HIV+ individuals who have experienced treatment failures in the current categories of HIV/AIDS medications. More studies are still needed, however, to determine the long-term effects of antagonizing the CCR5 receptor.

The CCR5Δ32 genetic mutation and the recent research investigating it and its therapeutic implications are very relevant topics given the fact that the HIV/AIDS pandemic is one of the greatest public health concerns in the world, especially in developing nations. As cited in Lieberman-Blum et al. (2008), the Joint United Nations Programme on HIV/AIDS and the World Heath Organization report that as of 2007 33.2 million people worldwide were HIV+, and 2.5 million of those cases were new infections. In addition, the virus’s high mutation rate makes viral resistance to current antiretroviral medications a growing problem for disease treatment. The research into the CCR5Δ32 mutation aided scientists in developing the new class of antiretroviral drugs known as CCR5 antagonists. Furthermore, most new infections of HIV-1 are caused by R5 (also known as CCR5-tropic or macrophage-tropic) viral isolates. Thus, gene therapy involving the complete downregulation of CCR5 by the CCR5Δ32 mutation inserted into cells via viral vectors could one day prevent transmission of HIV by removing the coreceptor in the semen-receiving individual. Through the CCR5Δ32 mutation, evolution and natural selection may have unwittingly supplied we humans with a very powerful weapon in the fight against the HIV/AIDS pandemic.


For more information, please see:

Agrawal, L., Jin, Q., Altenburg, J., Meyer, L., Tubiana, R., Theodorou, I., Alkhatib, G. 2007. CCR5Δ32 Protein Expression and Stability Are Critical for Resistance to Human Immunodeficiency Virus Type 1 In Vivo. Journal of Virology 81: 8041-8049.

Lieberman-Blum, S.S., Fung, H.B., Bandres, J.C. 2008. Maraviroc: A CCR5-Receptor Antagonist for the Treatment of HIV-1 Infection. Clinical Therapeutics 30: 1228-1250.

Nazari, R., Joshi, S. 2008. CCR5 as Target for HIV-1 Gene Therapy. Current Gene Therapy 8: 264-272.

The Dissidents' Views of HIV Tests

Momentum for the alternate HIV/AIDS explanation started in 1987 when Dr. Peter Duesberg, a professor of Molecular and Cell Biology at the University of California at Berkeley and initial demonstrator that the influenza virus has a segmented genome, published a paper claiming that HIV cannot be the cause of AIDS. Four years later, a number of scientists formed “The Group for the Scientific Reappraisal of the HIV/AIDS Hypothesis” which later established itself as an official non-profit organization. Within another four years, 32 scientists with advanced medical degrees published a statement in Science asking for the reconsideration of the current HIV/AIDS theory. Since this publishing, over 2,100 people have signed this statement. Should institutions acknowledge any concerns from this small, not-too-silent minority or are their claims completely unsubstantiated? I’m Colby Uptegraft from Dr. Dave Wessner’s Biology of HIV/AIDS class at Davidson College, and while AIDS dissidents have many claims, I will present their arguments regarding HIV testing.



HIV critics rest a substantial amount of their theory on the problems with HIV tests. Currently, there are three main types of tests—antibody tests, antigen tests, and PCR tests. Dissidents primarily scrutinize the antibody tests.

HIV antibody tests begin with an enzyme-linked immunosorbent assay (ELISA). A second test confirms a positive ELISA. These secondary tests include Western blot assays, indirect immunoflorescence assays, line immunoassays, or a second ELISA. When used in combination, these tests are 99.9% accurate in detecting HIV antibodies.

According to Rebecca Culshaw, author of Science Sold Out: Does HIV Really Cause AIDS?, the flaws in antibody tests originate in the proteins initially used to define reactivity on ELISA and Western blots. Before HIV had been isolated, scientists stimulated cell cultures from AIDS patients with mitogens to produce more proteins. Researchers found 30 of these proteins to have densities characteristic of retroviruses and selected the 10 that most commonly reacted in blood from AIDS and pre-AIDS patients to be from HIV alone. Do you see the circular logic? Researchers assumed HIV caused AIDS and automatically attributed the 10 most common reactive proteins to HIV. Positive test results may have a high correlation to developing AIDS, but according to Culshaw, they do not mean HIV is the cause. HIV supporters ascribe her claims to outdated data.

Robert Geraldo, a medical doctor working at the Cornell University hospital, added suspicion to these tests when he discovered that everyone reacts positive on the ELISA test for HIV. Lab technicians typically use a 1:400 dilution of HIV-suspected serum samples for these tests. Many antibody tests for other viruses such as hepatitis A and B, rubella, and syphilis use undiluted samples, and the ones that use dilutions such as the Epstein-Barr virus, use dilutions an order of magnitude less. When Geraldo tested 100 undiluted samples, including his own blood, they all produced positive ELISA results. When diluted 1:400, all specimens produced negative results. He claims his results indicate that we all have antibodies to HIV or at least ones that will cross-react with ELISA tests. AIDSTruth.org presents the counter argument. One cannot compare antibody tests for other viruses to the HIV test. All antibodies are unique and require different dilutions to eliminate false-positives resulting from non-specific binding.



The second HIV test detects antigens, substances that trigger generation of antibodies in organisms. The most common HIV antigen that provokes an immune response is the protein p24. According to Culshaw again, the dissidents assert that many AIDS patients do not have detectable levels of p24 and that many people without HIV infection produce positive p24 results. However, the HIV hypothesis acknowledges the disappearance of p24 in the bloodstream as AIDS progresses, and states lab technicians can use the p24 antigen test in conjunction with other antigen or antibody tests to increase its accuracy.

The third and final family of HIV tests uses PCR to amplify minute levels of RNA or DNA to quantities sufficient for detection. However, Kary Mullis, the inventor of PCR technology, proclaims, “Quantitative PCR is an oxymoron” and believes PCR is not applicable to HIV detection. PCR is too efficient in that it will amplify any DNA in a sample, whether it represents contamination or belongs to HIV. Therefore, scientists cannot use PCR to ascertain HIV infection status or viral load, the number of DNA or RNA copies per milliliter of blood. Even with these dissenting claims, the FDA approved these tests for monitoring the health of people with HIV and high statistical correlations exists between these tests and the onset and severity of AIDS.

While believing in Bigfoot or that the Holocaust never happened provides entertainment to some, the conspiracies cannot sustain actual scientific inquiry. The theory that HIV does not cause AIDS is not any different. AIDS dissidents cling to small individual details and pull them out of context with the vast majority of HIV evidence and research. In the case of HIV tests, critics ignore the use of multiple tests to predict HIV status and the combined accuracy of these tests in predicting the onset of AIDS and the causative nature of HIV. They instead focus upon the individual use of each test and make the illogical assertion that the unknowns in each are additive and cannot be used to support each other.

If you believe the United States never landed on the moon, then consider the arguments of the AIDS dissidents. If you like reality, then stick with the traditional explanation.

HIV/AIDS Orphans in Sub-Saharan Africa

More than twenty-five million people have died from AIDS since it was first recognized in 1981, making it one of the most destructive epidemics in history. It is undeniable however, that sub-Saharan Africa is the hardest hit and most affected area in the world. Of the global 2.9 million AIDS related deaths in 2007, 72% occurred in this area. AIDS has devastated the social and economic framework of societies in sub-Saharan Africa by mostly infecting people in the age group of 15-49, while 63% of the 40 million people living with HIV/AIDS today live in Sub-Saharan Africa. What is also startling is that, of the 2.9 million people who died from AIDS in 2007 one in seven was children. HIV/AIDS also has many indirect effects. Children of HIV positive parents compose the largest group of secondary sufferers. Africa is home to 95% of the world’s 13 million children orphaned as a result of AIDS. It is estimated that by 2010 a third of African children will be orphaned.

Caring for these orphans has become a severe humanitarian disaster. With the rapidly increasing numbers it is difficult to care and provide for all of these children. However, the potential for these children to form a large group of dysfunctional adults, which could further destabilize societies already weakened by AIDS, has increased the urgency of finding an effective solution to the crisis. The response to the problem has been unsustainable given the number of children that need aide. In Zimbabwe, fewer than 4,000 orphans out of an estimated 800,000 are accommodated in the country’s 45 registered institutions.

As an entire generation is being devastated by HIV/AIDS, major secondary effects are occurring on the children watching it all unfold. These impacts arise in a number of overlapping ways, including, economic consequences, changes in position of caregiver, education, nutrition, long term psychological effects, and even the likelihood of infection. What overarches all of these is how children psychologically process and respond to the stresses HIV/AIDS adds to their lives. It is important to focus on the psychological impact on a child who is forced to drop out of school, who must care for themselves and younger siblings, and face losing a parent or family member. These psychological effects are what lead children to destructive or with drawn behaviors that could make them more likely to become infected. If an attempt is made to better understand what these children are experiencing, it may be possible to reach them on a level that would help encourage them to protect themselves from the dangers of HIV/AIDS.

A child’s age effects not only how they respond to and understand AIDS as a disease but in what ways they are most affected. Pre-school aged children show the primary effects on growth and health in relation to losing a caregiver. School-aged children show more effects related to loss of education and therefore the development of a vulnerability to internalization and anti-social behaviors. It appears in several studies that children over the age of ten years are most vulnerable to becoming orphaned, but are a group neither specifically targeted by many current programs nor institutions that house affected children. In these cases family, community, or school based intervention is essential.

The loss of a parent or loved one generally speaking is associated with psychological conditions including anxiety, rumination, depression, social isolation, survivor’s guilt and low self esteem. Mel Freeman, former director of Mental Health and Substance abuse in the South African Department of Health, states that children after losing a parent will have difficulties with modeling, boundary setting and development of value systems necessary for moral development; as well as the support, caring and discipline needed for emotional stability. If children have problems figuring out how to set boundaries and develop moral standards then it is likely they will also be at a higher risk for HIV infection. This secondary impact of HIV/AIDS is a catastrophic one because it will cause a whole new generation to be at an even higher risk and only further the HIV/AIDS epidemic. Orphaned children have an increased incidence of internalized psychological problems, and 34% of AIDS related orphans have contemplated suicide within the year after their parent or parents’ death.

In response to preventing the majority of psychological disorders and their related effects, the main goal is to postpone the death of a parent. When extending the life of the parents, you increase his or her chance to complete school and possess the proper mechanism to establish a sound value system. Nearly one half of children who lose a parent to HIV/AIDS drop out of school. This is a secondary impact that can be reduced by attempting to supply more infected people with ARV treatment that is both successful and easily attainable. It will both extend their life span and improve the quality of life for their children.