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 Search for an HIV vaccine

I'm Paige Bates and this is The AIDS Pandemic

The RV144 study was a phase III HIV vaccine trial conducted by the US Army and Thai government over seven years on 16,402 volunteers—all HIV negative men and women between the ages of 18 and 30 in parts of Thailand. For ethical reasons, all participants were taught HIV prevention behaviors, given condoms, and promised lifelong antiretroviral treatment if they contracted HIV. Half of the volunteers were given a prime-boost vaccine regimen and half received placebo vaccinations. The prime-boost approach utilizes Sanofi Pasteur’s ALVAC-HIV vaccine as a prime and AIDSVAX (originally made by Genentech) as a boost. ALVAC-HIV is comprised of a canarypox virus with three HIV genes grafted onto it. AIDSVAX contains a recombinant gp120 protein found on the surface of HIV. These vaccinations were combined because one was designed to create antibodies and the other to alert white blood cells. These vaccinations were focused on the two strains of HIV commonly found in Thailand, but it is unclear whether this regimen would have any benefit elsewhere in the world. The participants were regularly tested for HIV for three years following the completion of the vaccine regimen. In September, the companies and agencies which implemented and funded the trial announced in a press release and interviews that new HIV infections were observed in 74 of the 8,198 people who received the placebo, but in only 51 of the 8,187 given the vaccine. They claimed that this was a statistically significant 31.2% reduction in infection. However, the vaccine did not reduce levels of HIV activity in those who became infected and did not appear to produce any neutralizing antibodies.

Source: Wall Street Journal, September 25, 2009

In the 1980s, top officials embarrassed themselves by predicting an HIV vaccine in five years. Reminiscent of these overly optimistic declarations, the backers of the RV144 trial claimed that “we now have evidence that a safe and effective HIV vaccine is possible.” In the first wave of press subsequent to the initial press release and interviews, many reputable news sources, such as the San Francisco Chronicle, New York Times, NPR radio and BBC news, suggested that these results were highly encouraging, and some even went so far as to suggest that this regimen might be the forerunner or basis for a usable vaccine in the near future. The LA Times suggested that these findings would “energize and redirect” the HIV vaccine field. Many articles quoted Dr. Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Disease which largely funded the $100 million dollar study, as saying “I don’t want to use a word like breakthrough, but I don’t think that there’s any doubt that this is a very important result.” The Wall Street Journal suggested that this finding could be the second “big game changer in AIDS research since the mid 1990’s” with the advent of drug cocktails. Many articles later qualified with the cautionary statement that much more research is necessary before the vaccine could be available to the public. Phrases urging the public to be “cautious” but “hopeful” and describing the results as “modest” yet “encouraging” rang throughout the media and press releases.

However, only days later, the LA Times wrote “By Thursday afternoon, the initial wave of euphoria had given way to the recognition that many vexing questions will have to be answered before researchers can produce a vaccine that will reliably shield people from HIV.” Experts predicted that it would require two to three years of research to unravel how and why the vaccine regimen worked, and then an additional five to ten years to produce a vaccine that was ready to test in people. The fact that this still overly optimistic statement was a step back from the “initial euphoria” shows the extent of the preliminary sensationalism. The media reported that the researchers would now compare the blood of those who were vaccinated and resisted infection, and those who did not in order to determine whether the regimen stimulated antibodies or other protective molecules against HIV infection. In an article entitled “If AIDS went the way of smallpox,” a New York Times reporter recognized many problems with the initial reports including that many headlines in the first 24 hours after the press release read “One Third Protected,” while in reality the margin of success was “razor thin.” In addition, even the experts overseeing the trial could not explain why blending two failed vaccines suddenly resulted in “working” vaccine. Finally, this article recognized the financial difficulties surrounding a regimen that requires six shots over the span of months resulting in minimal protection. While this might be practical in rich countries, AIDS generally burdens the poorest nations in this world. Only one article mentioned that some researchers were suggesting that the apparent reduction in infections might be a statistical fluke due to the small number of HIV infections observed. Throughout all articles, there were minimal reminders to keep vigilance about prevention, testing, and the necessity to utilize current retroviral care.

Source: Wall Street Journal, October 12, 2009

In 2004, there was so much skepticism about this trial that 22 top AIDS researchers published an editorial in Science magazine suggesting it was a waste of money. Five years later, the organizations which conducted the trial announced in a press release that there has been significant protection, before making the scientific data available to peer review. When the full details of the study were released on October 20th at a meeting in Paris, the statistic frailty of the study was revealed. The vaccine was not shown to protect people at the highest risk of HIV infection. As The Washington Post noted on October 21st, when the results are analyzed using alternate methods, the protection is no longer statistically significant. For example, when only the people who received all six injections are counted, the trend towards protection is no longer significant. This raises many questions. What are the societal implications of the press surrounding this vaccine? If this vaccine doesn’t have much, if any, effect, what is the societal consequence of the data being overstated? The possibility of a public backlash against vaccination efforts wouldn’t be too hard to imagine. In fact, Gregg Gonsalves, an AIDS activist, remarked that, “When this was rolled out a couple of weeks ago, it was terribly hyped by the investigators. Some people think that you have to dangle the slimmest morsels of hope in front of the general public in order to keep them interested in an AIDS vaccine. But I think that damages the credibility of the effort.” The extent to which these results might represent a breakthrough can only be determined after the mechanism behind the possible conferred immunity is discovered. As Gonsalves points out, the over-exaggeration of the success in the media will likely hurt the results of the study if they prove to be less remarkable than originally stated. Furthermore, this study raises a general question about scientific results: is it appropriate to have news press releases before data is available for full review by scientific peers?

While this trial may not have been the scientific breakthrough that it was praised as, at the very least, this tremendous study is an example of international and interagency collaboration in conducting a large-scale vaccine trial, including the Thai and US governments, private companies such as Sanofi Pasteur, and non-profit organizations such as Global Solutions for Infectious Diseases (GSID). In this regard, it provides incredible hope for HIV vaccine efforts in the future.

For more information, please see these articles.
US Military Research Program in Thailand

BBC news coverage of RV144


The Wall Street Journal: Data Call ito Question HIV Study Results

Intersecting Epidemics: HIV/AIDS and Tuberculosis

Hi, I’m Justin Eusebio.

While tuberculosis is one of the world’s oldest surviving plagues and HIV-1 infection is one of medicine’s newest challenges, there is an undeniable relationship between HIV/AIDS and tuberculosis. Independently, Mycobacteria tuberculosis and HIV are formidable pathogens but in concert, the prospects for controlling either epidemic are jeopardized. TB-HIV coinfection and interaction complicate all aspects of each disease: pathogenesis, epidemiology, clinical presentation, diagnosis, treatment, prevention, and even social and economic issues.

Not only are individuals more likely to undergo tuberculosis infection if living with HIV, depending on their geographic location, people living with HIV infection are 6-50 times more likely to develop active TB than people living without HIV. Thus, with one-third of the world’s population at least latently infected with Mycobacteria tuberculosis, the current pace of new HIV-1 infections threatens public health on a wide scale.

Tuberculosis infection is believed to have the greatest potential among other common opportunistic infections to increase viral load and to accelerate HIV-1 disease progression. This is in part due to the chronic nature of active TB disease, the marked increase in tumor necrosis factor-alpha (TNF-α) expression for macrophage activation, and intensified antigen presentation causing the recruitment of CD4 T lymphocytes to the site of TB infection.

Manoff and others demonstrated that active tuberculosis is associated with increased viral load in HIV-1 infected patients. Also, TB-HIV coinfected persons have a significantly higher HIV RNA load than persons without opportunistic infections and similar CD4 cell counts.

Figure 1. Schematic hypothetical individual’s of risk of TB infection compared to CD4 cell count.
From: Havlir, Diane V., Haileyesus Getahun, and Ian Sanne. “Opportunities and Challenges for HIV Care in Overlapping HIV and TB Epidemics.” Journal of the American Medical Association 300.4 (2008): 423-430.

Researchers from Case Western Reserve University demonstrated that not only do TB-HIV co-infected patients have significantly higher viral loads than those without TB, the timing of infection by M. tuberculosis affects HIV-1 disease progression. In fact, these researchers showed that TB had its strongest impact on HIV-1 viral load when patients are least immunodeficient. Furthermore, from the same study, more than 25% of TB-HIV coinfected patients developed TB when their CD4 cell counts were at least 500 cells/µl. Thus TB infection is unique because it can occur at any CD4 cell count level.
Perhaps the most problematic tuberculosis-induced effect contributing to HIV-1 disease progression is its apparent impact on HIV-1 evolution. While reverse transcriptase, a polymerase without proofreading capabilities, provides an effective mechanism for genetic diversity, M. tuberculosis infection increases HIV-1 heterogeneity through compartmentalization.

In a cohort of patients matched by their CD4 cell counts, dually infected TB-HIV patients were found to have greater systemic, or more general, HIV-1 heterogeneity and more frequent occurrences of distinct HIV-1 quasispecies than HIV-1 patients without TB infection. A population of diverse quasispecies increases the viral capacity to evolve and adapt to the host immunological response. Furthermore, upon examination of the lung sites of M. tuberculosis infection of TB-HIV coinfected patients, Collins and others found greater genetic HIV-1 heterogeneity and distinct quasispecies in the pleural space compared to blood samples. While phylogenetically distinct HIV-1 subpopulations have been shown to develop in other organs or tracts in humans (i.e. kidneys, brain, urogenital tract and blood), compartmentalization of HIV-1 occurs most significantly and is more defined in the lungs of co-infected TB-HIV patients. Therefore, the lungs, induced by active tuberculosis disease, function as a reservoir for genetically diverse HIV-1.

In addition to accelerating the disease progression of one another, their collision has highlighted underlying public health and human rights failures. Africa, although only home to 10% of the world’s population, is the major site of intersection between the two epidemics with an astounding 75% of the world’s TB-HIV coinfections.

Figure 2. The disproportionate incidence of HIV and HIV-TB coinfection in Africa in 2000. Each person indicates 5% of the global population. The African population is shaded red while blue represents the rest of the world.
From: Corbett, Elizabeth L, Barbara Marston, Gavin J. Churchyard, and Keven M. De Cock. “Tuberculosis in Sub-Saharan Africa: Opportunities, Challenges, and Change in the Era of Antiretroviral Treatment.” Lancet 367 (2006): 926-937.

Thus, novel TB diagnostic tests are needed in HIV-endemic regions because HIV infection reduces the sensitivity of current diagnostic methods such as direct smear sputum microscopy. In terms of treatment, high pill burden and toxicity often discourage adherence among many coinfected patients. Furthermore, rifampicin, a common antibiotic component of tuberculosis chemotherapy disrupts antiretroviral treatment by accelerating the metabolism of both protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTs). Finally, if antiretroviral treatment of coinfected patients is started too soon after treatment for TB, a rapid recovery of CD4 T cell levels may induce an overwhelming inflammatory response against previously hidden opportunistic infections resulting immune reconstitution inflammatory syndrome (IRIS).

The connection between the biology of the two diseases is clear and complications are numerous. Thus, experts in HIV and experts in TB should respond accordingly and move towards greater collaboration and shared research.

Until next, this is Justin Eusebio.


For more information:

Bartlett, John G. “Tuberculosis and HIV Infection: Partners in Human Tragedy.” Journal of Infectious Diseases 196 (2007): S124-5.

Collins, Kalonji R., Miguel E. Quioñones-Mateu, Mianda Wu, Henry Luzze, John L. Johnson, Christina Hirsch, Zahra Toossi, and Eric J. Arts. “Human Immunodeficiency Virus Type 1 (HIV-1) Quasispecies at the Sites of Mycobacterium tuberculosis Infection Contribute to Systemic HIV-1 Heterogeneity.” Journal of Virology 76.4 (2002): 1697-1706.

Collins, Kalonji R., Miguel E. Quioñones-Mateu, Zhara Toossi, and Eric J. Arts. “Impact of Tuberculosis on HIV-1 Replication, Diversity and Disease Progression.” AIDS Review 4 (2002): 165-176.

Kalonji Collins et. al, “Greater diversity of HIV-1 quasispecies in HIV-infected individuals with active tuberculosis.” Journal of Acquired Immune Deficiency Syndrome 24, 408-417.

Friedland, Gerald, Gavin J. Churchyard, and Edward Nardell. “Tuberculosis and HIV Coinfection: Current State of Knowledge and Research Priorities.” Journal of Infectious Diseases 196 (2007): S1-3.

Manoff, SB, H Farzadegan, A Muñoz, JA Astemborski, D Vlahov, RT Rizzo, L Solomon, and NM Graham. “The Effect of Latent Mycobacterium tuberculosis infection on Human Immunodeficiency Virus (HIV) Disease Progression and HIV RNA Load Among Injecting Drug Users.” The Journal of Infectious Diseases 174.2 (1996): 299-308.

Nunn, Paul, Alasdair Reid, Kevin De Cock. “Tuberculosis and HIV Infection: The Global Setting.” The Journal of Infectious Diseases 196 (2007): S5-14.

Vignuzzi, Marco, Jeffrey K. Stone, Jamie J. Arnold, Craig E. Cameron, and Raul Andino. “Quasispecies Diversity Determines Pathogenesis through Cooperative Interactions within a Viral Population.” Nature 439.7074 (2006): 344-348.

Preventing Mother to Child Transmission of HIV in Mwandi, Zambia- A Success

Welcome to this installment of the AIDS Pandemic, a podcast hosted by Dave Wessner of the Department of Biology at Davidson College. I am Sarah Bertram.

This past summer, I traveled to Mwandi, Zambia through a Davidson biology and pre-medical program. Mwandi is a predominantly Lozi village of about 7,000 people and the catchment area totals about 25,000 people. We spent 5 weeks in Africa, 3 of which were spent working in the Mwandi Mission Hospital, the Mwandi AIDS clinic, the Orphans and Vulnerable Children’s center, and the Mother and Child Health Center. We all went with a research topic to study that was based on some aspect of Mwandian life. I looked at Mwandi’s Prevention of Mother to Child Transmission of HIV, otherwise known as the PMTCT program, and its effectiveness over the past three years. Here, I will talk about my findings.

About out of every five pregnant women in Zambia is infected with HIV and without any prevention or treatment interventions, more than 300,000 babies would contract HIV from their mothers each year. Starting in 1999, many Zambian mission and government hospitals started PMTCT programs. The Mwandi PMTCT program was launched in 2005 by an American Pediatrician in conjunction with the Mwandi missionary who was going to serve as the leader of the program. The procedure for PMTCT at the Mwandi Mission Hospital is as follows: 1) discuss the PMTCT program and HIV/AIDS information during group antenatal care visits, 2) offer private pre-test counseling, 3) test the mother for HIV and CD4 counts and give her the results, and 4) offer post-test counseling and discuss further treatment and a re-test in three months. According to the hospital staff in Mwandi, HIV testing of any pregnant mother is required by law in Zambia.

If a woman tests positive, she is evaluated at the Pastoral Care Center for AIDS treatment. If she is considered a WHO stage IV or has multiple symptoms for WHO stage III, HAART treatment is usually started unless the woman chooses to undergo short-course treatment instead. Many of the HIV positive mothers choose to undergo HAART treatment because of its documented increased ability to treat HIV/AIDS symptoms and to lower the viral load by decreasing viral replication. The Mwandi hospital staff is good about giving options to the positive mothers and explaining each option and its risks and benefits. Due to the staff’s willingness to counsel and inform the HIV positive pregnant mothers of treatment options, a majority of these women decide to take part in a course of HIV/AIDS treatment in order to help themselves and to prevent the transmission of HIV to their babies.

Although record-keeping is sparse and sometimes hard to find and evaluate, some records for the PMTCT program proved helpful in evaluating the program’s success over the years. From March of 2005 to September of 2007 (before HIV testing was mandatory), 1,205 women attended an antenatal care appointment to sign up for the PMTCT program and of these 1,205 women, only 35 women or about 3% refused the HIV test. Of the 1,170 women who agreed to be tested, 24.4% tested positive for HIV. This statistic is quite high, but reflects the belief that about 1/3 to ¼ of Mwandi’s population is infected with HIV. Because the PMTCT program was in place, the HIV positive women were able to learn their status, get treatment, and prevent (for the most part) the transmission of HIV to their babies during pregnancy, delivery, and breastfeeding.

Mwandi’s PMTCT program has changed drug regimens in order to stay current with the most effective treatments. Originally, the program was based on a single dose of nevirapine given to the mother during delivery and to the baby right after birth. In April of 2006, the PMTCT program switched to a dual therapy involving both nevirapine and AZT for both mothers and babies. Starting in November of 2007, Mwandi updated its treatment regimen to the most current and effective triple therapy drug treatment. This drug therapy involves a mixture of AZT, 3TC, and NVP for the mother and baby. This new therapy has proven to be very effective and the PMTCT program workers approximate that transmission from mother-to-child rates have decreased to less than 10% and possibly even as low as 6% or 7%.

Possibly the most enticing aspect of the PMTCT program for pregnant women is the free formula feeding program provided to HIV-negative babies of HIV-positive mothers. Breastfeeding is the most common type of mother-to-child HIV transmission, so by providing free formula for those babies who test negative (after 6 weeks of age), the worry of transmission by breastfeeding can be alleviated. Currently there are over 100 babies receiving infant formula and most, but not all, are HIV-negative babies of HIV-positive mothers who participated in the PMTCT program. The program has never resulted in a case of child dysentery, a common negative outcome of formula feeding programs, which is often a result of incorrectly boiled water used to make the formula. This clean record is a result of the care and attention put forth into teaching the mothers how to correctly make the formula and clean the bottles.

Compared to many other Sub-Saharan African PMTCT programs, Mwandi’s program is doing a very good job of keeping the program advancing, as far as the number of women being treated and the updates to newer forms of drug therapies. The program could however still make larger strides in incorporating more women from far out in the catchment area and by possibly providing more rural village outreaches for the sole purpose of PMTCT.

The Case for Thai MSM and MSW

The prevalence of HIV/AIDS in certain high risk groups is on the rise today as government funding for prevention campaigns nears an all-time low in Thailand, a country once touted the ‘poster-child’ for HIV/AIDS prevention efforts. Hello, I am Devynn Birx-Raybuck and this is The AIDS Pandemic, a podcast hosted by Dr. Dave Wessner, associate professor of biology, and his students at Davidson College.

Though Thailand’s initial response to the AIDS epidemic was weak in its early years, in 1991, the new Prime Minister made HIV prevention and treatment a national priority. However, the country’s grip on the disease seems to be slipping recently, as evidenced by decreased funding in important sectors, increases in infection rates among MSM (men who have sex with men) and injection drug users, inconsistent condom use by sex workers, and increasing risky sexual behavior, especially by young people.

Thailand is notorious for its sex industry. Brothels, go-go bars, massage parlors, and other venues cater to native Thais as well as Western tourists, who travel to the country on “sex tours.” Unfortunately, commercial sex is not only omnipresent; it is often backed and funded by corrupt government officials. Thankfully, with initiatives such as the 100% Condom Program and Mechai Viravaidya’s (a.k.a. Mr. Condom) tireless public outreach, HIV prevalence among female brothel-based sex workers decreased significantly after the early 1990’s, when as many as four out of five of prostitutes were infected. The 100% Condom Program began in 1991, along with a substantial public education campaign. The goal of the Program was to encourage and enforce constant condom use by female sex workers in commercial sex establishments. However, male sex workers have been neglected during such efforts to protect their female counterparts and clients.

A famous street in Pattaya where many commercial sex extablishments are located (left). Kathoeys (tansgender males) outside a go-go bar (right).

By the turn of the century, these enormous gaps in focus and funding were revealed. In a comprehensive review of the situation written in 2000, authors McCamish, Storer, and Carl, made a case for the inclusion of MSM in the country’s prevention efforts. Indeed, male sex workers (MSW) and MSM are at high risk for HIV infection, according to several studies which identified infection rates as high as 30% in these groups. Education and prevention programs aimed at MSW have been infrequent, limited to tourist areas, and generally unsuccessful in the past. The authors advocated for bar-based interventions and peer-support groups, which they believed would impact both the freelance and employed MSW.

Finally, in February 2006, “Sex Alert,” a safe-sex information campaign directed at MSM, was founded, with the hope of reaching this community that has been largely neglected by other efforts. According to the regional director, Dr. Somchai, the organization uses several media to advertise and educate, including the Internet and text messages. They also provide counseling, free condoms, and information regarding other health issues. This new outreach effort, along with others, will hopefully curb the rising rates of infection among MSM. However, programs such as these cannot act in isolation. They require the support of the Thai government, people, and most importantly, those affected most by the epidemic. Perhaps, despite recent concerns over rising HIV/AIDS infection rates and risky sexual behaviors, Thailand will prevail once again in the fight against the AIDS pandemic.

Free clininc in Bangkok that a sex worker might visit for counseling or treatment. This particular building is a collaborative center run by the Thai Red Cross and Armed Forces Research Institute of Medical Sciences.

On behalf of Dr. Wessner and his students, I thank you for listening.

For more information, please visit:
AVERT.org
USAID
Thailand’s rising AIDS threat
UNAIDS Evaluation of 100% Condom Programme
Mr. Condom
Brothel-based sex workers

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.

US Travel Ban on HIV-infected Individuals

Welcome to this installment of The AIDS pandemic, a podcast hosted by Dr. David Wessner from the Department of Biology at Davidson College. I’m Middleton Chang.

Since 1987, the United States Department of Health and Human Services has imposed a travel ban on HIV-infected individuals, under the premise that HIV falls into their list of “dangerous and contagious” diseases which present a public health risk. The law specifically prohibited foreigners from immigrating or obtaining a travel visa to the United States. Activists had long decried the ban for several reasons, until this past summer. On July 30, 2008, President Bush signed into law a five-year, $48 billion bill to fight AIDS, malaria and tuberculosis around the world as well as lift the ban on HIV positive travelers. Yet the ban has still not actually been lifted. HIV/AIDS activists, at first praising the current administration are becoming impatient for an actual removal of the ban.

HIV/AIDS activists originally declared the ban to be unnecessary and unfair. The ban was not codified into law however until 1993 during the Clinton Administration, much to the chagrin of activists. This legislation made HIV the only specific medical condition mentioned as grounds for inadmissibility to the United States. Activists argue that the ban was just another in a long string on US inconsistencies on HIV/AIDS policy. Helene Gayle, president of CARE, stated that the ban was not consistent with the international leadership role the United States has taken with PEPFAR (President’s Emergency Plan for AIDS relief). Experts at the International AIDS conference this past fall were full of praise for the new legislation lifting the travel ban. However, little has been done to actually lift the ban. In order to do so, the Department of Health and Human Services must write a new rule, submit it for public comment, and finalize it. The Bush Administration has moved with the speed of a rolling stone gathering moss on this issue. Last week 58 house Democrats submitted a letter to President Bush urging “swift action” on the issue.
Due to the ban, no major AIDS conference has been held on US soil since 1993 as no activists or researchers infected with the virus may enter the country without embarking on a complicated waiver process. In 1991, 40,000 Haitian political refugees fled to the United States. Of these refugees, 158 were detained in Guantanamo Bay, Cuba due to the ban. For nearly twenty months, Guantanamo Bay hosted these 158 political refugees, due to either being HIV-positive, or a relative of one of the positive refugees. A court order was needed to force the Clinton Administration to close down the razor-wire encircled refugee camp setup in 1991 by the Bush Administration.

Despite the fact President Bush has signed the bill mandating removal of the ban into law, HIV remains on the list of “dangerous and contagious” diseases that may prevent entry into the United States. Recently, the Department of Homeland Security released a revised and “streamlined” process for obtaining a waiver, making it easier to obtain the necessary paperwork. However, the Department of Heath and Human Services has still not removed HIV from the list of medical conditions which are grounds for exclusion from entering the United States.

A study conducted in 2006 showed that of 1113 HIV positive survey respondents. 349 (31%) had traveled to the United States. Of those 349 that had traveled to the US, only 14.3% traveled with the mandatory waiver to obtain a travel visa. Many simply did not disclose their status. This study not only shows the inefficacy of the travel ban, but shows the harm presented to HIV positive individuals who desire to visit the United States. The study showed that patients on anti-retroviral therapy (212 patients) were more likely to go off their medication, increasing their chances of developing drug-resistant HIV strains or developing AIDS. The study concluded that people do so “with insufficient planning and advice.”

Only about a dozen countries around the world maintain a travel ban on people living with HIV. These countries are: Iraq, China, Saudi Arabia, Libya, Sudan, Qatar, Brunei, Oman, Moldova, Russia, Armenia, and South Korea. Should the United States still include itself amongst these countries in discriminating against people living with HIV?

Thanks for listening, until next time I’m Middleton Chang.

For more information:
Mahto M, Ponnusamy K, Schuhwerk M, Richens J, Lambert N, Wilkins E, Churchill DR, Miller RF, Behrens RH. “Knowledge, attitudes and health outcomes in HIV-infected travellers to the USA”. HIV Medicine 2006; 7: 201–204.

"Give me your tired, your poor,
Your huddled masses yearning to breathe free,
The wretched refuse of your teeming shore.
Send these, the homeless, tempest-tost to me,
I lift my lamp beside the golden door!"
-An excerpt from The New Colossus, which hangs within the Statue’s Pedestal.

Ryan White CARE Act

I'm Utsha Khatri.

The Ryan White Comprehensive AIDS Resources Emergency (CARE) Act, was the first piece of comprehensive AIDS legislation created to provide funding for people living with AIDS (PWAs) to access care and treatment. Ryan White was a young, Caucasian hemophiliac who contracted HIV through a blood transfusion. He was diagnosed with AIDS at age thirteen and died six years later. Prior to the media’s coverage of the Ryan White story, it was widely held that HIV/AIDS only affected marginalized sectors of society namely homosexuals, intravenous drug users, and racial minorities. However, because of the widespread media attention given to the Ryan White story, the American people soon realized that this was not the case and that it could potentially infect anyone. When Ryan White’s story was put on the media agenda in 1985, it changed the meaning of HIV/AIDS for the media, the public and policymakers.

Political scientist Mark Donavan explains that this shift in public consciousness allowed policy-makers to formulate an AIDS policy that would deliver benefits to what were considered “deserving” target populations. When people with AIDS were considered to be social deviants and dependents, policy-makers could not defend the use of tax dollars to provide care and treatment to these populations. However, when Americans realized that the HIV/AIDS epidemic started affecting “innocent victims” (whose infection was not caused by their behavior), policy-makers were able to create programs to provide benefits to a “deserving” population. For this reason, Ryan White CARE Act bills passed both houses with overwhelming bipartisan support in 1990.

Donavan emphasizes that during the drafting of the legislation, lawmakers attempted to, “downplay the receipt of benefits of gays while emphasizing the benefits granted to positively constructed populations, most notably children,” During floor debates lawmakers told moving stories of people with AIDS to win over support for the bill. Of the 19 stories told on the Senate floor, only one story was that of a homosexual. Lawmakers needed to justify the act by ensuring each other and the public that the recipients of the benefits did in fact deserve it. Donavan describes the final version of the bill emphasized women and children as the “victims” of the epidemic and deemphasized the extent to which benefits would be delivered to negatively constructed groups. The bill did nonetheless provide benefits to populations with negative social constructions as well; however, to the public, the policy was directed towards helping populations with positive social constructions.

The Ryan White CARE Act was first passed in 1990 as Congress’ attempt to financially assist many urban public hospitals that had not been compensated for care they provided to AIDS patients. It was reauthorized in 1996, 2000 and most recently in 2006. The reauthorization in 2006 changed the acceptable use of Ryan White funds. The amendments emphasized providing funding to urban areas with the highest prevalence of AIDS, encouraged outreach and testing and required that 75% of funding be spent on “core medical services.” Core medical services include services such medications, outpatient and ambulatory medical services, mental health services, substance abuse services, hospice care, early intervention services and home health care. Ryan White funds are also used for support services, including transportation, respite care, outreach and language services.

The Ryan White program presents the third largest source of federal funding for HIV/AIDS care, after Medicaid and Medicare. Currently, it provides about $2.2 billion a year to fund over 2,500 organizations and provides some level of care to about 500,000 people living with HIV/AIDS. Unlike Medicaid and Medicare, it is not a health insurance program. It is a series of flexible grants given to cities, states, and other public and private nonprofit organizations to develop and operate systems that deliver health and support services to uninsured or underinsured individuals affected by HIV/AIDS. Though the CARE Act was originally designed to fill the gaps in financing care, it has now grown into a major source of funding essential to the operation of HIV/AIDS programs across the country. The reauthorization in 2006 extended the program for an additional three years. After September 30, 2009 further legislative action will be needed to provide continued federal funding.

It is important to recognize that the program by itself is not capable of improving access to HIV/AIDS care and treatment for the majority of the infected population. The CARE Act is a discretionary grant program that receives annual appropriations from Congress. Services are provided only as long as the finite funds last. Therefore, it is not able to meet the rising demands in services due to the growing number of people living with HIV/AIDS. Furthermore, CARE Act programs vary from region to region due to the flexibility given to organizations in formulating programs and services. The programs therefore do not provide a single, unified policy solution to a national problem. Rebecca Haag, Executive Director of the AIDS Action Council, while expressing appreciation for the 2006 reauthorization, stressed the need of more funding. As Haag described, “…this bill alone is not sufficient to ensure that life saving drugs and medical treatment is available to all who are infected. Appropriations have fallen far short over the last several years while the epidemic is growing with 40,000 new infections every year.”