Info on HIV testing

The most important things a sexually active person can do to prevent the transmission of HIV is to practice safe sex and undergo routine HIV testing. What it’s like to get an HIV test will depend on the type of test you take and where you take it. One common facet of testing, though, is the availability of counseling regarding both the emotional and physical aspects of potentially being HIV-positive. Clinics that perform HIV testing work hard to protect the privacy of the individuals they test. The CDC can help you find a testing site.

An at-home test is also now available. Though there are many that tout themselves to be at-home testing kits, only one is approved by the FDA to be reliable. Read more about the types of tests and what it's like to get an HIV test.

Anti-HIV treatment may reduce transmission to partners

AZT - antiretrovirals

Individuals diagnosed with HIV are presented with a life-shattering possibility – transmission of the eventually lethal virus to their spouse/partner. Condom use and abstinence have been the recommended prevention methods, but on May 12, 2011, researchers announced startling findings that may aid in preventing transmission further. The antiretroviral drugs HIV-positive patients take to stave off AIDS may actually prevent them from infecting their partners.

The 73 million dollar study was funded by the National Institutes of Health and conducted in nine countries, mainly in Africa, where the majority of AIDS cases are found (only two American couples took part, presumably due to the possibility of not receiving treatment until later in the study). As summarized by the LATimes, the current results on transmission to partners among more than 1700 couples were released four years before the study is even supposed to end due to their outstanding nature. The researchers found that antiretroviral treatment reduced the transmission of the virus 96%. Twenty-seven of 28 new infections occurred among couples who were not treated until their CD4 T cell count reached 350 compared to one case of infection among couples treated when the count fell below 500. The results indicate that new guidelines to treat HIV infection earlier, when the CD4 count drops below 500 rather than 350 as previously recommended, are beneficial.

The Wall Street Journal estimates that the study results may add fuel to the treatment versus prevention debate for funding in AIDS research, as the two aspects now clearly overlap. Increasing the number of individuals who are treated decreases the overall community viral load, resulting in decreased transmission overall in addition to reduced transmission among partners of HIV-positive patients. In addition, it should put pressure on companies to make the drugs less of a financial burden, ensuring that those who need treatment can seek it, especially amid current under-treatment – according to the Journal, only a third of those who required treatment in 2009 received it. As noted in the LATimes, the drugs used in the study were provided free of charge by the pharmaceutical companies that made them. The cost would normally be in the hundreds of dollars per year in developing countries, and they have not traditionally been affordable according to the AIDS charity AVERT.

The researchers also found that the earlier treatment benefitted the HIV patients by reducing the incidence of disseminated tuberculosis. Tuberculosis is one of the primary causes of death among HIV-infected individuals.

The study began in 2005 and researchers will continue following the couples for another year to ensure the results hold up over time. Experts quoted in news reports remind people that more than one prevention method increases the chances of actually preventing transmission, so condom use should still be emphasized if receiving antiretroviral treatment.

 

Broadly neutralizing HIV antibodies and the hope for a vaccine

Antibody binding HIV. Peter Kwong, NIH

Yesterday I posted about how HIV antibodies are made. But why are they important? More specifically - why is the recent work on broadly neutralizing antibodies important?

Antibodies are produced against cell surface proteins, the portions of the infecting agent visible to immune cells. The problem thus far with HIV is the broad range of cell surface proteins expressed by the various strains currently infecting the human population, as well as the potential mutations to come. However, broadly neutralizing antibodies, though rare, have been identified in the blood of HIV-infected patients. They bind and affect portions of the cell surface that remain relatively constant among HIV strains.

Read more about the challenges and promise of broadly neutralizing antibodies in HIV vaccine development below the break.

 

 

 

HIV antibody production

To exploit the immune response and the natural system of neutralizing or killing a virus and preventing infection, researchers develop antigens that stimulate the human body to make the antibodies that are most efficient and effective at achieving the intended goals.

For HIV, though, this has been difficult because the surface antigens of HIV vary broadly among infected individuals. A solution to this problem is thought to exist with broadly neutralizing antibodies, naturally occurring human antibodies against relatively constant antigens on the surface of the HIV virion.

When a pathogen or foreign agent enters the human body, the immune system responds in both a broad and specific manner. The human immunodeficiency virus (HIV), the pathogen that causes AIDS, is no exception. The specific immune response involves the processing of the pathogen and presentation of its proteins, or antigens, by specialized immune cells (macrophages and dendritic cells) to other immune cells, one type of which, specifically B cells, are then activated to genetically rearrange and produce antibodies specific to the viral proteins. Antibodies are simply specialized proteins that are produced on an as needed basis under normal circumstances. When an antibody comes into contact with an antigen, usually on the cell or pathogen surface because of accessibility, it binds and causes the pathogen to either be neutralized or destroyed.

Vaccines are a method of artificially stimulating antibody production by exposing the immune system to antigens prior to infection. The human body produces antibodies specific to the antigens or strain with which it is infected. For HIV, this specificity makes vaccination thus far troublesome as the surface antigens of HIV vary broadly among infected individuals. A solution to this problem is thought to exist with broadly neutralizing antibodies, naturally occurring human antibodies against relatively constant antigens on the surface of the HIV virion. These consistent proteins are involved in the infectivity of HIV – the CD4 binding site (glycoprotein gp120) that allows the virus to bind T cells and gp41, the surface protein involved in HIV envelope and cell membrane fusion and viral entry.

To exploit the immune response and this natural system of neutralizing HIV and preventing infection, researchers develop antigens that stimulate the human body to make the antibodies that are most efficient and effective at achieving the intended goals. The most promising method of making HIV antibody is thought to involve creating a vaccine with components that mimic the HIV glycoproteins involved in CD4 recognition and binding – corresponding to the broadly neutralizing antibodies VRC01 and VRC02, which are reported to prevent 90 percent of global HIV strains from infecting human cells in the lab (work by the NIH). The previous most promising vaccine candidate was found in clinical trials to only benefit less than one-third of individuals, which does not meet the goals of vaccination. The discovery of the VRC antibodies is hoped to further advance work on a vaccine that will stimulate the human body to make HIV antibody effectively and in a manner that prevents infection with most, if not all, strains of the virus.

Profile: International AIDS Vaccine Initiative

The International AIDS Vaccine Initiative (IAVI) is a global nonprofit organization comprising three consortia of HIV/AIDS researchers: the Neutralizing Antibody Consortium (NAC), the HIV Live-attenuated Consortium, and the Vectors Consortium. The mission of the Initiative according to the IAVI website is to “ensure the development of preventive AIDS vaccines that are not only safe and effective, but also accessible to all people”. The consortia work with more than 50 academic, government, and private institutions and have so far tested nine vaccine candidates in 11 countries, concentrating on strains present in the developing world, as they account for 95 percent of new infections.

In 2006, the Initiative celebrated 10 years, releasing a timeline of its growth during that time: IAVI was founded in 1996 in response to the global need for an HIV vaccine and other methods to curb the spread of AIDS outlined in a 1994 conference held by the Rockefeller Foundation. The initial funding support was from notable charitable and humanitarian organizations: the Rockefeller, Starr, and Alfred P. Sloan Foundations, Foundation Merieux, Until There’s  a Cure, and the World Bank. The initiative also garnered support from the Joint United Nations Programme on HIV/AIDS (UNAIDS). Later support came from European governments and joint ventures were pursued with the National AIDS Trust. In 1998, IAVI released its “Scientific Blueprint for AIDS Vaccine Development”. The initiative is now funded by both private and public institutions, non-governmental organizations (NGOs), governments, and community groups.

In 2009, the AIDS vaccine community had proof-of concept success in Thailand, showing that a combinatorial vaccine was able to prevent 30% of HIV infections. Though this was not a success per se, it was a small step toward proving that their work is not fruitless. The research community made additional progress in 2010 with broadly neutralizing antibody research, the focus of one of its consortia. The antibodies identified by NAC in 2009 have been taken up by other research groups in the National Institutes of Health (NIH) who may have found a model antibody for preventing more than 90% of HIV infections, the best vaccine candidate to date.

The goal of a vaccine is to prevent new infections. Since AIDS emerged in the 1980s, 30 million deaths have been attributed to the syndrome, and UNAIDS estimates from numbers released in 2010 that more than 33 million people are currently living with HIV, the AIDS virus. The virus attacks cells of the immune system, leading to a state of immunodeficiency. This state allows opportunistic infections to wreak havoc and kill the infected individual, the syndrome known as AIDS. Despite decreased infections rates due to educational campaigns regarding safe sex and needle sharing, it is estimated that nearly 7100 people are infected with HIV each day. More than half of all infections occur in Sub-Saharan Africa, a region that also accounted for three-fourths of all AIDS-related deaths in 2008. Yet, the infection rates are also increasing in more developed countries, including China, Germany, Britain, and Australia. The lack of control of the epidemic over nearly three decades re-emphasizes the need for a vaccine and other more global preventative measures.

How AIDS is diagnosed

The lab values used to diagnose AIDS rely on recognizing deficient versus normal immune function in the presence of HIV infection. However, testing positive for HIV infection (via DNA or antibody tests) does not mean that an individual has AIDS or that they will develop it. CD4 T cell counts and ratios are used to determine immune function, but AIDS is also diagnosed in the presence of particular defining conditions. Read more about the lab values and AIDS-defining conditions used to diagnose AIDS.

Retroviruses integrated into the genome can teach us about HIV

Chimp endogenous retrovirus 2, or CERV 2, is an ancient virus that first infected chimpanzees after the Old World primate line diverged from that of humans several millions of years ago. Humans are not infected by the virus, and scientists are interested in knowing why, hoping that understanding the evolution of retroviruses and host resistance in chimps will unlock treatments and potential vaccine targets for retroviruses that do infect humans, like HIV.

Endogenous viruses are viruses that have integrated into the host genome (some refer to them as fossil viruses). An estimated 8 to 10 percent, if not more, of each mammalian genome consists of such retrotransposable elements. Chimp endogenous retrovirus 2, or CERV 2, is an ancient virus that first infected chimpanzees after the Old World primate line diverged from that of humans several millions of years ago. Humans are not infected by the virus, and scientists are interested in knowing why, hoping that understanding the evolution of retroviruses and host resistance will unlock treatments and potential vaccine targets for retroviruses that do infect humans, like HIV.

Retroviruses are different from other viruses in that their genetic code is RNA instead of DNA. This requires additional steps for replication after infection. Viruses are obligate parasites – they require the host’s machinery to replicate and survive, they cannot do so on their own. Retroviruses insert their genetic code into the host cells for its own survival, and the potential for integration into the host genome has been considered intuitive.

Out of 42 families of endogenous retroviruses in chimps, only two, CERV 1 and CERV 2, have not been found to have human orthologs (that is, a corresponding genomic element). CERV 2 has also been found in the genomes of gorilla and other old world monkeys, but not orangutans and new world monkeys. For the viral element to be integrated into the genome, the virus had to have once been capable of infecting that species. The lack of the viral element in some species also indicates that it could not infect those species. The difference in the virus’s ability to infect a species could be caused by the  manner in which the virus is transmitted (for example, biting, so it infects monkeys more readily than humans), the conditions for transmission (for example, some pathogens spread only in low hygiene conditions), and/or genetic elements, including cell surface receptors.

A team of retrovirologists at Rockefeller University identified a receptor that may be responsible for the infection of chimp cells by CERV2, copper transport protein 1 (CTR1). They published their findings in the Proceedings of the National Academy of Sciences in October 2010, and many have referred to the study as “reviving” an ancient virus. According to PhysOrg, the team had previously identified two proteins on human cells that protect against retrovirus infection, but they had not previously been able to determine why chimp cells were susceptible to CERV. However, the research group did find (2008, PLoSPathogens) that the protein APOBEC3 restricts retrovirus replication in some primates by applying mutational pressure, a mechanism potentially at work in humans.

The next possible AIDS vaccine

NewScientist is reporting that research from the Children's Hospital of Philadelphia has found an alternative vaccine method for preventing HIV infection. Using a virus to produce antibodies in the muscle - bypassing the immune system altogether and avoiding the cells that HIV infects.

They followed up on 9 macaques who were vaccinated and then exposed to SIV (the simian AIDS virus) over 85 weeks (roughly a year and half). None have been found to be infected. The control group was not vaccinated but exposed to SIV - 4 of the 6 monkeys have died of simian AIDS.

They hope that it makes it to the clinic, adjusted for HIV as opposed to SIV, in 2-3 years.

The issues I foresee being potential downfalls are:

• The length of protection by the injection - how long are the antibodies produced? How often is re-injection needed? How long does protection last (do the antibodies remain or are they transient)? It uses gene insertion, but as foreign DNA is it accepted indefinitely?
• The specificity of the antibodies for HIV as opposed to a less specific response (possibly even triggering autoimmunity or an immune reaction against the antibodies themselves - though the host muscle is producing the proteins so this isn't likely, it should still be examined)
• Which HIV strains will it cover? And will it be effective with co-infection?
• What is the long-term affect on the muscle?How specific is the gene insertion?

The researchers seem aware that this isn't a sure thing...yet. But it's a promising step forward in a battle against a disease that seems to be never-ending.

Genetic protections against HIV

Genetic similarities between individuals who are resistant to HIV infection or the progression to AIDS has been of interest to researchers because of the possibility for new therapies targeting these genes.

Many co-receptors for HIV binding to T cells and viral replication have been found in certain ethnic populations that tend to be less susceptible to infection.

Read more of the introduction to genetic protections against HIV...

A new attack against HIV

The human immunodeficiency virus (HIV) encodes vif, a virulence factor that deactivates the enzyme APOBEC-3G. This enzyme may be the key to the body's natural defense against HIV. A new study published in Nature discerning the crystal structure of the enzyme may be one of the first to show the potential of blocking vif and allowing APOBEC-3G to attack HIV in the fight against the ongoing epidemic of AIDS. The enzyme blocks HIV replication and, if vif is prevented from acting, the enzyme will continue to prevent HIV from causing AIDS. Knowing the structure of the enzyme will aid the development of drugs that prevent vif from binding.

HIV gels may benefit men

While the new anti-HIV gels being tested may benefit men, it's only at the expense of women. Researchers fear that the gels may promote the development of resistant HIV strains. There is still much research to be done, but current models show that caution is needed when it comes to the use of this new therapy.

A new HIV vaccine trial?

Despite the disappointing ending to Merck's recent HIV vaccine trial, the Partnership for AIDS Vaccine Evaluation (PAVE) is set to start a trial on the next potential vaccine - the PAVE 100 HIV vaccine trial.

The strain is a similar recombinant strain as used in the Merck vaccine, but the criteria for participants is slightly altered, which may aid in determining the effectiveness of the vaccine, but in my opinion, reduce it's generalizability. We'll see.

The AIDS Vaccine Research subcommittee voted 23-3 in favor of beginning the study. The groups responsible for the research are still reviewing the committee's recommendation to determine if they will proceed.

Roadblocks to eliminating AIDS

When I was finishing up my degree I taught graduate school courses on pathology. One topic that I was extremely interested in was HIV/AIDS. I had become interested in the topic in my undergraduate virology course when I had to help develop a class presentation on the virus.

Since then I've written several articles (see summarized update below) and commentaries on the subject. Recently I wrote a news update [broken link] on the clinical trials of the newest prevention technique - vaginal gel. Unfortunately, many of the latest trials have had to be halted due to the lack of usage among participants. Organizations are testing the female-based methods in Africa, the epicenter of the AIDS epidemic. Only 10% of women used the gel as directed! Several dropped out of the trial due to pregnancy. 1/4 of the women who initially signed up for the trial couldn't participate because they were already infected with HIV and didn't know it.

It's a shocking realization that after 25 years, there is still a place on the planet where condom use and HIV infection is not taken seriously. Thousands of children die or are made orphans by their parents deaths each day. Women and children are half of the victims. And the traditional high risk groups are no longer the ones to watch. Heterosexual partners of a high risk person is the largest growing group of HIV patients! Even in the United States, the prevalence of HIV infection is equivalent to the late 1980s [broken link] according to the latest information released by the CDC.

I'm just stunned, that as the number of infections and deaths has gone up, the level of prevention has not changed. You can bet that I'll still be writing on this in ten years, just as I was almost ten years ago. I hope it's to say that infection rates are down, but I doubt it will be about a cure. The virus is too able to adapt. It has to be stopped before it starts. Prevention!

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AIDS Epidemic Update January 2008

Acquired Immunodeficiency Syndrome (AIDS) was first recognized as a disease by scientists in 1981. To date, a reported 25 million deaths have been attributed to AIDS and its associated opportunistic diseases. AIDS is caused by the Human Immunodeficiency Virus (HIV), a retrovirus with counterparts in other species such as monkeys, cats, and horses.

The AIDS epidemic is believed to have peaked in the late 1990s though world health officials still contend there is much to do. The past year (2007) still saw 2.5 million new infections. In sub-saharan Africa AIDS affects men, women, and children. Elsewhere in the world outbreaks are mostly concentrated to high risk groups, but has been on a rise in heterosexual female partners of high risk group members since 1990 (NY Times 12/90, Journal Watch 1999). High risk groups include intravenous drug users, homosexual men, and sex workers.

New AIDS Infection Rate Estimates

The World Health Organization (WHO) and United Nations AIDS agency reported in November 2007 that the number of global AIDS cases fell from over 39 million to 33.2 million in 2007. This was due to new methodology that deflated previous estimates, mainly revised numbers from India and new data from sub-saharan Africa, the epicenter of the epidemic where AIDS is still the leading cause of death. Previous AIDS numbers were devised by projecting the AIDS rates of certain high-risk groups to the entire population at risk as well as the number of infected pregnant women at clinics. The new numbers include data such as national household surveys. Critics contend that even with revisions the numbers may still be too high and more revisions may be in store in the near future.

The Origin of HIV in America

New information about the origins of AIDS also came to light in 2007. A group involving evolutionary biologist Michael Worobey at the University of Arizona conducted genetic analysis on stored blood samples from early AIDS patients. Haitian immigrants in Miami as early as 1979 suffered from a mystery illness that turned out to be AIDS. The governments had stored the samples and the study was able to use five samples taken from Haitian immigrants in 1982 and 1983 along with 117 other early AIDS patients worldwide.

Other studies had previously suggested that the virus first entered the human population around 1930 in central Africa, most likely from slaughtered chimpanzees infected with the simian AIDS virus, SIV. Worobey’s group ruled out the possibility that HIV came directly to the United States from Africa. They found a 99.8% probability that Haiti was a link between the virus’s trek from Africa to the United States, a path long under debate by researchers. The study found that HIV was brought from central Africa to Haiti by an infected person around 1966, matching earlier estimates, but that HIV was brought into the United States in about 1969, earlier than previously thought. The virus was probably brought in by a single infected immigrant.

Reference

Gilbert, M.T.P. et al., 2007. The emergence of HIV/AIDS in the Americas and beyond. Proceedings of the National Academy of Sciences of the United States of America, 104(47), p.18566-70.