The first person to be cured of HIV, Timothy Ray Brown, died last week from a recurrence of leukaemia. His case raised many scientific questions and sparked a sense of hope that the epidemic would one day be eradicated. In this blog, we explore the origins of HIV and the research that has gone into identifying treatments and cures. We also address the associated stigma with this virus and how education, particularly in genomics, can help overcome some of this stigma.
Structure and Epidemiology
HIV, also known as human immunodeficiency virus, is a member of the Lentivirus genus, part of the Retroviridae family. Two types of HIV have been characterised: HIV-1 and HIV-2. HIV-1 is the most virulent and infective type, causing the majority of HIV infections globally. HIV-1 has been found mainly in infected individuals in Western Africa. In 2019, approximately 38 million people worldwide were reported to have HIV. Of these, 36.2 million were adults and 1.8 million were children (<15 years).
HIV is an enveloped virus with two copies of positive-sense single-stranded RNA. The RNA is enclosed by a conical capsid and is tightly bound to nucleocapsid proteins. The virus also contains enzymes needed for virion development, such as reverse transcriptase, proteases, ribonuclease and integrase. Viral entry occurs when the viral envelope glycoproteins attach to host cell chemokine receptors CCR5 and CXCR4. The virus then exploits host mechanisms in order to replicate.
All types are thought to be derived from zoonotic introductions from nonhuman primates. HIV-1 comprises of four distinct lineages: groups M, N, O and P. Each of these groups arose from independent cross-species transmission events. Group M was the first to be discovered and represent the pandemic form of HIV-1. In 1999, researchers identified a strain of Simian Immunodeficiency Virus – SIVcpz – in a chimpanzee. The strain was almost identical to the predominant HIV-1 group M strain in humans. Evidence since has supported the theory that the virus crossed from chimpanzees into human in the 1920s from the Democratic Republic of Congo. Researchers believe that HIV-1 was introduced into the human population when hunters ate chimpanzees in the area, becoming exposed to infected blood.
HIV-2 was first discovered in 2008 and it originates from SIVsmm strain in sooty mangabey monkeys. Researchers identified that humans in West Africa harboured HIV-2 strains that resembled locally circulating SIVsmm infections. At least eight distinct lineages of HIV-2 have been detected, each representing a single independent transmission event.
Unlike years ago, contracting HIV is no longer considered a death sentence. In fact, individuals who are aware of their status and take the prescribed regimens can get and keep undetectable viral loads. In turn, people are living longer healthier lives and have effectively no risk of sexually transmitting the virus to their HIV-negative partners.
History of treatment
The first treatment for HIV – azidothymidine – was introduced in 1987. In the years following this, other nucleoside reverse transcriptase inhibitors (NRTIs) were approved. By 1995, the first antiretroviral protease inhibitor drug, saquinavir, was approved. A year later, another class of antiretrovirals emerged called non-nucleoside reverse transcriptase inhibitors (NNRTIs), e.g. nevirapine. These drugs changed the way HIV was being treated and paved the way for a new era of combination therapy. Doctors began prescribing saquinavir plus azidothymidine or other antiretrovirals. This combination therapy became known as highly active antiretroviral therapy (HAART). This approach became the new standard of care for the virus in 1996. At of the end of 2019, 24.5 million people with HIV were accessing ART globally. It maximally suppresses the virus and stops its progression. It also prevents onward transmission of HIV.
In 2010, a study revealed that taking a daily dose of antiretrovirals not only helped HIV-positive individuals but could also protect healthy people from becoming infected. In 2012, the FDA approved Truvada for pre-exposure prophylaxis (PrEP). Additionally, post-exposure prophylaxis (PEP) is also now available which is taken within 72 hours of exposure. This has been shown to reduce dissemination and replication of the virus.
The sustained effects of HAART treatment are complicated by the prevalence of drug resistance. HIV is highly mutable and has resulted in a number of virus mutations that have reduced or negated the efficacy of some antiretroviral drugs. The primary cause of drug resistance is lack of regimen adherence of patients. Unfortunately, adherence of these regimens is poor. This results in multiple drug-resistant strains of HIV.
Progress in vaccine development for HIV has been slow. This is because developing a vaccine against HIV is difficult. Unlike other vaccines which aim to teach the adaptive immune system to generate antibodies, antibodies in HIV are unable to clear infection. This is due to the fact that HIV mutates very rapidly. Another challenge is the fact that HIV is divided into subtypes, which predominate in different parts of the world. As a result, a vaccine would have to be effective against all subtypes or several vaccines would need to be developed. Several types of experimental vaccines have been explored, including peptide vaccines, live vector vaccines and recombinant subunit protein vaccines. In a report, it was estimated that $845 million was spent on HIV vaccine research in 2017. In addition, to date, more than 40 potential vaccines have been tested.
Although the results for HIV vaccines have been disappointing, each trial has developed our understanding about HIV. In recent years, there has been an increase in the study of broadly neutralising antibodies (bNabs), particularly within vaccine discovery, as they target conserved epitopes of the virus.
In 2011, Timothy Ray Brown became the first person reported to be cured of HIV. Brown was diagnosed with HIV in 1995 while studying in Berlin. In 2006, he was then diagnosed with acute myeloid leukaemia. To treat his leukaemia, Brown underwent a haematopoietic stem cell transplantation. The doctors selected a CCR5Δ32 homozygous donor, a genetic trait which confers resistance to HIV. Three years on from his initial transplant, despite discontinuing ART, researchers were not able to detect HIV in Brown’s blood or in various biopsies. A second individual who also received a CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation was reported earlier this year to be free of detectable viral infection 30 months after stopping ART.
Interestingly, last month another individual was reported to have undetectable levels of the virus. However, this individual has controlled the virus without drugs or surgery, also known as an elite controller. While researchers could not confirm that this patient was cured of HIV-1 infection, they note that they were unable to falsify this hypothesis.
A significant development occurred in 2018, when He Jiankui and colleagues used CRISPR/Cas9 technology to modify the CCR5 gene in two twin embryos. He had initially planned to edit the genes for the CCR5∆32 variants. However, in his analysis, he actually revealed that he yielded mutations in CCR5 that have never been seen in humans before. In addition, unbeknownst to the mother, one of the twins in fact had a normal CCR5 allele, undercutting any protection she may have received. He’s actions were widely condemned by the scientific community.
If someone told you that they had the common cold or cervical cancer – how would you respond? Now, if someone told you that they had HIV – would your attitude differ? Why?
The first verified case of HIV was in 1959 from a blood sample taken from a man living in Kinshasa in the Democratic Republic of Congo. From here, the virus was able to spread through transport links, the growing sex trade and the high population of migrants. In the 1960s, the B subtype of HIV-1 (subtype of strain M) made its way to Haiti. At the time, many Haitian professionals were working in the colonial Democratic of Congo. Many blamed them for being responsible for the HIV epidemic and as a result, they suffered severe racism, stigma and discrimination.
In the 1980s, in the USA, people first started becoming aware of HIV. In 1981, there were cases of homosexual men in New York and California presenting with immunodeficiency symptoms, such as Kaposi’s Sarcoma. It was suspected that this cancer was the result of an infectious disease. The disease, at first, was argued to be related to the homosexual community.
However, it was not until mid-1982 that scientists realised that the disease was also spreading among other populations, including haemophiliacs and heroin users. By September of that year, the disease was finally named AIDS (acquired immunodeficiency syndrome). However, it was only in 1983 that the virus itself was isolated and identified by researchers at the Pasteur Institute in France. At this time, the Centers for Disease Control (CDC) in the US listed the main at-risk groups as homosexual men, heroin users, haemophiliacs and people of Haitian origin. This generated a lot of derogatory talk about the so-called ‘4-H Club’, which contributed to further stigmatisation.
HIV stigma has manifested for many reasons, including beliefs regarding associated behaviours (e.g. homosexuality), it’s association with death, sex being a taboo subject in some cultures and general inaccurate information. Although HIV/AIDS stigma exists across the world, it varies by country, community, religious group and individual. It is considered a major barrier to effective responses to the HIV epidemic. From 35% of countries with available data, estimates indicate that over 50% of people report having discriminatory attitudes towards people living with HIV. Stigma manifests in many different ways, including within healthcare settings, among families and peers and also within work and educational settings. These all limit access to HIV testing, treatment and other important services.
Efforts to combat stigma
Notably, in 1987, Princess Diana opened the UK’s first HIV/AIDs unit in London. At the opening, photographs were taking of her shaking hands with a HIV-positive man without gloves. At the time, it was falsely believed that you could ‘catch’ the virus through skin contact. Her actions at the time were revolutionary and made her a champion for gay rights. In March 2016, UNAIDS and WHO’s Global Health Workforce Alliance launched the Agenda for Zero Discrimination in Healthcare. This agenda aims to ensure that everyone, everywhere is able to receive healthcare without discrimination. It has been found that initiatives are most effective when they encompass a range of activities directed at several actors at multiple levels. These include at the interpersonal level (education), institutional level (policies and guidelines) and structural level (laws and mass media campaigns).
For the genomics community, ending this stigma is also our responsibility. In addition to our responsibility to help end HIV stigma in society generally, it is particularly important that we do so with research and education. There must be continued effort to study the HIV genome and its pathogenesis to slow the spread of the virus and reduce the number of deaths. This research will ultimately translate into better control and treatment options, which will lead to lower numbers of transmissions and deaths. As a result, this will reduce the fear associated with the virus and alter perceptions of it.
In addition, the knowledge gained from research must be disseminated appropriately to help educate the public on what the virus actually is and how it is actually spread. With clear and accurate information, the spread of misinformation will reduce, which again will impact people’s views. It is important that the genomics workforce support marginalised communities, such as the homosexual community, and advocate for groups that aim to remove HIV stigma from society.
Anyone is susceptible to HIV. It is difficult to comprehend how someone feels when they are diagnosed with HIV. Yet, it is 2020 and this should not be the case. We have come a long way since the first case of HIV was identified in 1959. The improvement in our ability to diagnose the virus, manipulate the DNA to research the virus and the use of our knowledge to develop treatments has been astounding. However, why for many does the thought of contracting HIV still seem like a death sentence? Now, more than ever, the need to educate and inform the public has been made clear. In recent months, with the transmission of the COVID-19 virus, we have seen how misinformation can cause mass hysteria. For HIV, such hysteria has caused long-lasting prejudices that continue to be difficult to shift.
The stigma associated with HIV is one of the main reasons why the virus is still being transmitted today. By educating the public, the stigma associated with HIV may decrease. The more the scientific community communicates advancements in treating HIV, the more the public will communicate about it. We must reverse years of damage and build on creating a better community for all. Genomics has been and will continue to be critical in identifying ways to combat the virus as the critical complexity of the virus is its ability to rapidly mutate. The purpose of our community is to support those with disease. If you have a disease or illness you should never feel ashamed or embarrassed, yet for many individuals living with HIV, this is the case. Just by sharing our research, we can start to support a community who frankly needed it a long time ago.
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