Review Article A M S J HIV/AIDS: let’s see how far we’ve come

Lauren Fowler Lauren is a third year medical student at Griffith University. She has an undergraduate degree Third Year Medicine (Undergraduate) in science from the University of Sydney, and completed immunology honours in HIV retroviral Griffith University genetics, studying microRNA changes during HIV infection. She has a passion for the intricacies BSc (Hons) of the immune system and the pursuit of a cure for HIV.

Now more than ever, HIV positive people are living longer and healthier lives because of access to antiretroviral therapy. Healthcare organisations are working to ensure that HIV positive people all over the world have access to the medical care they need to stay healthy. In the last few years, research into vaccine development, genetics-based approaches and novel therapies have achieved some progress and drug therapy regimens have become more effective. Public health strategies have aimed to reduce transmission, and early access to treatment has dramatically improved quality of life. With resources and funding aimed in the right directions, it will be possible to continue making significant progress towards better prevention, improved treatment options and perhaps even a cure for HIV and the elimination of the global AIDS epidemic. This article reviews some of the successes and difficulties in the scientific, research and treatment armof infection progression to AIDS, and divides the infection into stages combating the HIV epidemic. There is still much work to be done, reflecting the decline in immune function. [11] The stages of infection but for now, let’s see how far we’ve come. are: Stage 1: CD4 T-cells ≥ 500 cells/mm3 (≥ 29% of total lymphocytes) with Introduction no AIDS-defining conditions. The 2011 UNAIDS World Aids Day report concisely outlines the aims Stage 2: CD4 T-cells 200-499 cells/mm3 (14-28% of total lymphocytes) of global health efforts against HIV/AIDS: “Zero new infections. Zero with no AIDS-defining conditions. discrimination. Zero AIDS-related deaths”. [1] As global citizens and future medical practitioners, it is our duty to participate in the medical Stage 3 (Progression to AIDS): CD4 T-cells <200 cells/mm3 (<14% of issues that are of importance to the world. We should work to make the total lymphocytes) or the emergence of an AIDS defining condition eradication of HIV/AIDS one of those key issues. This paper discusses, (regardless of the CD4 T-cell count). from the scientific perspective, some of our triumphs and tribulations AIDS related conditions include a range of infections, such as esophageal with regards to combatting the complex, evasive and resourceful Candidiasis, Cryptococcus, Kaposi sarcoma, Mycobacterium avium/ opponent that is the HIV virus. tuberculosis and Pneumocystis jirovecii pneumonia. [11] AIDS related The Basics deaths are usually due to severe opportunistic infection as the immune system is no longer able to fight basic infections. [1] There are two main types of HIV: HIV-1 and HIV-2, with HIV-1 being the more common of the two. [2,3] HIV is a retrovirus with a high degree HIV is primarily transmitted via bodily fluids including blood, vaginal of variability, attributable to the error prone nature of its reverse secretions and semen, and across the placenta, however it isnot transcriptase enzyme and its high recombination rate. [4] The HIV readily found in the saliva, unless there are cuts or ulcers providing genome consists of a number of genes (see figure 1) includinggag , pol, access to the bloodstream. [12] Although sexual contact is the most env and nef all of which have been used as potential antigens for the common method of transmission, other mechanisms such as needle- generation of vaccines. [5] stick injury, sharing needles and transfusion of HIV infected blood are far more likely to result in infection. [12] The infectivity of a person with HIV is proportional to the number of copies per mL of blood. [12] HAART Therapy According to UNAIDS estimates, 34 million people around the world were living with HIV in 2010, with 2/3 of the global total in Sub-Saharan Africa. [1] By the end of 2012, this had increased to 35.3 million people. Figure 1. Simplified diagram of the HIV genome. [13] Now more than ever, HIV positive people are living longer and healthier lives. In part, this is due to the provision of effective treatment HIV primarily infects cluster-of-differentiation-4 cells (CD4) cells, in the form of Highly Active Anti-Retroviral Therapy (HAART). including CD4 T-cells, macrophages, monocytes and dendritic cells. [6] Initially, the immune response to viral infection (including CD8 T-cell The first antiretroviral drug described and approved for clinical use was mediated killing, complement activation and antibody production) is AZT (3’-azido-3’-deoxythymidine), a thymidine analogue. Now, there effective at removing HIV infected cells [7], but continued immune are seven categories of antiretroviral drugs, with more than 25 unique activation and antigen presentation spreads the virus to thelymph drugs. [14] HAART involves taking a combination of at least three nodes and the rest of the body. [8,9] Continued immune response drugs from at least two classes of antiretroviral drugs, with the aim to replicating virus drives development of escape mutations and of reconstituting lost CD4 T-cells, minimising viral load and reducing ultimately overwhelms the immune system’s ability to respond. [10] As viral evolution. [15-17] The efficacy of HAART has changed HIV from a the infection progresses, the rate of destruction of infected CD4 T-cells disease of significant morbidity and mortality to a manageable chronic exceeds the rate of synthesis and the CD4 count declines. condition. Further, HAART can minimise transmission of the virus, and prolongs the healthy lifetime of the individual by reducing viral load to The 2008 HIV infection case definition replaces past criteria for HIV

28 Australian Medical Student Journal Volume 6, Issue 1 | 2015 undetectable levels. [18] by 10%. [29] The problem this variation causes is illustrated in natural infection, where the antibodies present in infected individuals are At present, much research is focused on investigating the timing of functional, but do not eliminate the infection due to the genetic variety initiation of HAART therapy in HIV+ individuals, and the most effective seen in mutants created under the pressure of the immune system. combinations of drugs. [19,20] In general, those who initiate HAART [28,30] This variability makes it difficult to know which antigens to use therapy earlier are more likely to die at older ages and of non-AIDS to generate the required immune response to control the infection. causes. [21] Studies have found conflicting results when tracking the Strategies being explored to combat this include the use of consensus disease outcomes of patients commenced on HAART at different sequences (fusing the most conserved portions of the virus, and trying stages of disease. For example, a large collaborative study found that to produce immunity to such a sequence), conserved region antigens patients who are commenced on HAART with CD4 T-cell counts of (specifically choosing the most conserved antigens to generate immune 351-450 cells/mm3 have a lower rate of AIDS and death than patients responses) and multiple antigen cocktails (vaccination with multiple whose commencement on HAART was deferred until there was further variants of one immunogen, or several different ones in combination). CD4 T-cell decline to below 500 cells. [18,22] Another study has shown [31] that patients commenced on HAART at CD4 counts <500 cells/mm3 compared to deferring had slower disease progression, but this benefit The first prototype HIV vaccine tested utilised purified monomeric was not seen with commencing HAART at CD4 T-cell counts of 500- env gp120 immunogens (a component of the virus’s surface envelope 799 cells/mm3. [19] Recent evidence has shown that early treatment protein) in an attempt to generate virus-specific antibody responses. enhances recovery of CD4 T-cells to normal levels. [20,23] The World Unfortunately, early trials showed that this vaccine was unable to Health Organisation’s HIV treatment guidelines issued in June 2013 induce the production of neutralising antibodies, and did not prevent now recommend commencing treatment when an individual’s CD4 infection with HIV-1 in humans. [31,32] Since then, attempts have T-cell count falls below 500 cells/mm3, or immediately on diagnosis been made at prophylactic vaccination using a range of differing for pregnant women, children under 5, those with HIV-associated immunogens including Tat and Gag. In most cases, these vaccinations comorbidities like tuberculosis and Hepatitis B, and for HIV- people in have proven safe and well tolerated, and resulted in the production a serodiscordant couple with an HIV+ individual. [13] of anti-HIV antibodies that may not be seen in natural infection. [33] Promising results have come from a range of trials, including the control HAART requires strict adherence, and side effects can impact on the of infected CD4 T-cells by Gag-specific CD8 T-cells, proportionally to the patient’s quality of life. Long-term use is associated with toxicity, number of Gag epitopes recognised. [34] Success at eliciting immune particularly to the liver, kidneys, bone marrow, brain, cardiovascular responses demonstrated thus far with Gag may be to do with its system and gastrointestinal tract. [15,24] Further, It has been noted relatively well-conserved sequence patterns. [34] that illnesses that typically occur with ageing appear prematurely in HIV+ patients on HAART therapy. This is thought to be only partially The STEP Study and Phambili HIV vaccine trials both used an Adenovirus due to the infection, but also a side effect of the drugs involved in 5 (Ad5) vector and gag, pol and nef immunogens, which was shown to treatment. [25] Torres and Lewis (2014) provide an overview of what be successful at inducing a good CD8 T-cell response. [35] Subsequent is known about premature ageing in the HIV+ patient and how this trials demonstrated that the vaccine provided no additional prevention relates to HAART drugs. [25] from infection, nor a reduced early viral level. [36] Further, there was an increased rate of HIV-1 acquisition in groups of vaccinated individuals Non-compliance with HAART leads to the resurgence of viral replication from the STEP study, most particularly in men who were already Ad5 with increased viral load and the potential for development of drug seropositive and uncircumcised. [37] resistant mutant strains of HIV. [15,24] This can make it more difficult to treat the patient, as new drug choices may be limited and increases The primary challenge in the use of viral vectors to deliver a HIV in viral load can lead to risk of further spread of the virus. HAART also vaccine into cells is the pre-existing immunity of humans to viral does not purge reservoirs of latently infected cells [26], and as such, vectors, leading to the neutralisation and removal of vectors from there is currently no cure for HIV. the circulation before the transfer of the immunogen to cells. In addition, vectors induce mucosal homing in T-cells, making them more Integration, latency and treatment challenges susceptible to infection [38] and explaining the increased susceptibility There are a number of characteristics of the HIV virus that make it to infection observed in the Step Study. [37,39] challenging to eradicate. HIV exhibits significant genetic diversity, both within an individual patient and within a population. As a retrovirus, At present, there is much debate over the necessary aims for a successful HIV has an inherent ability to establish early latency within the DNA of HIV vaccine: for example, whether to focus on the development of anti- host cells, where it remains for the lifetime of the cells and is unable to HIV antibodies, or the induction of a CTL response. [30] Recent papers be removed by the immune system. [5] have described the ability of combinations of broadly neutralising antibodies to successfully neutralise HIV. [40,41] One major development was made in 2013, when Hauber et al. reported the successful use of an antiretroviral gene therapy. A site MiRNAs specific recombinase (Tre) targeted to the HIV-1 long terminal repeat A new area of interest is the use of microRNAs (miRNA) as potential next (LTR) was used to excise the HIV provirus from infected CD4 T-cells, generation therapeutic agents for the treatment of HIV infection and functionally curing infected cells of their HIV infection, without management of viremia. MiRNAs are small, noncoding RNA fragments, cytopathic effects. [27] This study provides promising evidence to responsible for fine-tuning and negatively regulating gene expression. suggest that in future, genetically oriented antiretroviral technologies Roles for microRNAs have been found in metabolism, development may have the potential to provide a cure for HIV infection. and growth, and dysregulation of miRNAs have been implicated in loss of tumour suppression and development of cancer. [42,43] Development of a prophylactic vaccine for HIV Although it was initially believed that HIV infection was a simple The utility of miRNA-oriented technology has already been illustrated illness of immunosuppression, we now know that HIV sufferers do in the context of hepatitis C infection. In 2005, Jopling et al. reported mount strong immune responses to the HIV virus, although this that miR-122 was highly abundant in human hepatocytes, and that its response is insufficient to control the virus or eradicate the infection. presence may facilitate replication of the viral RNA, and encourage [28] One of the major challenges in producing a prophylactic vaccine survival of the virus in the liver. [44] Since this pivotal paper, the first is the high variability of the HIV virus. There is a variation of 25-30% drug targeting a miRNA has been developed. Miraversen is a miR-122 between subtypes of HIV-1, and 15-20% variation within any subtype. inhibitor [45], which in human trials has been shown to exhibit dose Furthermore, viral quasi-species in any infected individual can range dependent antiviral activity [46], with no dose-limiting adverse events

Australian Medical Student Journal 29 A M S J or escape mutations observed. [47] learning more about how HIV interacts with the host immune system, and how to overcome it. However, progress on the development of a The first attempt to find human cellular miRNAs directly targeting HIV vaccine has stalled somewhat after the findings of the STEP and the HIV genome was by Hariharan et al. (2005). [48] It was then later Philambi studies. shown that one of the miRNAs identified was capable of inhibiting HIV nef expression, and decreasing HIV replication. [49] Further research It is important to acknowledge the significant achievements that have demonstrates that cellular miRNAs potently inhibit HIV-1 production in been made worldwide through HIV public health campaigns. In 2012, resting primary CD4 T-cells, suggesting that cellular miRNAs are pivotal a record 9.7 million people were receiving antiretroviral therapy, and in HIV-1 latency. [50] the incidence of HIV is falling each year, with a 33% decline from 2001 to 2012. [56] However, there is still much work to be done to ensure all In 2007, Triboulet et al. reported that HIV-1 infection caused a down- people are able to access HIV testing and treatment. One of the aims regulation of specific miRNAs in mononuclear blood cells, andthat of the Millennium Development Goals is to provide universal access to this was necessary for effective viral replication. [51] Witwer et al. treatment for HIV/AIDS to all those who need it, although this is yet to (2012) subsequently showed that the miRNA profiling of infected cells be achieved. [56,57] could be used to distinguish elite suppressors, viraemic HIV-1 patients and uninfected controls from one another [52], indicating significant Medicine has come a long way in the understanding and treatment changes to cellular miRNA profiles of cells when they are infected by of the complex and multifaceted problem that is the global AIDS HIV. From these studies it is evident that different cellular miRNAs epidemic. I urge medical students to be informed and interested modulate and are modulated by HIV infection, with different miRNAs in the HIV epidemic, and to be involved in the clinical, research and implicated in different cells, contexts and environments. More research community groups tackling this multifaceted problem. With continued in this area is required, and will hopefully give rise to a new generation efforts and dedication, there is hope that in our lifetime, we may see of therapeutic agents for HIV. The interested reader is referred to more the realisation of the ambitious aims of the 2011 UNAIDS World AIDS specific reviews [53-55] for more detailed information. Day report: “Zero new infections. Zero discrimination. Zero AIDS- related deaths”. Where to from here? HIV has proven itself a formidable opponent to our aims at a global Acknowledgements improvement in healthcare and quality of life. However, recent research Many thanks to my family and friends who make life fun and the effort gives hope that advanced treatments, better prevention and even a worthwhile. This article is in acknowledgement and appreciation of the cure may one day be possible. It is clear that the best way to tackle HIV hard work and dedication of HIV/AIDS researchers everywhere. is by a coordinated approach, where global health strategies, clinical medicine and research work together to help eradicate this epidemic. Conflict of interest None declared. We have had some success in the use of novel approaches like targeting cellular miRNAs and excising HIV DNA from the human genome, Correspondence and there have also been some promising results in the generation L Fowler: [email protected] of immunity to infection through a HIV vaccine. We are constantly

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