A One Health Perspective on the Molecular and Cellular Mechanisms of HIV Immune Evasion and the Barriers to Vaccine Development: A Narrative Review

Approximately 30 years ago, in June 1981, it was reported from theCenter forDiseaseControl andPrevention (CDC) that five, otherwise healthy, homosexual men in California had presented with pneumonia caused by Pneumocystis jiroveci pneumonia, a rare disease seen exclusively in individualswith a severely suppressed immune system. Several reports confirmed the initial observation and lent support to the possibility that a new sexually transmitted, infectious agent was circulating within the gay community in the United States. The clinical condition was named acquired immunodeficiency syndrome (AIDS). Two years later, a research team at the Institut Pasteur under the guidance of Francoise Barre-Sinoussi and Luc Montagnier isolated human immunodeficiency virus (HIV), the causative agent of AIDS, from a lymph node biopsy of a French patient. The isolation and characterization of HIV paved the way for the design of diagnosticmethods to identify the virus in blood andbloodproducts and towards the development of novel antiretroviral treatment (ART) to control HIV replication in infected patients. For their discoveries, Barre-Sinoussi and Montagnier were awarded the Nobel Prize in Physiology and Medicine in 2008.

HIV and sickle cell disease (SCD) are significant causes of morbidity and mortality in sub-Saharan Africa. Given their separate roles in immune dysregulation, our objective was to characterise the impact that SCD has on the presentation and progression of paediatric HIV. The study was a retrospective cohort study (study period 2004-2018). Cases of HIV+and SCD-afflicted patients (HIV+/SCD+) were obtained via electronic chart review from a paediatric HIV clinic in Kampala, Uganda and matched 1:3 with HIV+controls without SCD (HIV+/SCD-). Thirty-five HIV+/SCD+subjects and 95 HIV+/SCD- controls were analysed (39% female (51/130), age 3.6years (SD3.9)). At baseline, WHO clinical stage (64% total cohort Stage III/IV) and nutritional status (9.4% severe acute malnutrition) were similar for both groups, whereas HIV+/SCD+had higher though non-significant baseline CD4 count (1036 (SD713) vs 849 (SD638) cells/microlitre, P=0.20, two-tailed t-test). There were 19 deaths, 6 (17%) HIV+/SCD+and 13 (14%) HIV+/SCD-, with unadjusted/adjusted models showing no significant difference. Nutritional progression and clinical stage progression showed no significant differences between groups. Kaplan-Meier analysis showed a slower rate of treatment failures in the HIV+/SCD+cohort (P=0.11, log-rank survival test). Trajectory analysis showed that in the time period analysed, the HIV+/SCD+cohort showed a more rapid rise and higher total CD4 count (P=0.012, regression analysis). The study suggests that SCD does not adversely affect the progression of HIV in patients on ART. Further, HIV+/SCD+achieved higher CD4 counts and fewer HIV treatment failures, suggesting physiological effects due to SCD might mitigate HIV progression.

Mexico's evolving HIV epidemic.

An HIV (human immunodeficiency virus) vaccine is needed to combat the 1–2 million cases on new HIV infection each year. The goal of vaccination is to establish long‐term immunological readiness that allows rapid protection against infectious disease. All current successful vaccines achieve this by inducing neutralising antibodies, which are effective against acute, cytopathic infections that could otherwise prove fatal. By contrast, potential vaccines against highly variable pathogens that establish persistent infections, such as HIV, have had limited success. There have been multiple attempts to induce effective immunity to HIV in humans, with only one approach showing partial (31%) efficacy. Several clues on a better path forward have, however, emerged from HIV vaccine trials in humans, studies of humans who naturally control HIV infection and studies in animal models. There has been an improved understanding of anti‐HIV neutralising antibodies, which, if could be induced successfully, are likely to be highly effective. Antibodies that engage Fc receptors on innate immune cells (the so‐called ADCC (antibody‐dependent cellular cytotoxicity) antibodies) have emerged as a key component of successful vaccine strategies. New vaccine design and delivery strategies are now entering large‐scale human efficacy trials. These approaches offer real hope that a safe and effective HIV vaccine will eventually be developed to assist in the control of the HIV/AIDS (acquired immunodeficiency syndrome) pandemic. Key Concepts A HIV vaccine is urgently needed. There are many hurdles to induce effective HIV immunity. Only one HIV vaccine trial in humans has showed partial efficacy to date. Neutralising antibodies against HIV are highly effective in animal models but are difficult to induce by vaccination. Functional anti‐HIV antibodies that can engage innate immune cells to fight HIV are likely to be a key component of successful HIV vaccine strategies. T‐cell‐based immunity against HIV shows promise in certain settings. New HIV vaccines are entering human efficacy trials. There is considerable promise that an effective HIV vaccine will be developed in the future.

As the importance of quality in health care provision is increasingly recognised, it is opportune to consider quality care as a key link between clinical and public health approaches to human immunodeficiency virus (HIV) infection in developing countries, especially in sub-Saharan Africa. This region has the lion's share of the global epidemic and the least resources to respond. Looking at health problems using a 'quality lens' may help bridge the gaps between clinical care and public health, the current and desired standard of care, and prevention and treatment. Quality care, with prompt diagnosis and effective treatment, of people with HIV infection is crucial for good individual health outcomes, public health outcomes (in terms of decreased HIV transmission) and societal outcomes (increased productivity and decreased costs of health provision for HIV-related care). A spotlight on quality care can bring clinicians and public health practitioners together in working towards universal access to quality HIV care and prevention - one of the greatest health challenges faced in developing countries in Africa today.

Addressing HIV-1 latency with Flow-FISH: Finding, characterizing and targeting HIV-1 infected cells.

Human immunodeficiency virus (HIV) has one of the highest incidence and mortality rates of any infectious disease, with more than 33 million people infected worldwide. Specifically, HIV causes the destruction of helper T cells, ultimately resulting in the suppression of the immune system and leaving its human host susceptible to countless of other pathogenic agents. The development of an effective HIV vaccine has continued for more than 20 years. But the use of preventative vaccines using traditional vaccine technologies, which have proven successful for other diseases, has thus far failed with HIV. One vaccine, AIDSVAX, was the first HIV vaccine to reach a phase III efficacy trial, but has not yet been shown to eradicate HIV. Hope now lies in the development of therapeutic vaccines using novel technologies. One such vaccine is ALVAC-HIV, which when used in conjunction with other vaccines (AIDSVAX or Lipo-6T with IL-2 injections) has shown a great deal of promise in clinical trials suppressing viral replication and improving the immune system. Other therapeutic vaccines, such as Ad5, however, have been unsuccessful. While many believed that developing an effective HIV vaccine is impossible, efforts continue into researching its structure, transmission, immune system suppression, genetic variability, and immune system evasion. As long as research continues, hope remains that someday an effective vaccine will be developed. Key words: Vaccines, human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), recombinant, lymphocytes.

Human immunodeficiency virus (HIV) still infects more people per year than existing health systems are able to initiate and maintain on antiretroviral therapy. Therefore, the development of effective HIV population prevention strategies remains a high priority. There is no immediate promise for an effective HIV vaccine, risk behavior change has been difficult to implement, and biomedical prevention measures lack effectiveness due to inconsistent use. In contrast, antiretroviral therapy (ART) can benefit the infected individual and under clinical trial conditions has been shown to reduce transmission [1]. The use of ART as both treatment and prevention is now a well-established concept, which has been widely welcomed as the “missing link” that will curb HIV incidence [2]. However, a disconnect exists between the individual and transmission benefits of ART. Persons with advanced HIV disease (reflected by having a CD4 lymphocyte count <250 cells/μL), have clear benefit, documented by several randomized controlled trials (reviewed in [3]). Conversely, the target populations for transmission benefit are those with high CD4 counts, in whom observational studies have shown inconsistent or no clinical benefit (reviewed in [4]). Additional biological plausibility for early treatment has been the observation that untreated HIV infection activates host inflammatory processes associated with organ disease and cancers and that ART partly (but not completely) reverts immune activation. However, no specific anti-inflammatory intervention has been demonstrated to reduce the risk of these adverse outcomes, and changes in inflammatory biomarker levels have not been validated surrogates for clinical benefits of ART. Therefore, whether inflammation is causally involved in the pathogenesis of these events or merely an epiphenomena to the underlying pathology remains to be identified in HIV as it does in the general population. The uncertainties relating to net benefit of early ART are reflected in disparities between treatment guidelines. Guidelines based on consensus “expert opinion” recommend that all HIV-positive persons, as a matter of principle, should be started on ART [5, 6], and those based on available direct evidence [7–9] (including the 2010 World Health Organization guidelines) are more conservative. Unfortunately, consensus among experts can be prescient or subsequently shown to be incorrect. For example, 10 years ago, expert opinion was that ART could be used intermittently, but the SMART (Strategies for Management of Antiretroviral Therapy) trial demonstrated definitively that this view was wrong [10]. Gallant et al, in this issue of Clinical Infectious Diseases [11], highlight reasons why the recommendations of the US guidelines are not necessarily generalizable to other settings. They highlight a fundamental ethical obligation of clinicians to benefit patients while not causing harm. They note that although the individual benefits of early ART remain undefined in resource-limited settings, the risks associated with early ART may be higher. Cost constraints in resourcelimited settings limit the available ART repertoire, resulting in frequent use of older, cheaper drugs with poor adverse event profiles. In a setting where only stavudine-based ART regimens are available, for example, starting ART at a high CD4 count of 650 cells/μL would less likely maintain health than deferring to a more conservative threshold of 250–350 cells/μL. Lack of laboratory monitoring may also potentially increase risk by delayed recognition of toxicity. Tenofovir, which is included in most currently recommended ART regimens, may adversely affect kidney and bone physiology [12, 13]. Emerging reports of more severe renal diseases in settings without access to laboratory monitoring raise Received 30 May 2013; accepted 1 June 2013; electronically published 11 June 2013. Correspondence: Jens D. Lundgren, MD, DMSc, Department of Infectious Diseases (5112), Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen O, Denmark (jdl@cphiv.dk). Clinical Infectious Diseases 2013;57(6):888–90 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cit381

Hepatitis viruses and human immunodeficiency virus co-infection: pathogenisis and treatment

Can HIV Be Cured and Should We Try?

The human immunodeficiency virus (HIV) is a major worldwide health concern, affecting millions of people globally, and when untreated progresses into acquired immune deficiency syndrome (AIDS). With the availability of antiretroviral therapy (ART), HIV infection is defined as a manageable, but not curable, chronic health condition. ART inhibits viral replication and prevents HIV transmission but does not eliminate the virus due to viral latency in memory T cells, exacerbated by the rise in drug resistant mutations (DRMs), so lifelong treatment and monitoring is required. In this review, we discuss the justifications and research approaches towards finding a “cure” for HIV i.e. complete elimination or control of the virus without the need for further treatment. The two main barriers to developing a cure for HIV infection are the property of HIV viral latency and high mutation rate of the virus. A few cases of HIV have been cured through bone marrow transplants to treat acute myeloid leukaemia, where the donors had rare mutations in the CCR5 gene, required for viral entry. More viable approaches to a cure include the “Shock and Kill” method which aims to use reverse viral latency allowing these cells to be detected and destroyed with ART, and the “Block and Lock” method aims to block viral transcription in HIV-infected latent cells, preventing a rebound viral replication after the cessation of ART. The possibility of vaccination has been widely explored, but an effective HIV vaccine has yet to be developed after more than 40 years of the pandemic. Currently, the “Block and Lock” approaches appear to be the most favourable, possibly in conjunction with other recently developed interventions such as passive immunisation with broadly neutralizing antibodies. However, approaches taken to develop a cure for HIV cannot be detached from ethical concerns which need to be acknowledged and navigated.

More Surprises in the Development of an HIV Vaccine (General Commentary)

British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review).

Expanding directly observed therapy: tuberculosis to human immunodeficiency virus

Are HIV-infected patients candidates for liver transplantation?