Wellington and York Partners: Using Travel Promotions for Traveling to Zurich, Switzerland

Travel promotions can be a blessing in disguise. It can help travelers save money when you are going on a trip somewhere. It may include accommodation and restaurant discounts, as well as a way to give exclusive access to tourist spots.

Switzerland may not be the top country chosen by most travelers. Most people love to go to France, New York, or Spain. It is less likely that travelers go to Zurich unless they have a sweet tooth. The country isn’t only known for their remarkable yet expensive watches. Tourists can also enjoy the food products like cheese and chocolates. It is a great place for adventurers and hikers because of the famous mountain range called the Swiss Alps.

Zurich is also one of the famous places in Switzerland. According to surveys, it has the highest quality of life compared to other places in the world. Travelers can enjoy a lot of incredible accommodations, as well as outstanding cuisine. There are a lot of restaurant services you can find in the city. After a gastronomic adventure, an ideal way to do is enjoy a great shopping experience in various shops. You can even see celebrities strolling around the place.

The sweet in Switzerland

Switzerland is a haven for lovers of confections because of their rich history of chocolate making which is traced back to the 17th century. Chocolate making can be considered an art and a lucrative industry in the country. Milk chocolate is one of the best-known products.

You can find a great-tasting Swiss chocolate in local shops. A lot of supermarkets around the world showcase a lot of sweet treats from Switzerland but to taste the fresh and delicious confection, better to head to a local sweet shop than the grocery stores.

The selection of Swiss chocolates will not disappoint you. If you go to local chocolatiers, you can even get a free taste of their products. While you’re in Zurich, don’t just focus on the wrapped chocolate treats. There are other selections of goodies such as Swiss hot chocolate which is far different from the ones sold in supermarkets.

Switzerland has astonished people who go in and out of the country. Travelers can see a combination of rolling mountains, crystal blue lakes, stunning architectures, as well as a busy yet astounding city streets. It may be small since travelers can cross the country by train in just 5 hours. However, it is worth the time to experience the Swiss sights and sounds. The public transit is reliable and a good way to go around the tourist spots.

The lack of travel reviews should not be a hesitation for would-be travelers planning to take a trip to the country since it is still extremely underrated.

Stellamc.info

Stellamc.info

HIV-1 dynamics drive CD4+ T cell turnover

The hallmark of HIV-1 infection is a progressive reduction in CD4+ T cells, which leads to a general decline in immune function and is the primary factor responsible for the clinical course of disease. Although the discovery of CD4 as a receptor for HIV-1 in the 1980s (MILESTONE 3) could help explain thesusceptibility of CD4+T cells to infection, the mechanisms responsible for their decline remained elusive. In 1995, two seminal studies by the groups of George Shaw and David Ho published in Nature provided important insights on the dynamics and pathophysiology of HIV-1 infection, including pivotal observations concerning CD4+ T cell decline.

The advent of new quantitative assays for measuring HIV-1 RNA concentrations (viral load) and experimental drugs that could potently inhibit HIV-1 replication enabled both groups to perform experiments in which the rates of CD4+ T cell and viral turnover could be extrapolated from measurements of changes in plasma viral load and CD4+ T cell counts following antiviral therapy. In both studies, abrupt inhibition of viral replication led to a substantial rise in CD4+ T cell numbers and revealed a scenario in which continuous and highly productive viral replication drove rapid turnover of CD4+ T cells.

The initial stage of HIV-1 infection is followed by an asymptomatic period that can last for years before disease progresses and results in the development of AIDS. Given that this asymptomatic period is accompanied by relatively stable levels of CD4+ T cells and viral load, loss of these cells was initially thought to involve a gradual process of destruction. However, these new findings challenged this view, supporting a model of accelerated CD4+ T cell destruction, which Ho and colleagues likened to a ‘tap-and-drain’ scenario.

In this analogy, the destruction of CD4+ T cells (the drain) is counterbalanced by homeostatic production of T cells (the tap) during the asymptomatic period; however, once production of T cells becomes exhausted, this balance is disrupted, resulting in eventual loss of CD4+ T cells (emptying of the sink) and AIDS. Although the mechanisms underlying this imbalance were an area of debate and later evidence pointed to the existence of other (potentially non-mutually exclusive) models of CD4+ T cell depletion (MILESTONE 10), the findings nonetheless had important clinical implications.

In both studies, evolving resistance to the antiviral drug led to a rise in viral load and a concurrent decrease in CD4+ T cell numbers to pretreatment levels. The previously unrecognized regenerative capacity of CD4+ T cells in HIV-1 infection along with the idea of drug resistance and immune escape fueled the search for effective antiviral strategies.

The findings also raised questions about the utility of CD4+ T cell count as a predictor of long-term survival (at the time, it was the main surrogate marker of disease progression). Just one year later, John Mellors and colleagues linked viral load and HIV prognosis in a paper published in Science. By measuring plasma HIV-1 RNA concentrations in a cohort of 180 HIV-seropositive men who were followed for >10 years, they reported that plasma viral load (irrespective of duration of infection) was a better predictor of patient outcome (that is, progression to AIDS or death) than number of CD4+ T cells.

Thomas Quinn and colleagues later revealed that viral load was also a risk factor for viral transmission. Of the factors they measured (including various behavioral and biological risk factors) in a study of 415 couples who were followed for up to 30 months, viral load was the best predictor. Indeed, measurements of viral load are now routinely used for the clinical assessment and monitoring of patients infected with HIV-1, alongside CD4+ T cell count.

These findings spurred the development of antiviral therapies and therapeutic strategies (such as combination therapies) to reduce viral load in individuals infected with HIV-1, with the aim of improving long-term patient outcomes and potentially preventing viral transmission (MILESTONE 14, 20, 21).

First HIV protease inhibitor approved: key to combination antiretroviral therapy

The first antiretroviral therapies (ARTs) for people with HIV were nucleoside reverse-transcriptase inhibitors (NRTIs), but these drugs were only partially effective. The addition of an orally administered protease inhibitor, the first of which was approved in 1995, reduced HIV plasma concentrations and increased CD4+ cell counts to levels that enabled patients to have fairly normal life expectancies. This combination—two nucleoside analogs and a protease inhibitor—is now the cornerstone of ART.

The HIV genome encodes a long polypeptide that must be cleaved into functional proteins by the HIV protease. Following virus uncoating and reverse transcription of the RNA genome, a polypeptide is produced that contains all viral gene products, including the structural proteins and enzymes. The HIV protease then cleaves this polypeptide into its constituent viral proteins. Inhibiting the activity of the protease is therefore an attractive means to prevent virion production.

The first protease inhibitors were peptidomimetic molecules designed to look like the peptide linkages in the precursor polypeptide and therefore compete with the substrate. However, like most peptidomimetic proteins, the early protease inhibitors had poor pharmacokinetic properties, namely, low oral absorption and rapid elimination. Key medicinal chemistry–led structural changes improved these properties. For example, substituting a pyridine with the less electron-rich thiazole to produce ritonavir improved both metabolic stability and aqueous solubility. This molecule was also more potent in animal studies than its parent, predominantly because it also had a lower inhibitory constant (Ki).

These drugs wowed the community in early clinical trials. The addition of a protease inhibitor to two NRTIs approximately halved the number of patients whose disease progressed to AIDS or death. In 90% of patients taking the three-drug combination, the number of HIV RNA particles in the blood went from >20,000 particles per milliliter to <500 in 24 weeks.

The first protease inhibitor to be approved by the US Food and Drug Administration (FDA) was saquinavir, in December 1995, a mere 97 days after the FDA received its marketing application. Within months, two other protease inhibitors, ritonavir and indinavir, were also approved. There are currently ten FDA-approved protease inhibitors on the market for HIV.

The remarkable results from the clinical trials of this first wave of protease inhibitors also highlighted important aspects of the biology of HIV infection. First, the clearance rate of virus was independent of initial viral loads and suggested that, on average, half of plasma virions turn over every two days. Second, the number of CD4+ cells destroyed and replenished each day was close to the total number of infected cells. The potential to generate viral diversity (and resulting drug-resistant clones) is therefore substantial, arguing for early initiation of ART.

ART has changed the course of HIV. In the US, mortality among patients with advanced HIV infection declined from 29.4 per 100 person-years in 1995 to 8.8 once ART including a protease inhibitor became the standard of care. In geographic locations with high rates of HIV infection, ART has also changed economics and demographics. Places with high rates of infection, such as Swaziland, saw a 10- to 15-year decrease in life expectancy during the peak of HIV deaths. In the neighboring rural KwaZulu-Natal region of South Africa, where an estimated 29% of adults are HIV positive, adult life expectancy (the mean age to which a 15-year-old could expect to live) increased from 49 to 61 years in the ~10 years after government programs for HIV treatment were initiated. Because many people with HIV were dying during their most economically productive years, the knock-on societal and economic effects are substantial.

Since 1995, new protease inhibitors and combinations with improved dosing have become available, but the protease inhibitors developed in the mid-1990s changed the course of the disease and formed the foundations of ART.

Identification of CCR5 and CXCR4 as HIV-1 co-receptors

Following the discovery of CD4 as the main receptor for HIV-1 in the mid-1980s (MILESTONE 3), it became clear that expression of a CD4transgene rendered human cells, but not mouse cells, permissive for infection with HIV-1. There was also a growing awareness that different HIV-1 isolates have different tropisms in vitro for the infection of different human CD4+ cell types. Macrophage-tropic virus strains (which infect primary macrophages and T cells, but not immortalized T cell lines) predominate during the asymptomatic phase of infection, whereas T cell–tropic strains (which infect primary T cells and T cell lines, but not primary macrophages) become more common during progression to AIDS. The viral envelope protein Env, a ligand for CD4, was known to be the main viral determinant of this cell tropism. Together, these observations led to the suggestion that additional human-specific receptors for Env are required for infection, the expression of which determines cell tropism.

In May 1996, Berger and colleagues identified, in an unbiased manner, the first of these co-receptors for HIV-1. They developed a method to study Env–receptor-mediated cell fusion by expressing a phage T7 polymerase in a CD4+ mouse cell line and a reporter gene linked to the T7 promoter in a second, Env-expressing mouse cell line. Expression of the reporter would occur only in the cytoplasm of fused cells. By screening a cDNA plasmid library from HeLa cells for cofactors that would enable fusion of these nonhuman cells, they cloned a G-protein-coupled receptor of unknown ligand and function, but with the greatest homology to the receptor for the chemokine CXCL8. This cofactor was named ‘fusin’ in the original paper and was renamed later that year as CXCR4 when its ligand was identified as CXCL12. Importantly, fusin was shown to enable entry mediated by Env from T cell–tropic HIV-1 but not macrophage-tropic HIV-1, which led to a race to identify the second cofactor for macrophage tropism.

That the T cell–tropic factor fusin had homology to an α-chemokine receptor fit well with an observation made the previous year by Cocchi et al. that the β-chemokines RANTES (CCL5), MIP-1α (CCL3) and MIP-1β (CCL4) produced by CD8+ T cells inhibit infection with macrophage-tropic HIV-1. Thus, it seemed likely that a β-chemokine receptor was the cofactor for infection of macrophages.

Five papers published within eight days of each other in June 1996 identified CCR5 as the second co-receptor for HIV-1. Another study by Berger’s group, using the same fusion assay that had identified fusin, described the role of CCR5 in macrophage infection. Deng et al. showed that CD4 and CCR5 function cooperatively in mouse cells to permit membrane fusion with macrophage-tropic HIV-1. Similarly, Choe et al. described that macrophage-tropic HIV-1 uses CCR5, as well as CCR3, to facilitate infection. In keeping with the switch in viral tropism that accompanies pathogenesis in vivo, Dragic et al. identified CCR5 as a second co-receptor for macrophage-tropic HIV-1 in primary CD4+ T cells, and Doranz et al. showed that a dual-tropic ‘intermediate’ HIV-1 isolate used both fusin and CCR5.

Discovery of CXCR4 and CCR5 as co-receptors provided an explanation for the long-standing puzzle of Env-related differences in HIV-1 tropism and opened up the possibility of developing new antiretroviral drug therapies to block infection. Soon thereafter it was recgonized that individual differences in the expression or activity of these co-receptors could underlie susceptibility to infection and disease progression, and this was confirmed by three papers published later in 1996. Liu et al., Samson et al. and Dean et al. described a 32-base-pair deletion in the coding region of CCR5 that was variously shown to protect homozygotes from infection, partially protect heterozygotes from infection and delay disease progression in heterozygotes. The lack of an obvious phenotype associated with the mutation, together with the later description of the Berlin patient (MILESTONE 18), gave hope that pharmacological or genetic targeting of CCR5 could be a safe and effective therapeutic approach.

Latent integrated HIV-1 forms a stable, inducible viral reservoir

The advent of combination therapy for HIV treatment in the mid-1990s had a huge impact on patient morbidity and mortality (MILESTONE 14). Together, reverse-transcriptase inhibitors and newly developed protease inhibitors caused plasma virus to fall to undetectable levels within 2–4 months. It was presumed that integration of HIV-1 DNA into the host genome could enable persistence of the virus, and indeed, a 1995 paper by Chun et al. had detected integrated proviruses in some infected patients. These proviruses were found in resting CD4+ T cells, which did not produce virus unless activated. But in 1995 it was not clear how much of an obstacle this potential latent reservoir of integrated proviruses would be to ultimate eradication of the virus by the new combination therapy.

A 1997 paper from the group of David Ho described two phases of viral decline in infected patients treated with combination therapy: a first phase in which virus levels dropped by around 99% within the first two weeks of treatment and a second phase of slower decline, which the authors concluded was driven by loss of long-lived infected cells. Extrapolating from these decay characteristics, they predicted that around 2–3 years of effective treatment would be required to eradicate HIV-1, perhaps longer if the virus persisted in sanctuary sites. Sadly, this estimate proved too optimistic.

Papers from the groups of Robert Siliciano and Douglas Richman, published in 1997, began to characterize and quantify the latent reservoir of HIV-1 virus in patients. Chun et al. provided the first snapshot of the latent reservoir of virus, in a group of 14 asymptomatic HIV-1-infected donors. Looking in the lymph nodes, the authors found that around 0.5% of resting CD4+ T cells harbored HIV-1 DNA, but that less than 0.05% of resting cells contained integrated provirus. The relatively small size of this latent reservoir was a surprise, but the authors cautioned against underestimating its importance, due to the long survival of memory CD4+ T cells. In work published later that year, Finzi et al. looked at 22 patients successfully treated with drugs for up to 30 months and reported the sobering finding that, despite apparently complete suppression of virus replication, highly purified resting CD4+ T cells from each of these individuals could be induced to make replicating virus. Furthermore, levels of inducible replication-competent virus did not decline with increasing time on therapy and the inducible viruses had not acquired mutations conferring drug resistance, suggesting that they were derived from long-lived cells that were infected before the initiation of therapy. Similar findings were also reported in the same issue of Science by Wong et al. and in PNAS by Chun et al.

Today, we know that the latent reservoir of HIV-1 is a formidable obstacle to eradication of the virus. We know that the reservoir is maintained at least in part by clonal expansion of CD4+ T cells containing integrated provirus and that it is hard to measure, as the vast majority of integrated proviruses are defective. The reservoir also extends beyond quiescent cells in the blood and lymph nodes, to sanctuary sites such as the brain that are poorly penetrable to antiretroviral drugs. Nevertheless, achieving at least a functional cure of HIV infection remains a hotly pursued goal and there is intense interest in learning more about the HIV reservoir and how to prevent the virus from rebounding so that medication might be stopped.

Identification of host-encoded HIV restriction factors

Numerous positively acting cellular factors and pathways support HIV replication, but in the 1990s evidence emerged that suggested that cells express dominantly acting factors that suppress HIV replication. For instance, HIV replication is affected by the animal origin of target cells and requirements for the viral accessory genes vif and vpu vary significantly between human cell lines. These observations hinted that primate cells express antiviral proteins (termed restriction factors) that block infection. The existence of restriction factors has important implications for understanding viral replication and pathogenesis, host range and HIV evolution, and for developing animal models.

In 2002, Sheehy et al. reported the isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein—the first identification of an HIV restriction factor. In this initial report, a subtracted cDNA screen using cells that were permissive and non-permissive to infection by vif-deficient HIV-1 identified the human APOBEC3G gene as responsible for suppression of vif-deficient HIV-1 infection. Subsequent studies determined that APOBEC3G can restrict HIV-1 by incorporating itself into nascent virions through its RNA-binding activity and subsequently hypermutating newly synthesized viral DNA through its cytidine deaminase activity, leading to a catastrophically altered nucleotide sequence. It was also found that Vif–APOBEC3G binding leads to degradation of the restricting factor, enabling HIV-1 to circumvent this intrinsic immune response.

This initial study represents an important milestone in HIV/AIDS research, as it revealed an integral part of the host’s first line of defense against HIV and suggested that further HIV restriction factors might exist.

APOBEC3 proteins do not alone account for the observed infection restriction phenotype in non-permissive cells. Since the discovery of APOBEC3G, numerous restriction factors that target diverse components of HIV-1, HIV-2 and SIV during various stages of their life cycles have been identified. For instance, identification of the monkey TRIM5α and TRIMCyp proteins in 2004 that restrict HIV through interactions with the viral capsid revealed that this class of molecules is responsible for the majority of restriction phenomena in mammalian cells following virus entry. Later, the discovery of tetherin (also known as BST2), a transmembrane protein, revealed a crucial function of the lentiviral vpu gene. In the absence of vpu expression, tetherin physically tethers nascent virions to the surface of infected cells and the virions are subsequently internalized into endosomes, thus preventing onward transmission.

Similarly, an important function of the HIV-2 (and SIV) Vpx accessory protein was elucidated through the discovery of SAMHD1, a deoxynucleotide triphosphohydrolase that limits reverse transcription of incoming viral RNA genomes: the viral Vpx protein induces ubiquitin–proteasome-dependent degradation of SAMHD1.

More recently, further restriction factors with distinct or unknown mechanisms of antiviral activity have been implicated as having a role in the outcome of initial HIV infections (for example, Mx2, SERINC3 and SERINC5, and ZAP), highlighting the important and complex involvement of restriction factors in the life cycle of HIV and in the evolutionary battle between host and virus. Indeed, a major raison d’être for lentiviral accessory proteins is to remove or displace host antiviral proteins.

During this evolutionary battle, humans have not emerged as the victors, as HIV-related illnesses cause thousands of deaths each year. HIV has an extraordinary degree of genetic plasticity that has enabled the virus to adapt to new host proteins when crossing species barriers and during the evolutionary arms race. Despite HIV’s ability to evade host restriction factors, the discovery of these factors and understanding of how they interface with viral accessory proteins provide remarkable insight into the evolution of HIV. Their discovery also provides targets for new antivirals and valuable knowledge in the development of primate animal models for HIV/AIDS, which may lead to HIV losing the battle.

The Berlin patient

Timothy Ray Brown—also known as the ‘Berlin patient’—is the only person ever to be cured of HIV. His story and the research that followed are intimately linked to the discovery, back in 1996, that homozygosity for a CCR5 allele with a 32-base-pair deletion (delta32/delta32) renders some individuals resistant to infection despite exposure through sexual intercourse with HIV-positive partners (MILESTONE 15).

Brown was diagnosed with HIV in 1995 and a decade later underwent allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. But the transplant, performed by Gero Hütter of Charité–Universitätsmedizin Berlin, had a twist. Hütter used peripheral blood stem cells from a human leukocyte antigen (HLA)-identical donor that harbored the CCR5 delta32 allele.

The procedure led to complete remission of the cancer and, remarkably, despite the long-lived viral reservoir (MILESTONE 11, 16) being expected to lead to HIV rebound and disease progression during the process of immune reconstitution, no active virus and no viral RNA or proviral DNA could be detected in the blood, bone marrow or rectal mucosa, even almost two years after transplantation and interruption of antiretroviral therapy (ART).

Although at the time of transplant Brown also carried HIV variants tropic for the CXCR4 chemokine receptor, Hütter reasoned that their numbers might have been too low to allow reseeding of the new immune system. A follow-up study showed that Brown’s long-lived CD4+HIV target cells had been successfully replaced with donor-derived cells. Thus, the CCR5 deletion in donor stem cells and their ability to engraft—killing Brown’s infected cells—may have together contributed to the functional cure of HIV.

Yet, a similar approach subsequently performed in the so-called ‘Boston patients’ proved the latent reservoir of HIV to be far more resilient than previously thought. Timothy Henrich and Daniel Kuritzkes at Brigham and Women’s Hospital in Boston gave HSCT to two HIV-infected men diagnosed with lymphoma, but used donor cells with wild-type CCR5. In this approach, despite a significant reduction in the size of the reservoir following transplant, both patients eventually experienced rebound viremia after cessation of ART.

Still, these landmark studies demonstrated the critical role that CCR5 has in maintaining HIV-1 infection and prompted further research into gene-based therapies to target HIV.

Although genome editing had been proven efficient in rendering T cells refractory to HIV infection, it was not until years later, in 2014, that a team led by Pablo Tebas and Carl June at the University of Pennsylvania in Philadelphia showed this could be done in infected individuals. The clinical trial enrolled 12 patients who were infused with autologous CD4+T cells modified at the CCR5 locus by zinc-finger nucleases (ZFNs). The patients who stopped ART after cell transfusion exhibited slow viral rebound and proliferation of the modified T cells, indicating enhanced control of the virus. Moreover, one study participant with no viral rebound during ART interruption was found to harbor a single mutated copy of CCR5 and after transfusion a large proportion of this patient’s T cells were resistant to HIV.

Together, these findings demonstrated that gene-targeting approaches could provide a safer and more practical approach than the risky and restrictive HSCT and opened the door for ZFNs and other gene-editing methods, such as TALENs and CRISPR, to be exploited in the targeting of latently infected cells.

Although many challenges remain, these groundbreaking discoveries, together with those on early ART initiation (MILESTONE 20, 21), broadly neutralizing antibodies (MILESTONE 19) and new-generation latency-reversing agents, are paving the way toward the development of a broad-scale and safe strategy for the complete eradication of HIV or its control in the absence of lifelong therapy.

Advancing broadly neutralizing antibodies

HIV induces antibody responses in infected individuals, but only a few of these individuals manage to produce antibodies that are capable of viral neutralization—and even fewer produce antibodies that can neutralize different strains of HIV. First attempts to find such broadly neutralizing antibodies (bnAbs) date back to the early 1990s, when phage libraries were used to identify, isolate and amplify antibodies from asymptomatic individuals with HIV-1 infection. Further antibodies were isolated from hybridomas. However, hopes to translate these early bnAbs for use in passive immunization strategies were dashed when it became clear that they displayed only moderate breadth and potency for viral neutralization.

Breakthroughs had to wait for almost 20 years and were eventually facilitated by the development of single-cell antibody cloning, advances in screening methods and a better understanding of structurally conserved epitopes across the diverse circulating strains of HIV-1.

In 2009, Dennis Burton and co-workers used a systematic approach to search for bnAbs in the sera of 1,800 HIV-1-infected individuals. This was followed by a high-throughput neutralization screen of activated memory B cells from one individual. The effort proved worth it—they identified two bnAbs (PG9 and PG16) with remarkable potency and breadth, neutralizing 73% and 79% of viruses tested, respectively. Interestingly, the two antibodies targeted a previously undescribed epitope of the HIV-1 envelope (Env) protein, which is located within conserved regions of the variable loops of the gp120 subunit of Env.

The discovery of these antibodies was followed in 2010 by a report by Gary Nabel, John Mascola and co-workers that described the rational design of probes for the targeted identification of bnAbs. At this time, a conserved site on gp120, which facilitates binding of the virus to the host receptor CD4, had been identified as a common target for naturally occurring bnAbs. With new insights into Env structure and using computer-assisted protein design, antigenically resurfaced glycoproteins were designed that specifically bound to neutralizing antibodies. These were used to screen sera for the presence of bnAbs, and then to screen for probe-specific memory B cells. These efforts led to the identification of two antibodies, VRC01 and VRC02, that neutralize over 90% of all major circulating HIV-1 strains.

An accompanying paper showed that VRC01 had undergone extensive affinity maturation, resulting in an antibody that partially mimics the interaction of CD4 with gp120. A slight shift in binding allows it to overcome the glycan and conformational masking that diminish the neutralization capacity of other antibodies.

Since then, many more bnAbs have been identified and the first clinical studies have been initiated. VRC01 and 3BNC117, a bnAb that targets a similar site, first entered the clinic in 2015–2016. They suppressed viral titers in HIV-infected individuals for 6–10 weeks, before viral rebound due to escape mutants. Much longer viral suppression was achieved in recent combination trials. In patients undergoing treatment interruption from antiretroviral therapy (ART), three doses of 3BNC117 and 10-1074, a bnAb that targets a different site in Env, achieved a median of 21 weeks of complete viral suppression before viral rebound. Encouragingly, no viral escape mutants were detected. This indicates that combinations of bnAbs provide durable control in the absence of ART and therefore provide an alternative, less toxic treatment.

Preferable to passive treatment would be a vaccine that elicits bnAbs. This could allow for a functional cure of infected individuals and protect those at risk of infection. Given the rarity and complexity of bnAbs (they typically contain 40–100 somatic mutations and unusual structural features), making such a vaccine is exceptionally challenging. However, insights into their development, structure and function, as well as the immunological mechanisms that make their generation such a rare event, have led to the design of promising vaccination strategies in animal models.

Antiretroviral treatment as prevention

Since the first reports identifying patients with AIDS in 1981 (MILESTONE 1) and the discovery of HIV-1 as the etiological agent in 1983 (MILESTONE 2), a major goal has been to find and develop effective anti-HIV therapeutic options. This yielded results in 1987 with the approval of the first antiretroviral therapy, azidothymidine (AZT), only a year after it was first administered and shown to reduce HIV viral load in patients. Further antiretroviral drugs targeting other aspects of the retroviral lifecycle were discovered and resulted in combinations of drug classes associated with successful and sustained prevention of AIDS progression (MILESTONE 14).

The advent and widespread use of combinatorial antiretroviral therapy resulted in successful virological control in HIV-infected patients. However, this did not address another key tenet of HIV medicine: the prevention of viral transmission. For most viruses, lower viral loads are known to minimize the chance of transmission, and it is on the basis of this that the initial premise of antiretrovirals for prevention came to fruition. Proof of concept for antiretrovirals as prevention was first shown in 1994, where administration of AZT reduced mother-to-child transmission of HIV. Since this first clinical demonstration, antiretrovirals as prevention have gathered momentum, which has resulted in pivotal strides forward.

On the basis of these initial findings showing reduced rates of transmission by minimizing viral loads in HIV-seropositive patients, two key studies demonstrated a crucial role for such applications of early antiretroviral intervention. Initiation of early antiretroviral therapy and reduction in viral load in confirmed HIV-positive patients was shown to successfully reduce sexual transmission in serodiscordant couples, establishing the potential benefits of early commencement of therapy and the associated reduction in HIV transmission.

Complementary approaches utilizing antiretroviral therapy in HIV-seronegative persons have also shown efficacy in terms of preventing infection in at-risk populations. Two large-scale, randomized, double-blind, placebo-controlled studies paved the way toward the advent of pre-exposure prophylaxis (PrEP). The iPrEx trial assessed the administration of the anti-retrovirals emtricitabine plus tenofovir disoproxil fumarate (Truvada) in 2,499 high-risk HIV-negative men or transgender women who have sex with men. The Partners PrEP trial evaluated administration of Truvada or tenofovir disoproxil fumarate monotherapy among 4,758 HIV-serodiscordant heterosexual couples. PrEP administration to seronegative individuals in both settings was estimated as conferring greater than 90% protection from HIV infection in persons with good adherence to the PrEP regimen.

Consequently, in 2012, the US Food and Drug Administration approved the use of Truvada as PrEP for HIV on the basis of the initial data from these studies, which established that its use was well tolerated, safe and effective in reducing HIV transmission in high-risk individuals. Although the implementation of antiretrovirals for prevention in both HIV-positive and HIV-negative persons is still in its relative infancy and the further impact of such interventions remains to be fully determined, collectively these pivotal studies transform the risk of HIV transmission and firmly establish the importance of antiretrovirals for prevention as a potential game changer in preventing HIV transmission and turning the tides of the HIV epidemic.

START trial shows benefit of early antiretroviral treatment

In August 2015, the INSIGHT START study group published the results of the START trial investigating the timing of initiation of antiretroviral therapy (ART) in patients with asymptomatic HIV infection. The trial results showed that immediately initiating ART in adults who were positive for HIV and had CD4+ T cell counts of >500 cells/mm3 was more beneficial than deferring treatment until their CD4+ T cell counts dropped to ≤350 cells/mm3.

For years, when to start ART had been a topic of debate, and initially patients at a high risk of developing AIDS (those with low CD4+ T cell counts of ≤200 cells/mm3) were prioritized for treatment. However, evidence emerged of the benefits of initiating treatment early. In 2009, the results of a cohort study suggested that initiation of ART before CD4+ T cell counts fell below 351 cells/mm3 or 500 cells/mm3 improved survival. Interim analysis of HPTN 052 study data in 2011 showed that starting ART in patients with CD4+ T cell counts between 350 and 550 cells/mm3 before symptoms manifested or CD4+ T cell counts were ≤250 cells/mm3 reduced the rate of HIV transmission and clinical events.

The case of the ‘Mississippi baby’ also provided some evidence for the benefit of early ART initiation. This baby was given ART 30 hours after being born to an HIV-positive woman and tested positive for HIV herself. Treatment was continued until she was 18 months old, and she had undetectable levels of HIV between the ages of 29 days and 3 years, 10 months. Although HIV became detectable after treatment was stopped, these observations suggested that starting ART early is beneficial in controlling HIV. As new data such as these became available, the cutoff for starting ART progressively increased, eventually reaching ≤500 CD4+ T cells/mm3.

In this context, the START study aimed to assess the benefits and risks of immediately initiating or deferring ART. This study was conducted at 215 centers in 35 countries, included 4,685 patients with CD4+ T cell counts of >500 cells/mm3 and the mean follow-up duration was three years. Patients in the immediate-treatment arm received ART straight away, whereas those in the deferred-treatment arm were not given ART until their CD4+ T cell counts decreased to ≤350 cells/mm3. Overall, 41 events (including death, AIDS and serious non-AIDS events) occurred in the immediate-treatment group compared with 86 events in the deferred-treatment group—a 57% reduction. Furthermore, no increase in the rate of adverse events was observed in the immediate-treatment group.

The original completion date for the START study was 2018. However, after the interim analysis in May 2015, the data and safety monitoring board decided that the study question had been answered and recommended that all patients in the deferred-treatment arm be offered ART.

The results of the START study contributed to the World Health Organization (WHO) issuing a recommendation to treat all patients as soon as possible after diagnosis (the treat-all policy, also known as test and treat) in September 2015. The results are also cited as supporting evidence in the WHO’s consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, which were published in 2016. These guidelines contain the new recommendation that “ART should be initiated in all adults living with HIV, regardless of WHO clinical stage and at any CD4+ cell count.”

Starting ART early can preserve intestinal lymphoid structures and dendritic cell maturation pathways in the gut. Early initiation of treatment can also help to maintain HIV-1-reactive memory B cells in the gut and follicular T helper cells. Furthermore, early ART reduces the size of the HIV reservoir in the long term compared with deferring treatment.

In 2017, analysis of self-assessed quality-of-life (QOL) outcomes from patients involved in the START study showed that immediate ART resulted in better outcomes than deferred ART after a mean follow-up duration of three years. QOL outcomes were improved for those receiving immediate treatment regardless of demographic or clinical subgroup. Later the same year, the WHO published analysis of the adoption and implementation status of the treat-all policy. As of November 2017, adoption rates were promising, with 70% of low- to middle-income countries and 89% of countries in the Fast-Track strategy for ending AIDS signing up to the treat-all policy. These adoption rates support the 90–90–90 targets for ending the AIDS epidemic by 2030.