ASHM Report Back

Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.

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Serena Spudich presented information about HIV infection causing ongoing active injury to the central nervous system (CNS) - comprising the brain, meninges and cerebrospinal fluid (CSF) - despite antiretroviral therapy (ART). Abstract #66

CNS injury can be measured by:

- Neurocognitive testing: persistent milder forms of HIV associated neurocognitive disorder (HAND) can be demonstrated in 18-50% of individuals on ART.

- Inflammatory biomarkers: examination of CSF shows elevated levels of neurofilament light chain (NFL) which is a marker for axonal injury marker

- Neuroimaging: structural or functional imaging shows persistent abnormalities of HIV positive individuals on treatment.

 

The mechanism of CNS injury is unknown, but is likely multifactorial:

 

- CNS injury prior to treatment. HIV is brought into the brain by infected lymphocytes (and perhaps infected monocytes) in the setting of immune activation. The viral load of CNS HIV is reflective of the plasma HIV levels in primary infection. Infection of brain cells occurs, with immune activation of microglia and macrophages, leading to breakdown of the blood brain barrier and release of cytokines. This results in axonal death and further HIV infection and mutation in the CNS of susceptible cells.

- Persistent compartmentalised infection. Despite suppressed plasma viral load, researchers can still demonstrate detectable virus in the CSF ("CSF escape"). Active CNS replication of HIV occurs despite apparent peripheral control. HIV in the CNS undergoes distinct evolution, with analysis of CSF showing that CSF HIV is distinct from plasma HIV during suppressive ART.

- Ongoing immune activation. Elevation of inflammatory biomarkers such as neopterin (a derived product of activated monocytes and macrophages in the brain) demonstrate ongoing immune activation.

- Contribution of vascular disease. Vascular immune activation and/or co-morbid risk factors contribute to vascular disease in HIV positive individuals on ART. Higher stroke rates are seen in HIV positive women and younger patients, compared to their HIV negative counterparts.

- Acceleration of normal brain ageing. Normal brain ageing may be accelerated in the setting of HIV and ART, with increased macrophage activation and increased permeability of the blood brain barrier.

- Effect of co-morbidities. Higher rate of cognitive impairment are seen in HIV positive individuals with concurrent depression and substance abuse.

- CNS penetration of antiretrovirals. Antiretroviral medications with higher CNS penetration show lower CSF viral loads, but this may not reduce the risk of CNS disease. 

 

Additionally, the use of mono/dual therapy may increase risk of CSF escape. Potential neurotoxicity is only seen with particular antiretrovirals such as efavirenz.

Apart from the persistent smouldering immune activation in the CNS compartment, viral latency and integration may be important. HIV-1 DNA can be found in microglial cells, macrophages and astrocytes. Animal models show that by day 4 of primary infection with treatment, SIV RNA is no longer found in CSF, but SIV DNA can be demonstrated.

In the future there may be the ability to block HIV entry into CNS during primary infection. While the exact reasons for CNS perturbations is unknown, and likely multifactorial, there is plenty of opportunity for further research.

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The discussion generated by this, quite complex topic, was stimulating. CDC reported that a dried blood spot sample gave comparable performance to a liquid serum/plasma sample, an obvious practical benefit in much of the world. They were reporting on performance for one of the available tests trying to infer recent infection rates, the Limiting-Antigen Avidity EIA. Then 2 other presenters raised issues about the rate of miscalculation of this recently licensed  LAg test, and the evidence that Clade D infection really confuses it. Finally, Alex Welte expressed his groups reservations about relying on any one of the 5 available tests yet, saying that viral suppression, by ART or being an elite suppressor, were 2 major causes of error. Issues then discussed were whether there was any agreement about what should be defined as the cutoff time for a recent infection, whether there should be an agreed viral load limit to incorporate in an algorithm, what would be an acceptable level of "False Recent Rate", how great the lag time would be between the current recent infection rate, and Incidence calculation "look back" rate, and whether combining 2 of the assays would make results reliable. Although work on improving these current tests and algorithms is proceeding in a somewhat cooperative way, new bio marker research is also being funded hoping to find a single novel marker to overcome current limitations. Bottom line, we could probably use these tools now if we didn't need to believe they were totally accurate. Abstracts  #1005,#1006, #1007, #1008

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Supplementing starters on ART containing Efavirenz and Tenofovir with 4000 iu Vit D, and oral calcium, reduced BMD loss by 50% in the first year, say ACTtG A5280. Expected elevations in both PTH and bone turnover were reduced. It at least suggests that those with low Vit D levels at initiation should be identified, and have this considered. Abstract #133

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Jeffrey Johnston from CDC Atlanta presented results of highly sensitive resistance testing showing transmitted resistance in 16%, rather than the 8% previously identified by standard tests. The study population was a broad sample of new US infections 2009 to 2011. Abstract #87

Maybeof significance in future decisions about recommended PrEP and PEP.

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Many presentations pushed the need to get going now with oral PrEP for it's already proven benefit, even though what we have isn't perfect, isn't used perfectly, and isn't going to be for everyone.

Interesting potential future options are suggested by macaque monkey trials investigating 3 monthly IM injections of GSK744, and vaginal rings releasing dapivirine. Both approaches seem much more likely to achieve uptake when further proven, and available. Abstracts #40LB and #41

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A much anticipated late breaking presentation from London was a study looking at transmission from people with Viral Loads less than 200, who practised condomless sex. No observed transmission occurred, where on accepted transmission data 86 new infections would have been expected in the study group. BUT the science cautioned that they could still be concealing a 32% 10 year transmission risk, if related to receptive anal sex. The caution was a worst case statistic, because of the small numbers so far studied. It seems there will be a lot of explaining to patients to be done in the next few months when the study results get widely published. Researcher's suggestion, tell them "our best guess is its safe, but we can't tell you that", isn't  very useful. Abstract #153LB

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Katherine Luzuriaga presented data showing that early cART (initiation before 6 weeks of age) leads to a restricted latent reservoir of HIV, and although the reservoir decays over 2 years, HIV remains detectable. There continues to be a 4-12 fold reduction in this latent HIV reservoir from 2 years through 14-18 years of age. Abstract #53

Early effective cART in infants leads to:

- clearance of HIV specific antibodies

- durable HIV RNA suppression

- markedly reduced HIV related mortality

- preservation of immune function

- lack of viral evolution over time in replication competent virus

- reduced HIV infection of long-lived CD4+ T CM cells

The use of early ART does not distract from the need to focus on preventing HIV transmission (viz. there were 260,000 new infant infections worldwide in 2012)

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HIV-1 infection and Type-1 interferon

The interaction of HIV-1 and Type-1 Interferon (IFN-1) is complex. High levels of IFN-1 during acute HIV infection results in viral suppression. Administration of IFN-1 in primary infection can result in a drop in viral load, but this effect is not seen if administered later in the disease course and there is variability in response between individuals. Continued elevation of IFN-1 in chronic HIV infection is associated with long-term immune dysfunction, including viral expansion and T cell depletion. Abstract #119

 

Early treatment in acute SIV Infection limits the size and distribution of the viral reservoir

Compared with starting ART at 6 weeks after infection, initiating treatment at 7 days post-infection results in a 2-log decrease in peak viral load. Initiation at 10 days results in a 1-log drop in peak viral load. Researchers also found early initiation of treatment led to improved viral control, suppression of cell associated viral RNA, and decreased levels of SIV DNA in circulating lymphocytes, suggesting a lower established reservoir of SIV in CD4 memory T cells. There was a direct correlation between peak plasma viral load and total SIV DNA in peripheral blood mononuclear cells (PBMC) at 32 weeks. Very low levels of replication competent virus were found in circulating lymphocytes of early treated animals. Viral rebound still occurs after prolonged control in these early treated animals, but there was a slower dynamic of rebound, suggesting a degree of immune mediated control. Abstract #136LB

 

CD4 T cell subset composition reservoirs in gut, lymph node and blood during HAART 

Higher levels of HIV DNA were found in rectal mucosa, particularly in CD4 T EM cells. Peripheral blood showed a higher percentage of HIV DNA in CD4 T CM cells, and lymph nodes demonstrated a greater percentage of infected naïve CD4 T and CD4 T TM cells. Abstract #137

 

Proliferation of cells with HIV integrated into regulatory genes is a mechanism of persistence

HIV was found to be frequently integrated into multiple chromosomal sites, particularly into genes that control cell activation, differentiation and proliferation. The results from the study strongly suggested that the genes disrupted by HIV integration may impact cellular proliferation and survival. Proliferation of these infected cells with disrupted DNA contributes to the persistence of HIV in cellular reservoirs, particularly as the integrated HIV modifies gene function, facilitating prolonged persistence of specific infected cells. Abstract #138


"Kick and Kill"

The use of latency reversal agents (LRA) such as Histone Deacetylase inhibitors (HDACi) are being investigated to purge latently infected T cells. The theory is to reverse the latency in the infected cell, then induce an immune response to kill the cell. Researchers are finding that combinations of LRA may be required, as single agents may be insufficient to force the cell into expressing viral markers. Also, although initial administration of an LRA (Vorinostat studied in this case) may cause a transient burst in transcriptional activity, prolonged administration over 14 days results in compensatory mechanisms associated with transcriptional repression and cell survival. Abstracts #139 and #140

 

Cyclophosphamide (CTX) enhances SB-728-T engraftment to levels associated with HIV RNA control

CCR5 is a major co-receptor for HIV entry into cells. As found in the Berlin patient and two Boston patients, the CCR5 Δ32 mutation produces non-functional proteins where homozygotes are resistant to HIV infection and heterozygotes have slower disease progression. Researchers used CTX to enhance the engraftment of CCR5 modified autologous CD4 T cells transplanted into HIV positive subjects on ART. Subjects achieved a reduction in HIV viral load after treatment interruption, but this was not sustained. Abstract #141

 

Stimulation of subdominant cytotoxic lymphocyte (CTL) response is required for the elimination of HIV-1 latent reservoir

Plasma HIV-1 develops CTL escape mutations to evade the body's immune response. CD4+ T cells infected by these escape variants are insensitive to epitope-specific CTL clones, but can be killed by a broad spectrum CTL response. Research is underway to identify and stimulate subdominant CTL clones in chronically infected patients which can recognise and kill autologous target cells infected with these escape variants, and eliminate the latent viral reservoir. Abstract #142

 

Dendritic cell bases HIV therapeutic vaccine increases residual viraemia in individuals on ART

Vaccination with an autologous dendritic cell-HIV vaccine did not prevent viral rebound after treatment interruption and caused increased residual viraemia in 40% of subjects despite continuous ART. The vaccination may actually increase HIV-1 replication or expression from latent reservoirs. Abstract #143

 

HIV-1 rebound following allogenic stem cell transplantation and treatment interruption. 

Two subjects underwent allogeneic hematopoietic stem cell transplantation (HSCT) from CCR5 wild-type donors, while remaining on ART. With HIV-1 remaining undetectable from blood and rectal tissue biopsy from large samples of PBMC, analytical treatment interruption (ATI) was performed. One patient had no detectable virus for 3 months and the other for 8 months before viral rebound occurred. Both patients developed symptoms of acute retroviral syndrome. Symptoms rapidly resolved with initiation of active ART with subsequent viral suppression. Researchers propose that long-lived tissue reservoirs, such as host macrophages that may be replaced more slowly than T-lymphocytes following HSCT may have contributed to viral rebound. Abstract #144LB

 

Impact of Systemic Cytotoxic Chemotherapy for Malignancies On HIV-1 Reservoir Persistence

HIV infected individuals undergoing cytotoxic chemotherapy for malignancies (including haemopoetic malignancies) were studied for the persistence of HIV reservoirs. Generally there was a persistence of peripheral blood reservoirs, although decreases in CD4+ T cell associated HIV-1 DNA were seen. Chemotherapy may have an impact on the viral reservoir size, but the effect depends on the type of malignancy, chemotherapy given and viral factors. Abstract #418

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Injectable GSK744 LA (long acting) is an analogue of Dolutegravir currently undergoing trials as a potential PrEP agent. Abstracts #39 and #40LB

Trials in rhesus macaques showed it to be 100% effective as PrEP. Quarterly injections protected against rectal SHIV infection, while monthly injections were protective against repeated vaginal exposure. 

Proposed dosage in man would be quarterly 800mg of GSK744 LA IM injection. Presented as 200mg/mL, it would be given as divided doses - 2x2mL gluteal injections).

Clinical evaluation in high risk MSM with phase 2 safety & tolerability trials begin in the northern hemisphere spring 2014.

Dapivirine (DPV) & Maraviroc (MVC) vaginal rings were trialled as a PrEP device in the MTN-013 study. Vaginal rings provide sustained drug delivery, minimal user action is required and they are discrete. The rings were well tolerated with primarily mild to moderate adverse effects. Abstract #41

With DPV, 100,000 fold higher concentration of drug was found in vaginal fluid compared to plasma. The levels of DPV in cervical tissue dropped to below the lower limit of quantification (LLOQ) 3 days after ring removal. Vaginal MVC levels were 2-4 times lower than DPV, and MVC plasma levels and cervical tissue were below LLOQ.

Researchers found that the anti-HIV activity of DPV ex-vivo from cervical biopsies correlated to the concentration of drug.

In the FAME-02 study, DPV film and gel were trialled as delivery mechanisms for vaginal PrEP. Abstract #42LB

Films were akin to Listerine strips that dissolve on contact. Researchers found that subjects had difficulty using the film, with sticking to the finger and poor placement noted on follow up. Cervical levels of DPV were equivalent to 1 month of vaginal ring use (10^6 pg/mL). Vaginal drug levels were about 4 fold higher - reflecting tissue surface adherence. Similar plasma levels were seen for both film and gel, comparable to the vaginal ring.

This study could provide lower cost, on demand PrEP for women. Modified film size/shape could improve placement issues.

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HPV Vaccines: Progress to date and future worldwide directionsAbstract #19

Douglas R. Lowy presented on current effects of HPV vaccination and future directions for second generation vaccines. Interestingly, the current HPV vaccine has unprecedented immunogenicity for a protein based sub-unit vaccine. Even with one dose, persistence of antibodies to HPV 16 lasts for around four years. However, the antibody effect is orders of magnitude lower than if 2 or 3 vaccines are given.

Administration of two vaccine doses has just been licensed in Europe for the bivalent (Cervarix) vaccine and approval is expected soon for the quadrivalent Gardasil.

Second generation vaccines are expected to provide broader protection and/or be less expensive. Examples of possibilities are simplified administration regimens (e.g. add HPV 16 L1 to measles vaccine) or broader protection against more serotypes.

Merck is currently trialling a 9-valent vaccine with the 5 next most oncogenic HPV subtypes 45, 31, 33, 52, 58. So far results look promising.

Currently, HPV vaccines are against L1 proteins, which are serotype specific. Future possibilities are for vaccines against HPV L2 proteins, which contain cryptic cross-neutralisation epitopes. If a successful vaccine was created, then there is the potential for a pan-HPV vaccine. However, no vaccine has ever been developed against cryptic epitopes.

 

Response to early ART initiation in infants - Abstracts #922, #923, #924, #925, #926

This series of presentations demonstrated the role for early ART in infants. Where there is early treatment, infants become seronegative. Use of antibody status should not be used for diagnosis of HIV if ART started before 6 months of age. Where there is older ART initiation, infants show higher anti-gp120 IgG, which is associated with higher cumulative viral loads.

The age of ART initiation influences the degree of viral suppression and virologic control after viral suppression (better results where initiation is before 6 months of age).

Early viral suppression also correlates to better neurocognitive outcomes in HIV infected children with better testing scores (WISC III and IV), which becomes statistically significant around age 4-5 years.

An interesting point raised that the lack of antibodies in early treated infants reflects a lack of inflammation or immune activation. This may represent a functional cure, and may lead to better clinical outcomes.

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Illicit drug use and HIV

Adeeba Kamarulzaman from Malaysia presented on HIV in people who inject drugs (PWID). Due to time constrains, PrEP and HCV co-infection was not discussed. Abstract#20

Overall illicit drug use causes 1% of global disease burden and is the 8th largest contributor to years lost to disability among males. In countries where HIV incidence is increasing, 70-80% of HIV cases are among PWID.

Effective strategies such as needle exchange programs and opiate substitution therapy have been shown to be effective in several countries. However, worldwide there is poor overall implementation of such programs. Globally for every 100 PWID only 8 are on opiate substitution therapy, and only 2 needles per PWID per month exchanged.

There are unmet needs amongst further marginalised groups - notably women, adolescents and men who have sex with men (MSM) drug users.

Prisons are a high risk environment for the ongoing transmission of HIV and other infectious diseases such as TB. Prisons do present an opportunity to treat, and when treated, AIDS related mortality reaches parity with the general population. However, this effect is not sustained once prisoners are released, as continuity of care cannot be guaranteed.

Treatment can be used as prevention in high income countries - as shown by studies in Vancouver and Baltimore. This is more difficult in lower income countries, where active drug injection, incarceration and lack of an HIV care provider result in poorer adherence to ART and poorer HIV suppression.

Addressing the stigma of addiction and HIV among PWID will not only have benefits for individuals, but lower the overall burden of disease for a country, leading to positive economic outcomes.

 

Effect of ART early in HIV infection

Increasingly the role of ART initiation at or soon after primary infection is gaining significance. Not only does early ART result in a higher chance of post-treatment control, but preservation of the immune system is seen, with more chance of a higher CD4 level and CD4/CD8 ratio ≥1. Correspondingly, there is a lower HIV reservoir established, with the potential for "functional cure".

Early HIV control is important because many of the long-term effects of chronic HIV infection and ART are related to chronic immune activation for example, diverse conditions such as cardiovascular disease, neurocognitive effects and various cancers.

 

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Hi. I'm Ken Hazelton, a GP S100 prescriber from Orange NSW, and the grateful recipient of an ASHM scholarship to CROI,  Boston 2014. HIV is important to my daily General Practice, but not my main work.

I don't  think my blog is for anyone who is full on with HIV medicine, I think it might be of more interest and relevance to GPs who see a few patients or are interested in where HIV is going, and who might relate to the things that get my attention.

Having cleared the decks.....day 1 of CROI started with positive messages about the likelihood, sometime, of a cure for HIV. The qualification was that cures would probably start with subgroups like babies, and that there are still major barriers to eradicating the last of virus from reservoirs in lymph tissue and macrophages. The famous cure of Tim Brown, the  "Berlin patient", is a one off, involving whole body irradiation and 2 sequential stem  cell transplants from a donor with a HIV-favourable genotype. None of this is feasible for others, as fascinating as it is medically.

The other really interesting but frustrating session for me was an interactive Hepatitis C treatment decision panel. The annoying thing was the right answers from a US perspective were always Sofusbuvir and Semepravir, and that Telepravir and Bocepravir were old hat. This was on the basis of inferior effect, and much nastier side effects, but the latter two are the agents we are only now getting funded access to in Australia. More another day.

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David Bangsberg, Abstract #7 was a thorough discussion on the impact of adherence problems in the PrEP studies.  He discussed complicated issues such as how the dynamics in a relationship affects PrEP adherence.  Craig Hendrix Abstract #61 was an excellent speaker and gave one of the clearest discussions on pharmacodynamics and pharmacokinetics to explain the heterogeneity of the results of all the PrEP trials I have ever heard.  I would encourage people like me who sometimes get lost in these concepts to watch his webcast.  He makes it simple.  This, coupled with Abstract #64 given by David Glidden who discussed choosing populations for maximal impact of PrEP certainly had me thinking about how we should be framing our policies on PrEP provision.  And again, if anyone is confused about concepts such as Number Needed to Treat and Population Attributable Fraction, it’s a webcast worth watching.

In my notes, I wrote “I love this talk” next to Nelly Mugo who works for the Kenya Medical Research Institute, Abstract #62.  And from the reaction of the attendees, everyone else did too.  She gave an inspiring talk on the field implementation of PrEP in a resource constrained setting, including the problems of vulnerable populations and the urgent need to get demonstration projects going and move to implementation.  She stressed, “this is an option that does not need the negotiation of safe sex”, and we know, that this negotiation is close to impossible for vulnerable populations.

I expected to hear many data rich talks at CROI, but the inclusion of a presentation on the Community Perspective On PrEP, Abstract #63 that involved a participant talking about his experience on a trial brought a human face to the numbers that I think we all need to be reminded off from time to time.

Getting away from PrEP.  The opening Bernard Fields Lecture was given by Paul Bieniasz from the Aaron Diamond AIDS Research Centre.  His lecture was on host restriction factors and the struggle between virus and host genomes and how they have evolved in both populations.  Being a clinician, I am constantly amazed at how scientists can manipulate viruses and host mechanisms and reminded that this is where drug development all starts. 

The Plenary on Tuesday morning.  Douglas Lowy Abstract #19 gave an update on HPV vaccines.  It was a nice overview, but nothing really new.  He did comment that Australia was the first country to have high uptake of the vaccine and that it showed a substantial reduction in HPV disease in women, but also conferred significant herd immunity, as HPV disease in men also declined (study published before vaccination commenced for boys).

Adeeba Kamarulzaman from the University of Malaysia Abstract #20, gave an excellent talk on HIV in People Who Inject Drugs (PWID, we commonly use IVDU here in Australia and I have not seen this acronym used here yet).  You could hear her exasperation as she presented the number of research studies and economic evidence that show harm minimisation efforts such as Needle Syringe Programs and Opiate Substitution therapy works to reduce HIV transmission.  “Do we really need another study?....I think it’s for the sceptics....”.  Her view was that so long as the “War on Drugs” and the criminalisation of drug use continues in the USA, there will be little that can be done for PWID.  It does not look promising, as there was a recent reversal of the lifting of the ban for federal funding for needle exchange programs in the US.

 

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Hong-Ha Troung, presented more data from San Francisco characterising new HIV infections. STIs remain a significant cofactor in new infections and 57% of recent infections are related to clusters. The definition of cluster was quite restrictive and did not include sequential infections so perhaps underestimates related infections. Important for the Australian setting was the very strong take home message that STI testing, treatment and prevention messages must become decoupled from HIV prevention activities. Abstract #37

Alison Rodgers presented data from UCL on condomless sex. This work goes to the heart of what we are seeking which is greater understanding of the extent of the prevention benefit of treatment. The data looked impressive with no transmissions reported, in any of the arms where partners had a VL <200 copies. But Rodgers was eager to point out that the confidence levels meant that this did not translate to 100% protection and that this was particularly the case with the MSM group. A factor which makes answering this question difficult is that most studies are looking at condom use AND treatment. So it was useful to see an analysis of condomless sex. Abstract #153LB

The importance of adherence to PrEP was highlighted by a number of speakers throughout the day. A number of speakers in the Prevention and Epidemiology session Evolving Trends (Session O-3) made reference to poor performance being a result of lack of adherence rather than failure of prophylaxis. And many speakers reflected on this emphasising the need for a good understanding of the social and other pressures on study participants.

PrEP is getting attention from both developing and developed country settings. It is sobering that so few studies are actually underway. Nelly Mugo, Abstract #62, found that only 1 of 10 studies had actually started, yet drugs for use as PrEP have been licensed for a considerable time. 

 

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Attending my first CROI in Boston, I am amazed by two things. Firstly, how cold it is during the day. I'm sure my eyeballs were going to freeze walking to the conference venue. More of that to come - it's only reaching a maximum of 0 degrees Celsius all week. At least the locals are warm and friendly.

Secondly, the scale of CROI is enormous. Over 4000 delegates this year and the main auditorium is imposing for any speaker. Thankfully there are large screens and excellent amplification. You can still sit way down the back and still see/hear what's going on.

This evening, Dr Paul D. Bieniasz from the Aaron Diamond AIDS Research Center presented the Bernard Fields Lecture on "Making and Breaking Barriers to Cross-Species HIV-1 Transmission". 

The lecture centred on the role of intrinsic host cell factors that directly inhibit viral replication. They work through a diverse mechanism of actions on invariant or genetically fragile viral features. For HIV these defences are called restriction factors. A number of restriction factors have been studied as potential inhibitors of HIV replication. Tetherin was used as an example - the expression of which causes retention of mature, fully formed infectious HIV-1 on surface of infected cells. Tetherin works by inserting its c-terminal anchor into viral envelope, trapping nascent HIV-1 virions by a direct tethering mechanism, leading to endocytosis and signalling.

The Research Center had created an artificial tetherin that was structurally similar but not the same protein sequence as the human protein. Remarkably, this artificial tetherin had action (not as good as real tetherin) to trap virions on the cell surface, preventing release of the virus and further viral replication.

However, viruses have evolved defence mechanisms to counteract these restriction factors. HIV has the Vpu protein that binds tetherin to overcome the cell's defence mechanism. The HIV-1 Vpu protein specifically evolved to work against human tetherin.

These defences are largely species specific, making it difficult to use animal models to study the actual HIV-1 virus. Many Simian immunodeficiency viruses (SIVs) do not encode a Vpu protein, and evolved a different mechanism - the Nef protein which interacts with simian tetherin via the protein's cytoplasmic tail.

Another HIV-1 restriction factor discussed was APOBEC3. APOBEC3 is antagonised by HIV-1 Vif proteins, which also has species specific action like Vpu. The researchers developed an HIV-1 strain with SIV Vif inserted that allowed the virus to replicate in pig-tailed macaque lymphocytes. Infecting successive groups of macaques, the researchers generated a terminal AIDS defining illness in phase 4 animals, when they artificially caused CD8 depletion at the time of infection using anti-CD8 antibodies. The phase 4 macaques developed a B cell lymphoma which showed marked CD4 depletion.

Interestingly, the HIV-1 Vpu in this modified strain adapted to antagonise the pig-tailed macaque tetherin, at the expense of the ability to antagonise human tetherin, providing an insight into viral mutation and cross-species infectivity.

Although Dr Bieniasz was hopeful on the ability to develop more realistic animal models for HIV-1, he cautioned against the use of such models for more advanced research such as vaccine development. While this adapted HIV-1 strain can cause AIDS in a non-hominid species, the adaptation is incomplete. Notably, in this experiment the researches needed to induce CD8 depletion at the time of infection, as the animal quickly adapted and post-infection depletion of CD8 was ineffective at inducing an AIDS defining illness.

 

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Please join us for a memorial event celebrating the life of one of Australia’s leading HIV advocates, Levinia Crook… https://t.co/N7dof5xaGa

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