HIV “can never be cured”

A controversial news commentary in the subscription-only journal Nature on 14th February (Happy Valentine’s Day) reports on

HIV’s status as an ‘incurable’ infection, although in many cases doctors are able to stave off the onset of full-blown AIDS by giving patients sustained courses of drugs.

This item was based on an article published in May 2007:

Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus.
J Infect Dis. 2007 195:1762-1764
The persistence of latently infected resting CD4+ T cells has been clearly demonstrated in human immunodeficiency virus (HIV)-infected individuals receiving effective antiviral therapy. However, estimates of the half-life of this viral reservoir have been quite divergent. We demonstrate clear evidence for decay of this HIV reservoir in patients who initiated antiviral therapy early in infection. The half-life of this latent viral reservoir was estimated to be 4.6 months. It is projected that it will take up to 7.7 years of continuous therapy to completely eliminate latently infected resting CD4+ T cells in infected individuals who initiate antiviral therapy early in HIV infection.

which was recently backed up by a second publication from the same research group:

Persistence of HIV in Gut-Associated Lymphoid Tissue despite Long-Term Antiretroviral Therapy.
J Infect Dis. 2008 Feb 8
Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4(+) T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4(+) T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4(+) T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around the GALT of HIV-infected individuals despite long-term viral suppression and suggest that the GALT may play a major role in the persistence of HIV in such individuals.

Many HIV patients can manage their infection with a cocktails of antiretroviral drugs which can reduce their “viral load” - the amount of virus circulating in the blood plasma - to undetectable levels. But this work shows that even in such “non-infectious” patients HIV is still lurking in gut tissues, and still infecting other immune cells in the blood. It might not ever be possible to completely eradicate the virus from the body, even though people are doing well, says Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases.

MMR: our children, our choice?

In 2002, the BBC’s Panorama series included an edition entitled MMR: Every Parent’s Choice which investigated the origins of the controversy over measles, mumps and rubella (MMR) vaccination in the UK. In particular, the programme focussed on the role of Dr Andrew Wakefield and his, now refuted, claims concerning the link between the use of “triple-jab” MMR vaccine and childhood autism and bowel disease. Although the public controversy surrounding this vaccination has now largely been settled, MMR uptake still remains below the level required to ensure population (or “herd”) immunity…

Read more

Measles in sub-Saharan Africa

Although vaccination has almost eliminated measles in parts of the world, the disease remains a major killer in some high birth rate countries of the Sahel. On the basis of measles dynamics for industrialized countries, high birth rate regions should experience regular annual epidemics. This article shows that measles epidemics in Niger are highly episodic, particularly in the capital Niamey. Models demonstrate that this variability arises from powerful seasonality in transmission - generating high amplitude epidemics - within the chaotic domain of deterministic dynamics. In practice, this leads to frequent stochastic fadeouts, interspersed with irregular, large epidemics. A metapopulation model illustrates how increased vaccine coverage, but still below the local elimination threshold, could lead to increasingly variable major outbreaks in highly seasonally forced contexts. Such erratic dynamics emphasize the importance both of control strategies that address build-up of susceptible individuals and efforts to mitigate the impact of large outbreaks when they occur.

The dynamics of measles in sub-Saharan Africa. 2008 Nature 451: 679-684

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T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection

The human genome contains a number of remnants or fossils of ancient viral infections referred to as human endogenous retroviruses (HERV). Like fossils, these HERV are usually considered to be dead or inert as under normal circumstances, HERVs are functionally defective or controlled by host factors. However, recent work has demonstrated that T cells in the human immune system respond to HERV when a person is infected with the human immunodeficiency virus (HIV). In HIV-1-infected individuals, intracellular defense mechanisms are compromised. The T cells responding to HERV share characteristics with T cells that effectively control cytomegalovirus, a common chronic viral infection. T cells responding to HERV can also kill target cells carrying HERV protein. For some HIV-positive people, the strength of their response against HERV is related to having a lower HIV viral load. This study has important implications for new directions in HIV vaccine research. One of the key obstacles to creating an effective HIV vaccine is overcoming the ability of some of the virus variants produced when HIV evades the immune responses that the body mounts to control infections.

The authors hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. They show that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, they examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. There was an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design. If T cells that recognize HERV can stably target HIV-infected cells, they could be an important factor in controlling HIV infection.

T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection. 2007 PLoS Pathog 3(11): e165

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Natural Regulatory T Cells and Persistent Virus Infection

Suppressor T cell is an old term, originally found in the 1970s literature, but it was short-lived because advances in molecular biology soon afterward proved that the gene locus, thought to be associated with suppression, was nonexistent. Our recent understanding started with the finding that a small proportion of CD4+ T cells in mice constitutively expressed the high-affinity interleukin-2 (IL-2) receptor alpha-chain, CD25, and depletion of these cells (now designated natural regulatory T cells [Treg]) caused autoimmune disease and enhanced responses to foreign antigens. This study resulted in a rebound of intense interest in suppressor T cells, and similar cells in humans were identified shortly afterward. It is now well established that natural Treg suppress a diverse range of immune responses in a contact-dependent manner in vitro and in vivo, in response to T-cell receptor (TCR)-mediated stimulation. Human Treg are less well defined than their murine counterparts and less well studied in general, although the two have features in common. Differences between human and murine Treg, which may complicate the interpretation of human data, have been noted. For instance, in nave inbred pathogen-free mice, natural Treg can be reliably isolated based on their CD25 expression; however, this population in adult outbred humans is inevitably a mixture of Treg and recently activated T effector cells, with the latter expected particularly during an ongoing infection.

Opinions are divided over whether Treg play a pathogenic role in chronic viral infection in humans, especially in infections for which the development of a vaccine has so far failed, such as in the case of human immunodeficiency virus (HIV) and hepatitis C virus (HCV). This review considers the key findings in Treg biology and discusses the current position for Treg in viral infection, with particular emphasis on the key aspects of persistent viral infections in humans.

Treg dysregulation has been reported to be present in many examples of persistent viral infections. It is unclear if the altered Treg function is a cause or effect of viral persistence in the host. However, since the deficiency in Treg number and/or function may cause virus-associated autoimmune tissue destruction and enhanced Treg frequency and activity may suppress antiviral immunity, Treg dysregulation does not appear to be an innocent coincidence of viral persistence. It is hard to predict whether therapeutic manipulation of Treg could help to resolve chronic viral infection or limit its damage. In patients with persistent HCV infection, virus-specific Treg outnumbers virus-specific T effector cells by far, and we wonder if, during the long course of the disease, Treg are somehow expanded while T effector cells are deleted. A central question remaining for HCV, as well as for other viral diseases, is whether Treg require priming to recognize virus antigen, and if so, how this priming would occur. Work with HIV and FV supports the hypothesis that certain viruses can subvert DC function so that a nave T cell is primed to become a Treg rather than an effector T cell, or alternatively, if Treg and T effector cells are distinct lineages, nave Treg may be preferentially primed over T effector cells. In some situations, Treg are deleted as a consequence of virus replication or by unknown mechanisms, adding one more layer of complexity to this already difficult topic. One important practical consideration is whether dominant Treg epitopes exist. Although it is speculated that Treg and T effector cells may recognize the same epitopes, the location and hierarchy of Treg epitopes in any viral protein are largely unknown. Given that vaccine development has so far failed for HIV and HCV, the removal of dominant Treg epitopes, if they exist, may increase the chances of developing successful vaccines.

Natural Regulatory T Cells and Persistent Viral Infection
J Virol 2008 82: 21-30

Maybe Not Quite The End

This post is from regular guest blogger:

Ed Rybicki, Department of Molecular and Cell Biology, University of Cape Town, South Africa.

Given the current scare over H5N1 influenza virus in swans in the UK, it is possibly timely to recall that I wrote a little while ago in MicrobiologyBytes about how easy it appeared to be for the highly pathogenic H5N1 avian influenza virus to change receptor and therefore host specificity: all it apparently needed was substitutions at position 129 and 134 in the HA protein to change from binding avian-type sialic acid (SA) α2,3Gal(actose) receptors to the human-type SA α2,6Gal receptor. And the outlook was gloomy, and panic was close at hand.

Fortunately for us, it turns out that things are not so simple. According to a letter in the January 2008 issue of Nature Biotechnology, it is a characteristic structural topology, and not just the α2,6 linkage, that enables specific binding of HA to α2,6 sialylated glycans. The authors state:

…recognition of this topology may be critical for adaptation of HA to bind glycans in the upper respiratory tract of humans. An integrated biochemical, analytical and data mining approach demonstrates that HAs from the human-adapted H1N1 and H3N2 viruses, but not H5N1 (bird flu) viruses, specifically bind to long α2-6 sialylated glycans with this topology. This could explain why H5N1 viruses have not yet gained a foothold in the human population.

Apparently the critical shape in humans is umbrella-like, whereas the avian receptor is characteristically cone-like. Again from the paper:

The topology of α2-3 and α2-6 is governed by the glycosidic torsion angles of the trisaccharide motifs-Neu5Aca2-3Galb1-3/4GlcNAc and Neu5Aca2-6Galb1-4GlcNAc, respectively (Supplementary Fig. 3 online).

Ram Sasisekharan and colleagues showed that human-adapted viruses with mixed α2,3/α2,6 binding ability that bound the umbrella-type receptor were efficiently transmitted, whereas viruses with the same basic specificity that did not have HA binding specificity to “long” α2,6, were not.

This means that the perceived threat of H5N1 human adaptation and rapid spread has receded somewhat, as the virus HA needs considerably more adaptation than the simple mutations that were previously assumed to change the specificity. Furthermore, these findings also allow the possibility of using glycan arrays with long α2,6 molecules for the screening of H5N1 and other avian virus isolates for possible evolutionary adaptation to the appropriate receptor binding form. They close their paper with these encouraging words:

A sufficient understanding of the avian H5N1 HA mutations leading to long α2-6 binding specificity offers an opportunity for intervention through vaccine development to negate the eventuality of a H5N1 pandemic.

Now while I am happy that the threat may not be as imminent as I thought it was, I must point out that H5N1 flu is still one of the nastiest pandemic prospects facing humanity. The virus is established as an endemic pathogen worldwide, meaning it could break into the human population just about anywhere people keep domestic poultry. While the threat of mutation leading to rapid adaptation may be a lot less severe than we thought, there is still the possibility of
recombination / reassortment leading to a virulent, human-adapted virus - and we should recall that the flu pandemics of the 1950s and 1960s were due to reassortment between the prevailing H1N1 virus and a H2N2 type in 1957, and between a H3-containing virus and the prevailing H2N2 in 1968. And the contributing avian viruses were nowhere near as well distributed as H5N1 is now, nor as virulent …

So the apocalypse is still nigh - but possibly less nigh than we may have thought. However, as the inimitable Gregory House has observed, “It’s not paranoia if they’re really after you”. And I think they still are.

If you would like to be a guest blogger on MicrobiologyBytes, click the Guests tab above.

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Vaccination against polio should not be stopped

The striking 50-year-long decline in the incidence of poliomyelitis has stalled in the past seven years, which has led to calls for an urgent re-assessment of eradication and post-eradication campaign strategies. The current plan of eliminating the circulation of wild poliovirus so that further immunization will be unnecessary does not take into account recent scientific data and political realities that limit the likelihood that this strategy can sustain prevention of the disease. It is crucially important that high levels of population immunity are maintained against polio in the foreseeable future.

The evidence summarized above strongly suggests that any strategy that renders human populations vulnerable to infection by poliovirus is associated with an unacceptable risk. Therefore, the goal of the polio-eradication programme should be to achieve the widest-possible vaccination coverage. We may have no other choice than to continue immunization against a non-existing disease to prevent ourselves from becoming hostages to the threat of the devastating return of poliomyelitis. The short-term choice between OPV and IPV should depend on local conditions. The combination of IPV with other routine immunizations against important paediatric infections will be optimal in the long term.

Continued research on poliovirus should be encouraged and should focus on the improvement of the existing IPV. These improvements would include cost reduction, bundled delivery with other vaccines for children and boosting its ability to induce local immunity. In addition, the development of fundamentally new vaccines, as well as efficacious anti-polio drugs, should be explored. Such efforts could radically change vaccination policy decisions and eventually lead to the true eradication of poliomyelitis.

Nature Reviews Microbiology 5, 952-958 (December 2007)

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MicrobiologyBytes 2007: Year in Review

2007 has been a record breaking year for MicrobiologyBytes, so here’s a look back at some of the highlights:

We started January off with noroviruses and ancient plague, then relaxed a bit by playing with Lego and brewing beer.

In February, we looked at yaws and Mimivirus, then went green by reducing our carbon footprint with microdiesel.

And in March we marked World Tuberculosis Day by looking at new drugs for an old foe.

April started off with an exploration of whether viruses evolve to protect their hosts, then we took out first look at colony collapse disorder affecting bees.

May was dominated by news about extreme drug resistant tuberculosis (XDR-TB) and chikungunya, then later looked at probiotics.

In June we looked at the origins of yellow fever and quorum sensing in Serratia (quorum sensing remains one of the most popular topics on MicrobiologyBytes).

July began with flesh eating bacteria and finished up with prions and Alzheimers disease.

In August, most people took a holiday and this was the quietest month of the year in terms of visitors, but we still managed to fit in Hendra, chikungunya and Marburg viruses.

September brought lots of bad news for UK farmers, so we looked at the biology of the bluetongue and foot and mouth disease virus outbreaks in the UK.

In October we covered the bacterial SOS system and debated the strategy for HPV vaccination in the UK.

November started with the terrorist threat posed by glanders and melioidosis then considered the dangers of Chlamydia infection and the opportunities presented by DNA microarrays.

We finished up the year with bacteriocins and bacterial morphology.

Phew. Overall, the most popular posts of the year were:

1. Hepatitis C Virus: a mountain to climb
2. Fungal Infections and All About Fungi
3. Infectobesity
4. Toll-Like Receptors
5. DNA microarrays

See you next year!

Vaccination is up to 99% effective

National vaccine recommendations in the United States target an increasing number of vaccine-preventable diseases for reduction, elimination, or eradication. For the United States, pre-vaccine baselines were assessed based on representative historical data from primary sources and were compared to the most recent morbidity (2006) and mortality (2004) data for diphtheria, pertussis, tetanus, poliomyelitis, measles, mumps, rubella (including congenital rubella syndrome), invasive Haemophilus influenzae type b (Hib), acute hepatitis B, hepatitis A, varicella, Streptococcus pneumoniae, and smallpox. Estimates of the percent reductions from baseline to recent were made without adjustment for factors that could affect vaccine-preventable disease morbidity, mortality, or reporting. A greater than 92% decline in cases and a 99% or greater decline in deaths due to diseases prevented by vaccines recommended before 1980 were shown for diphtheria, mumps, pertussis, and tetanus. Endemic transmission of poliovirus and measles and rubella viruses has been eliminated in the United States; smallpox has been eradicated worldwide. Declines were 80% or greater for cases and deaths of most vaccine-preventable diseases targeted since 1980 including hepatitis A, acute hepatitis B, Hib, and varicella. Declines in cases and deaths of invasive S. pneumoniae were 34% and 25%, respectively. The number of cases of most vaccine-preventable diseases is at an all-time low; hospitalizations and deaths have also shown striking decreases.

Historical Comparisons of Morbidity and Mortality for Vaccine-Preventable Diseases in the United States
JAMA 2007 298: 2155-2163

Hurting rather than helping?

Today’s post is from regular guest blogger:

Ed Rybicki, Department of Molecular and Cell Biology, University of Cape Town, South Africa.

It should not have escaped the eye of the interested bystander that there has been a most unfortunate and premature end to a HIV vaccine trial recently - and that something that had been tested as “safe” and “immunogenic” in Phase I and II trials went on to not only to not show any efficacy at all, but may actually have increased susceptibility in recipients to HIV-1 infection. The so-called STEP trial in North and South America, the Caribbean and Australia, and the Phambili trial in South Africa, were “Phase IIB” or international test-of-concept trials in at-risk populations of the efficacy of Merck & Co. Inc. Adenovirus 5-based vectors (MRKAd5) encoding subtype B-derived Gag, Pol and Nef proteins. The outcome was about as gloomy as could possibly have been predicted, and was nothing like what researchers expected from preliminary primate testing.
The trials - more formally designated as “HVTN 502 and HVTN 503 HIV Vaccine Clinical Trials” by the HIV Vaccine Trials Network - were testing a mixture of three replication-defective Adenovirus 5 vectors, containing gag, pol and nef genes respectively, aimed at stimulating mainly CD8+ T-cell responses. There had earlier been some disagreement in the research community about the ethics of trialling a subtype B-specific vaccine in a subtype C-dominated epidemic region - and in a population known to have a high incidence of high titres of antibodies against Ad5, which is after all a common cold virus. However, regulatory bodies were in no doubt that the trials were appropriate, and standard Phase I and II trial results were non-contentious, leaving the way clear for the present exercise.

The study was designed as a randomized, double-blind, placebo-controlled Phase IIB clinical trial, sponsored by Merck and the National Institute of Allergy and Infectious Diseases (NIAID), which enrolled HIV-negative volunteers between 18 and 45 years of age at high risk of HIV infection. Participants were randomly assigned to receive three injections of either the study or a placebo vaccine. Some 3000 participants were planned for each of the two trials; HVTN 502 was closed while 503 was still recruiting, when the Data and Safety Monitoring Board (DSMB) of the STEP trial (HVTN 502) - an independent committee providing oversight of the study - decided on September 18th that “… the trial as originally designed should be discontinued because the trial would not meet its efficacy endpoints”, as there was no evidence for protection. In fact, of people with low anti-adenovirus titres at enrollment who had received one vaccine/placebo dose, 24 of 741 vaccinees became HIV+, while among placebo-vaccinated people, 21 of 762 became infected. Among two-dose trialists, the figures were 19 HIV infections in 672 vaccinated volunteers, and 11 HIV infections among the 691 placebo recipients. This led to the discontinuing of the Phambili trial in South Africa as well, given no additional expectation of success.

And inevitably, things got worse: among male volunteers with high levels of antibodies against Ad5, 21 of 392 vaccinees became infected, but only 9 of 386 in the placebo group. Thus, it could be that pre-existing immunity to the vector virus actually increases susceptibility to HIV infection: one mechanism that has been proposed is that the secondary response to the Ad5 transiently boosts production of CD4+ T-cells - the preferred host cells of HIV.

The upshot of all this is that researchers worldwide are taking a hard look at Adenovirus-based HIV vaccines, even those which do not naturally occur in humans, and to which there should be no immunity: for example the Vaccine Research Center at the NIH has another Adenovirus-vectored candidate about to enter clinical trial, which may yet be delayed as the results of the STEP and Phambili trials are analysed in minute detail. The STEP volunteers are to be informed what they were inoculated with, and all Phambili volunteers have been advised to report back to the clinics for counselling. From the Merck site:

The Phambili DSMB also recommended that Phambili volunteers be told whether they received the vaccine or placebo, be strongly encouraged to return to study sites for protocol-related tests, and be counseled about the possibility that those who received the vaccine might have an increased susceptibility to HIV infections. STEP volunteers will also be counseled about this possibility, and discussions are underway to define the details of continued follow-up for STEP volunteers, including when STEP volunteers will be unblinded. Detailed analyses of the available data are being conducted, including analyses to better understand if there may be an increased susceptibility to HIV infection among those volunteers who received the vaccine.

Inevitably, there has also been political fallout in South Africa: the Minister of Health, Manto Tshabalala-Msimang, announced a moratorium last week on HIV vaccine trials, which could affect the home-grown vaccines due for trial next year.

This is not the only bad news recently on the HIV vaccine front: there seems to be evidence that another hitherto-promising HIV vaccine vector, the adeno-associated viruses (AAVs) may help to exhaust memory T-cells, by over-stimulating them with continuously-produced antigen.

All of this bad news looks, at first sight, to be a major body-blow to efforts to develop viable HIV vaccines. However, this is exactly what clinical trials are for: to test vaccines, for safety, immunogenicity, and efficacy. It is actually encouraging in a perverse sense that the trials work as they should - even though the first two HIV vaccines that have made it as far as efficacy trials are both abject failures. Lessons from the AIDSVAX debacle were that large trials can be done for an HIV vaccine; that HIV infection is a reasonable endpoint for a HIV vaccine trial; that HIV gp120 is not a good vaccine candidate. While it is still too early to be specific, lessons from this trial may be that immunogenicity / efficacy results from monkeys may not be a good predictor of human results, and that Ad5 is not a good HIV vaccine vector in pre-immune populations.

So the search goes on: the longest, most expensive vaccine development exercise in human history, with no clear end in sight.

If you would like to be a guest blogger on MicrobiologyBytes, click the Guests tab above.

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