MicrobiologyBytes

Nearly 35 million people across the globe are infected with the human immunodeficiency virus type 1 (HIV-1) and an additional 2.5 million new infections occur annually. The current pandemic is the result of viruses that are genetically diverse and have been divided into 9 different subtypes and at least 28 circulating recombinant forms. The mechanisms by which HIV-1 is transmitted sexually across a mucosal barrier remain poorly understood.

Previous studies of HIV transmission have yielded conflicting results regarding the genetic heterogeneity of the virus establishing infection in the newly infected individual. The new results explain why prior infection by other sexually-transmitted diseases (STDs) makes individuals more susceptible to HIV infection. The team of researchers identified 20 heterosexual couples soon after infection occurred and obtained virus genetic sequences from both partners. They examined the most variable region of the virus’ env gene, which encodes a protein on the outer coat of the virus. Approximately 90% of the couples were found to be infected by a single virus variant of HIV-1. However, that variant was not the same in each case. For comparison, the researchers also analyzed a group of newly infected individuals who were infected by someone other than their spouse. This group showed more variety in virus sequences, with 3 out of 7 individuals infected by multiple variants. The homogeneity of the virus population in the newly infected recipient, as well as the presence, in some cases, of identical virus variants in the donor, allowed them to precisely identify the transmitted variant.

Overall, out of 42 newly infected people studied to date, all five infected by multiple virus variants had evidence of genital inflammation or ulceration. In these cases, it appears that the bottleneck was enlarged due to the disruption of normally protective mucosal barriers by STDs. They were able to examine the clinical history of each newly infected individual and observed that all individuals infected by multiple variants also showed evidence of inflammatory genital infections. These findings suggest that the genital mucosa provides a natural barrier to infection by multiple genetic variants of HIV-1 that can be lowered by inflammatory genital infections.

Inflammatory Genital Infections Mitigate a Severe Genetic Bottleneck in Heterosexual Transmission of Subtype A and C HIV-1. PLoS Pathog 5(1): e1000274
The HIV-1 epidemic in sub-Saharan Africa is driven largely by heterosexual transmission of non-subtype B viruses, of which subtypes C and A are predominant. Previous studies of subtype B and subtype C transmission pairs have suggested that a single variant from the chronically infected partner can establish infection in their newly infected partner. However, in subtype A infected individuals from a sex worker cohort and subtype B individuals from STD clinics, infection was frequently established by multiple variants. This study examined over 1750 single-genome amplified viral sequences derived from epidemiologically linked subtype C and subtype A transmission pairs very early after infection. In 90% (18/20) of the pairs, HIV-1 infection is initiated by a single viral variant that is derived from the quasispecies of the transmitting partner. In addition, the virus initiating infection in individuals who were infected by someone other than their spouse was characterized to determine if genital infections mitigated the severe genetic bottleneck observed in a majority of epidemiologically linked heterosexual HIV-1 transmission events. In nearly 50% (3/7) of individuals infected by someone other than their spouse, multiple genetic variants from a single individual established infection. A statistically significant association was observed between infection by multiple genetic variants and an inflammatory genital infection in the newly infected individual. Thus, in the vast majority of HIV-1 transmission events in cohabiting heterosexual couples, a single genetic variant establishes infection. Nevertheless, this severe genetic bottleneck can be mitigated by the presence of inflammatory genital infections in the at risk partner, suggesting that this restriction on genetic diversity is imposed in large part by the mucosal barrier.

Related:

• HIV mutation and the immune response
• Parasitic worm may increase susceptibility to AIDS virus
• What have the Romans ever done for us?
• You’ve Got Mail
• HIV-2 – a kinder AIDS virus?

discovermagazine.com

It was just a matter of time before someone discovered that Madagascar is a museum for viruses. The discovery came when a team of American and English scientists perused the genome of the gray mouse lemur. Nestled among its genes were segments of DNA that bore a remarkable resemblance to HIV. How on Earth could a deadly virus’s genes become part of a primate’s own genome? Some kinds of viruses, known as retroviruses, replicate by inserting their DNA into host cells, where their DNA can guide the production of new viruses. But many studies indicate that sometimes these viruses infect the cells that will give rise to sperm and eggs. The virus ends up in a fertilized egg and gets passed down to ever cell in the developing embryo–including its own sex cells. Now the virus gets passed down through the generations. It may still retain the ability to infect other cells for a while, but mutations typically knock out that ability. Instead, the virus can only insert copies of its DNA back into its own host cell’s genome. Over millions of years, this viral DNA spreads through the host genome. Our own DNA contains 98,000 stretches of this virus DNA, plus 150,000 tiny viral fragments, making up about 8% of our genome – about five times more DNA than the DNA that encodes proteins.

Read more

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• Phoenix from the ashes: The 5 million year old virus

HIV-2 is retrovirus a closely related to HIV-1, but seems to cause AIDS in only a minority of infected individuals (HIV-2: the forgotten AIDS virus. Trends in Microbiology 2008 Oct 27). Determining exactly why HIV-2 causes asymptomatic infection in most people could further our understanding of HIV immunopathogenesis. Studies to date have suggested that both enhanced immune responses and lower virus replication could play a role. Investigating immune responses in HIV-1-infected long-term nonprogressors (LTNPs) is one of the main approaches used to identify aspects of protective immunity to HIV, but the study of LTNPs is restricted by the small proportion of HIV-1-infected individuals who display slow or no progression to AIDS. In contrast, valuable insights might be gained into HIV immunopathogenesis from studies of HIV-2 cohorts with their high proportion of LTNPs.

HIV-2 is estimated to have entered the human population in 1940 (±16 years), approximately a decade after the introduction of HIV-1 into humans. The prevalence of this virus is highest in West Africa. Although the clinical features of HIV-2 AIDS mirror those of HIV-1, the AIDS-free survival rate at 5 years is significantly greater and the rate of CD4+ T cell decline was much slower than with HIV-1.

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HIV-2 does not appear to be an attenuated virus since it is able to replicate equally as well as HIV-1, however, virus load and plasma RNA levels during the asymptomatic stages of HIV-2 infection are approximately 30-fold lower than with HIV-1. The reason for this seems to be better host immune control of HIV-2 infection. There is evidence that innate, cellular and humoral immune responses might all be more effective at controlling HIV-2 infection than HIV-1. Immune activation is also lower in HIV-2 patients than HIV-1 patients, resulting in a lower rate of CD4+ T cell decline. Unfortunately, HIV-2 infection offers no protection against HIV-1.

HIV-2 offers tantalizing glimpses into how HIV-1-induced AIDS might be approached, although as yet this has not had any tangible practical benefits.

Related:

• What have the Romans ever done for us?
• Parasitic worm may increase susceptibility to AIDS virus
• HIV mutation and the immune response
• How does HIV cause AIDS?
• Immune exhaustion in HIV infection
• HIV “can never be cured”

Notifying sexual partners of their potential exposure to a sexually transmitted disease (STD) has been a mainstay of disease prevention and control since the 1930s. This week’s PLoS Medicine describes a project called inSPOT, an internet-based STD partner notification system that uses electronic postcards (e-cards) to assist people in disclosing an STD diagnosis to their sexual partners.

Now, nobody loves technology more than me, but I’ve never been fond of e-cards, the technology that says “I couldn’t be bothered”, and if I received one from a former partner saying

You’ve always been a happy chap
Unfortunately you’ve got the clap

I wouldn’t be too happy. I’m just old-fashioned I guess.

inSPOT: The first online STD partner notification system using electronic postcards. 2008 PLoS Med 5(10): e213

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• Chlamydia Infection
• Low uptake of Chlamydia screening in the UK

BBC News

According to new research, the spread of the Roman Empire through Europe could help explain why those living in its former colonies are more vulnerable to HIV.

People once ruled by Rome are less likely to have a gene variant which protects against HIV. In countries inside the borders of the Roman Empire for longer periods, such as Spain, Italy and Greece, the frequency of the CCR5-delta32 gene, which offers some protection against HIV, is between 0% and 6%. Countries at the fringe of the empire, such as Germany and England, the rate is between 8% and 11.8%, while in countries never conquered by Rome the rate is greater than this.

The latest issue of the Journal of Viral Entry (free online) has some interesting articles:

CCR5 Antagonists in the Clinic: A Review. J Viral Entry 2008 3: 42–53. New antiretroviral agents, in both existing and new classes, have expanded the range of therapeutic options for treatment-experienced patients infected with HIV, and shifted the therapeutic goals for patients with previously limited drug options. CCR5 antagonists have demonstrated clear benefits over placebo in highly treatment-experienced subjects, with favorable toxicity and safety profiles in both treatment-experienced and naïve individuals. Virus tropism testing is crucial in determining susceptibility to CCR5 antagonists and refinement of current assays may better define those for whom these agents are suitable. Pending pharmacokinetic and longitudinal tropism studies, CCR5 antagonists may provide an ideal alternative for patients who have toxicity or tolerability issues with other antiretrovirals. This article reviews the role of CCR5 inhibitors in clinical practice.

Chemokine Receptors CCR5 and CXCR4: More Than Mere Portals for HIV Type 1 Entry. J Viral Entry 2008 3:54–60. Chemokines and their specific G protein-coupled receptors orchestrate the migration of leukocytes under both homeostatic and inflammatory conditions, which constitutes a pivotal part of the host immune defense. This has not gone unnoticed by microbes, which utilize both chemokines and their receptors to subvert the immune system for their own benefit. Perhaps the best known example of such exploitation is the use of chemokine receptors CCR5 and CXCR4 by HIV type 1 to gain entry into macrophages and T cells, respectively. This has helped fuel intensive research into both molecules, leading to a greater understanding of the fascinating biology of these receptors. This review discusses the properties and roles of CCR5 and CXCR4 in health and disease, and highlights current strategies for targeting both receptors as potential therapies in a variety of diseases.

Mechanism and Inhibition of Hepatitis C Virus Entry. J Viral Entry 2008 3: 61–67. Inhibition of viruses at the stage of viral entry provides a means for therapeutic intervention. Owing to difficulties in propagating hepatitis C virus (HCV) in cell culture, the study of molecules that block HCV entry into host cells has long been hampered. However, the development of surrogate models and the recent progress in amplification of HCV in vitro have finally allowed the study of HCV entry, as well as the identification and characterization of inhibitors targeting the early steps of the virus life cycle. Recent data indicate that HCV enters target cells in a complex multistep process that involves several entry factors, each stage providing an opportunity to be exploited for design of new anti- HCV drugs. Today, polyclonal and monoclonal neutralizing antibodies constitute the most promising entry inhibitors, and the therapeutic activities of some of these are currently being evaluated in clinical trials. Furthermore, other types of molecules that specifically inhibit HCV entry have recently been reported. This review discusses recent advances in the understanding of the mechanisms of HCV cell entry, and the potential antiviral activity of some inhibitors of this major stage in the HCV lifecycle.

Drug-resistant HIV at levels too low to be detected by standard tests is not unusual and may contribute to treatment failure, according to new research. Mutations in the AIDS virus commonly occur during treatment, especially if HIV drugs are not taken consistently, and may cause treatments to fail. HIV treatment in developed countries normally includes testing for these mutations, both to select first-line drugs for a given patient and to choose second-line drugs if the virus rebounds from initial treatment. However, tests used by clinical laboratories cannot reliably detect mutant viruses that make up less than about 20% of the virus in a patient s blood. To investigate the role of resistant virus present at lower levels, researchers studied HIV from more than 500 recently infected patients in Canada and the US. Although these individuals had not received anti-HIV drugs, a highly sensitive test developed by the researchers showed that more than 10% carried HIV with common drug-resistance mutations that were not detected using usual tests. The researchers then studied 316 samples from a separate study of about 1400 patients who were started on their first HIV treatment, which included the drug efavirenz. Before starting treatment, none of these patients had resistance to efavirenz according to standard tests. However, highly sensitive testing showed that 7 of the 95 patients who experienced treatment failure had low levels of HIV with resistance mutations to efavirenz prior to treatment. Of 211 patients whose treatment did not fail, only 2 showed low level resistance prior to treatment. These data suggest that sensitive testing for resistance could avert failures in HIV treatment. However, given the small number of cases in this initial study, larger studies are needed to confirm the results – although a sizable proportion of treatment naïve HIV infected individuals harbor a minority population of drug-resistant HIV, many patients with positive results on highly sensitive resistance testing might not go on to experience treatment failure.

Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naïve populations and associate with reduced treatment efficacy. 2008 PLoS Med 5(7): e158
Since the mid-1990s, several powerful antiretroviral drug combinations have been developed that have greatly improved the prognosis of HIV infection. All antiretroviral therapy (ART) regimens combine drugs that act against HIV in different ways (so-called different drug classes). Multiple drugs are necessary because HIV continually accumulates random changes (mutations) in its genetic material (genome). Some of these mutations make HIV resistant to individual antiretroviral drugs, so a mixture of drugs is needed to keep the virus in check. However, the efficacy of ART (which itself selects for drug-resistant variants by giving them a growth advantage over drug-sensitive variants) is substantially reduced when these variants account for more than about 20% of the viruses in an infected person. This level of variant virus can be detected in blood samples with a technique called bulk sequencing. In North America and Europe, where ART has been widely used for many years, around 20% of HIV-infected people who have taken ART themselves develop this level of drug-resistant virus, which can be transmitted by the same routes as nonresistant HIV (typically unprotected sexual intercourse or needle sharing). In such cases, the person acquiring drug-resistant HIV may experience treatment failure when drugs later fail to work against the resistant virus. In these countries, therefore, resistance testing by bulk sequencing is done routinely before ART is initiated to decide which antiviral drugs are likely to be effective.

Several years usually elapse between the time a person becomes infected with HIV and the time he or she starts ART. During this time, the absence of selection pressure from antiviral drugs means that transmitted drug-resistant variants tend to decline to levels undetectable by bulk sequencing. These ‘‘minority drug-resistant variants’’ can be detected using other more sensitive tests but it is not known what proportion of HIV-infected people who have never taken ART carry minority drug-resistant variants (the ‘‘prevalence’’ of these variants). It is also unknown whether the presence of minority drugresistant variants reduces the success of ART. In this paper, the researchers first report a ‘‘cross-sectional’’ study in North America using a sensitive assay to determine the prevalence of minority drug-resistant viruses among HIV-infected people who had never received ART. They then investigate whether minority drug-resistant variants have any impact on the effectiveness of ART in a ‘‘case-control’’ study.

In their cross-sectional study, the researchers used a highly sensitive test for detecting mutations (called a real-time PCR-based assay) to look for low levels of viruses carrying any of eight major drug-resistance mutations in people with newly diagnosed HIV infection who reported no prior treatment with ART. Seventeen percent of the people who had only wild-type (nonmutated) virus by bulk sequencing (205 participants) were found, in fact, to carry low levels of virus variants with 1–3 drug-resistance mutations; 2% of them carried viruses resistant to two different drug classes (called multi-drug resistance). Among the people with resistance mutations detected by bulk sequencing (303 participants), 10% had at least one additional minority drug-resistant variant, often a viral variant that was resistant to a drug class different from that detected by bulk sequencing. In the case-control study, the researchers used their sensitive assays to measure the levels of viruses containing any of the three most common drug resistance mutations likely to affect viral responses to the antiretroviral drugs efavirenz and lamivudine in 316 people just before they started their first HIV treatment, which included these drugs. Of people for whom ART failed, 7% were infected with minority drug-resistant virus variants at baseline compared with only 0.9% of people for whom ART worked; this difference was statistically significant.

The findings of the cross-sectional study indicate that conventional bulk sequencing fails to detect a large proportion of transmitted HIV drug resistance and suggest that the transmission of drug-resistant variants from infectious ART-experienced people to ART-naive individuals might not be uncommon. The findings of the case-control study suggest that the minority drug-resistant HIV variants may have clinical consequences. That is, the presence of such variants in individuals who have not previously taken ART may reduce the efficacy of some ART regimens. However, the number of participants meeting the criteria for analysis in the cross-sectional study was limited, and the association between minority resistance and treatment failure may have been influenced by other factors. Taken together, these findings suggest that, to ensure that first-line ART is as effective as possible, greater efforts should be made to prevent HIV transmission, whether from ART-experienced or ART-naive people. However, because data on minority drug-resistant virus are limited, more studies – particularly with recent populations – are needed before testing for these variants can be considered appropriate in the clinical management of newly diagnosed HIV infection.

Related:

• HIV treatment in Africa as successful as in Europe, if started in time
• Roche abandons HIV research
• Parasitic worm may increase susceptibility to AIDS virus

People infected with schistosomes, and possibly other parasitic worm infections, may be more likely to become infected with HIV than persons without worm infections, according to a new study. Researchers at the U.S. Centers for Disease Control and Prevention and the Dana-Farber Cancer Institute and Harvard Medical School found that the infectious dose of an HIV-like virus necessary to infect rhesus macaques was 17-fold lower in animals with acute schistosomiasis than in controls. The study represents a novel in vivo demonstration that parasitic worms increase a host’s susceptibility to becoming infected with an AIDS-causing virus. The macaques co-infected with Schistosoma mansoni also demonstrated higher peak viral loads and higher memory cell concentrations of virus, both predictors of more rapid progression to AIDS. These findings are consistent with the hypothesis that persons living in areas highly endemic for parasitic worms may also have a higher risk of acquiring HIV/AIDS. Previous studies by this and other research groups have demonstrated that presence of schistosome infections increases viral replication in animal or human hosts with established immunodeficiency virus infections. The earlier findings, combined with the increased susceptibility to AIDS virus transmission shown in this study, may have profound public health implications for areas of the world where both parasitic worms and HIV-1 are endemic.

Acute Schistosoma mansoni Infection Increases Susceptibility to Systemic SHIV Clade C Infection in Rhesus Macaques after Mucosal Virus Exposure. PLoS Negl Trop Dis 2(7): e265
Individuals living in sub-Saharan Africa represent 10% of the world’s population but almost 2/3 of all HIV-1/ AIDS cases. The disproportionate HIV-1 infection rates in this region may be linked to helminthic parasite infections that affect many individuals in the developing world. However, the hypothesis that parasite infection increases an individual’s susceptibility to HIV-1 has never been prospectively tested in a relevant in vivo model. We measured whether pre-existing infection of rhesus monkeys with a parasitic worm would facilitate systemic infection after mucosal AIDS virus exposure. Two groups of animals, one consisting of normal monkeys and the other harboring Schistosoma mansoni, were challenged intrarectally with decreasing doses of R5-tropic clade C simian-human immunodeficiency virus (SHIV-C). Systemic infection occurred in parasitized monkeys at viral doses that remained sub-infectious in normal hosts. In fact, the 50% animal infectious (AID50) SHIV-C dose was 17-fold lower in parasitized animals compared to controls (P,0.001). Coinfected animals also had significantly higher peak viral RNA loads than controls (P,0.001), as well as increased viral replication in CD4+ central memory cells (P = 0.03). Our data provide the first direct evidence that acute schistosomiasis significantly increases the risk of de novo AIDS virus acquisition, and the magnitude of the effect suggests that control of helminth infections may be a useful public health intervention to help decrease the spread of HIV-1.

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• Multiple parasite infections synergize to increase the risk of anemia
• HIV treatment in Africa as successful as in Europe, if started in time
• Immune exhaustion in HIV infection